Conditions: Dermatitis Dermatitis, Atopic Eczema Skin Diseases Skin Diseases, Genetic Genetic Diseases, Inborn Skin Diseases, Eczematous Hypersensitivity Hypersensitivity, Immediate Immune System Diseases
Keywords: atopic dermatitis atopic eczema eczema JAK janus kinase
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1235
Healthy volunteers: no

Brief summary:
B7451014 is a Phase 3 study to investigate PF-04965842 in patients aged 12 years and over with a minimum body weight of 40 kg who have moderate to severe atopic dermatitis. Subjects responding well to an initial open-label 12 week treatment of PF-04965842 (200 mg) taken orally once daily (QD) will be identified and randomized in a double-blind manner to receive 200 mg QD PF-04965842, 100 mg QD PF-04965842, or QD placebo. Efficacy and safety of 2 doses of PF-04965842 will be evaluated relative to placebo over 40 weeks. Subjects experiencing significant worsening of their symptoms, i.e., protocol-defined flare, enter 12 weeks rescue treatment and receive 200 mg PF-04965842 together with a marketed topical medicine. Eligible patients will have the option to enter a long-term extension study after completing the initial 12 week treatment, the 12 week rescue treatment, and the 40 week blinded treatment.

Detailed description:
Responder criteria for randomization at week 12 are defined as a) achieving an IGA of clear (0) or almost clear (1) (on a 5 point scale), b) a reduction from IGA baseline of 2 or more points, and c) reaching an EASI-75 response compared to baseline. Flare requiring rescue treatment is defined as a loss of at least 50% of the EASI response at Week 12 and an IGA score of 2 or higher.

Arms:
arm 1: Double-blind randomized treatment following open label run-in period. arm 2: Double-blind randomized treatment following open label run-in period. arm 3: Double-blind randomized treatment following open label run-in period.

Interventions: intervention 1: PF-04965842 100 mg intervention 2: PF-04965842 200 mg intervention 3: Placebo
Intervention descriptions: intervention 1: PF-04965842 100 mg, administered as two tablets to be taken orally once daily for 40 weeks intervention 2: PF-04965842 200 mg, administered as two tablets to be taken orally once daily for 40 weeks intervention 3: Placebo, administered as two tablets to be taken orally once daily for 40 weeks

Protocol document:
Prot_000.pdf: 
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A P H A S E 3 R A N D O MI Z E D WI T H D R A W A L, D O U B L E -B LI N D, 
P L A C E B O -C O N T R O L L E D, M U L TI- C E N T E R S T U D Y I N V E S TI G A TI N G T H E 
E F FI C A C Y A N D S A F E T Y O F P F -0 4 9 6 5 8 4 2 I N S U B J E C T S A G E D 1 2 Y E A R S A N D 
O V E R, WI T H M O D E R A T E T O S E V E R E A T O PI C D E R M A TI TI S WI T H T H E 
O P TI O N O F R E S C U E T R E A T M E N T I N F L A RI N G S U B J E C T S
I n vesti g ati o n al Pr o d uct N u m ber:
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I n vesti g ati o n al Pr o d uct N a me:
N ot a p plica ble ( N/ A)
U nite d St ates ( U S) I n vesti g ati o n al Ne w 
Dr u g (I N D) N u m ber:
E ur o pe a n Cli nic al Tri als D at a b ase 
( E u dr a C T) N u m ber:
2 0 1 8 - 0 0 0 5 0 1- 2 3
Pr ot o c ol N u m ber:
B 7 4 5 1 0 1 4
P h ase:
3
T his d oc u me nt a n d acc o m pa n yi n g materials c o ntai n c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer.  E xce pt as 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese d oc u me nts, y o u a gree t o h ol d t his i nf or mati o n i n 
c o nfi de nce a n d n ot c o p y or discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or use it f or 
u na ut h orize d p ur p oses.  I n t he e ve nt of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer m ust be 
pr o m ptl y n otifie d.
C CI


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D oc u me nt Hist or y
D oc u me nt
Ve rsi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
A me n d me nt 5
2 8 Oct o ber 2 0 1 9
T he C ol u m bia S uici de Se verit y Rati n g 
Scale ( C -S S R S) will be a d mi nistere d t o all 
o n g oi n g s u bjects at all re mai ni n g 
sc he d ule d visits i n R u n I n a n d Bli n de d 
treat me nts, a n d Resc ue wee ks 0, 8, 1 2, 1 6, 
a n d u p t o a n d i ncl u di n g t he E n d of 
Treat me nt/ Earl y Ter mi nati o n ( E O T/ E T) 
a n d/ or t he E n d of St u d y ( E O S) visit t o 
ali g n wit h ne w cr oss - pr o gra m pr ocesses.  
T he secti o ns of t he pr ot oc ol affecte d
i ncl u de Sc he d ules of Acti vities a n d i n 
Secti o n 6.
E n d p oi nts were re w or de d f or clarity.
Re m o val of E Q - 5 D-5 L / E Q- 5 D-Y, 
F A CI T - F/ Pe ds-F A CI T -F, a n d S F -3 6, ac ute
patie nt -re p orte d o utc o me ( P R O) e n d p oi nts
fr o m sec o n dar y o bjecti ves t o ali g n wit h t he 
Statistical A nal y sis Pla n.
A d mi nistrati ve c ha n ges a n d clarificati o n s
ha ve bee n ma de i n vari o us secti o ns of t he 
pr ot oc ol t hat are n ot c o nsi dere d s u bsta ntial 
b y  Pfizer beca use t here was n o i m pact t o 
t he safety of t he t rial partici pa nts, t he sc o pe 
of t he trial, or t he scie ntific i nter pretati o n 
of t he st u d y . T hese c ha n ges i n clu de:

A d mi nistrati o n of t he last d ose of 
o pe n -la bel r u n-i n peri o d st u d y  dr u g 
( 2 0 0 m g Q D) at t he Wee k 1 2 visit 
( Secti o ns 5 a n d 6);

Initiati n g a d mi nistrati o n of ra n d o mize d 
bli n de d t reat me nt o n t he da y after t he 
Wee k
1 2 visit ( Secti o ns 5 a n d 6);

A d mi nistrati o n of t he first d ose of 
o pe n -la bel Resc ue treat me nt at t he start 
of flare ( Secti o n 5);

A d diti o nal bl o o d c ollecti o n at t he 


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c urre nt P K sa m ple ti me p oi nt f or 
a nal ys is of P F-0 4 9 6 5 8 4 2 meta b olites
( Secti o ns 1, 2 , a n d 7);

U p date a n d clarificati o n of was h o ut 
peri o d f or C Y P 2 C 9 a n d C Y P 2 C 1 9 
i n d ucers ( A p pe n di x 3).
A me n d me nt 4
2 7 N o ve m ber 2 0 1 8
F or Tai wa n o nl y:
Si milar t o C hi na, ot her c o u ntries i n Asia, 
s uc h as Tai wa n, ha ve a hi g h pre vale nce of 
he patitis B s urface a nti ge n ( H Bs A g) 
ne gati ve, he patitis B c ore a nti b o d y  
( H BcA b ) p ositi ve, a n d he patitis B s urface 
a nti b o d y ( H Bs A b) p ositi ve ser ol o g y.  
T heref ore, Tai wa n will a d o pt t he sa me 
c ha n ges as t h ose pr o p ose d f or C hi na i n 
A me n d me nt 3 t o m o nit or t he ris k of 
he patitis B reacti vati o n.
T he f oll o wi n g 
secti o ns of t he pr ot oc ol are affecte d:
Sc he d ule of Acti vities, Secti o ns 4, 6, a n d 7, 
as a p plica ble.
A me n d me nt 3
1 2 Se pte m ber 2 0 1 8
T he f oll o wi n g c ha n ges , re q ueste d b y a n 
E t hics C o m mittee i n C hi na f or st u dy 
B 7 4 5 1 0 1 3, are bei n g a p plie d t o t he 
P F -0 4 9 6 5 8 4 2 pr o gra m.  
T hese c ha n ges are i n effect for C hi na o nl y :
S u bjects w h o are he patitis B s urface 
a nti ge n (H Bs A g ) ne gati ve, he patitis B c ore 
a nti b o d y (H Bc A b ) p ositi ve, a n d he patitis B
s urface a nti b o dy ( H Bs A b ) p ositi ve at 
Scree ni n g will ha ve refle x testi n g f or 
he patitis B vir us de o x yri b o n uclei c aci d 
(H B V D N A ). S u bjects w h o ha ve H B V 
D N A a b o ve t he l o wer li mit of 
q ua ntificati o n ( L L Q) will be e xcl u de d.  
S u bjects w h o are H B V D N A ne gati ve or 
bel o w L L Q ma y  e nr oll b ut will ha ve H B V 
D N A testi n g re peate d at Wee ks
1 2, 2 8, 4 0, 
5 2, Resc ue Wee k 1 2, a n d earl y ter mi nati o n 
fr o m st u d y d uri n g a n y treat me nt peri o d. 


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A si n gle H B V D N A test res ult a b o ve t he 
L L Q re q uires i m me diate a n d per ma ne nt 
disc o nti n uati o n fr o m treat me nt. 
T he f oll o wi n g secti o ns of t he pr ot oc ol are 
affecte d:
Sc he d ule of Acti vities , Secti o ns 4, 6, a nd 7 ,
as a p plica ble.
A me n d me nt 2
2 3 J ul y 2 0 1 8
S u m mar y a n d Secti o n 1 :

U p date d Bac k gr o u n d a n d Rati o nale 
te xt t o ali g n acr oss t he J A K 1 pr o gra m.
S u m mar y  a n d Secti o n 2:

Clarifie d t he pri mar y  a n d sec o n dar y 
o bjecti ves a n d e n d p oi nts.

A d diti o n of Ke y  Sec o n dar y e nd p oi nt.
S u m mar y  a n d Secti o ns 1, 3 a n d/ or 4 :

Clarifie d St u d y  desi g n.

Clarifie d i nf or me d c o nse nt 
re q uir me nts.

F or clarit y , defi ne d me dicate d t o pical 
t hera py as a t o pical pr o d uct t hat 
c o ntai ns a n acti ve p har mace utical 
i n gre die nt i n dicate d f or t he treat me nt of
A D (irres pecti ve of w het her it is a n 
o ver -t he-c o u nter [ O T C] or prescri be d 
pr o d uct).
S u m mar y  a n d/ or Secti o n 9 :

Clarifie d per -pr ot oc ol a nal y sis set 
maj or de viati o ns.

Clarifie d w or di n g/ gr o u p defi niti o ns a n d 
ot her clarificati o n of e n d p oi nts.

A d diti o n of Ke y  Seco n dar y  e n d p oi nt. 


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Secti o n s 3, 5, 6, 7 a n d Sc he d ule of 
Acti vities ( As A p plica ble): 

A d de d g ui da nce f or t he te m p orar y  
i nterr u pti o n t o d osi n g.

A d de d L y m p h oc y te S u bset t o t he 
Cli nical L a b orat or y tests t o s u p p ort 
a d diti o nal a nal ys is.
Sc he d ule of Acti vities, Se cti o ns 6 a n d 7:

Clarif y i n g t hat s u bjects in re gi o ns
a b o ve a l o w ris k f or t u berc ul osis 
(e g, > 1 0/ 1 0 0, 0 0 0 pre vale nce) will 
ha ve T B test re peate d after o ne ye ar of 
treat me nt e x p os ure.

A d de d Ast h ma Q uesti o n naire as a 
P R O a n d re m o ve d it as a safet y 
assess me nt.
S ecti o n 7.8 Patie nt Re p orte d O utc o mes:

Clarifie d pr ocess f or c ollecti o n of 
Patie nt Re p orte d O utc o me data.
Secti o ns 1 1. 1, 1 1. 2, 1 2. 3 u p date d wit h ne w 
Gl o bal Data Pr otecti o n Re g ulati o n 
la n g ua ge t o ali g n wit h re q uire me nt f or 
i ncl usi o n of rece ntly p u blis he d E u ro pea n 
U ni o n ( E U) Data Pri vac y la n g ua ge a n d 
le gislati o n. 
A p pe n di x 3 Pr o hi bite d C o nc o mita nt 
Me dicati o ns u p date d t o re d uce n u m ber of 
pr o hi bite d me dicati o ns base d o n c urre nt 
u n dersta n di n g of meta b olis m, a n d t o 
pr o vi de clarit y ar o u n d was h -o ut peri o ds .
A p pe n d i x 4 u p date d t o ali g n wit h ne w 
Te m p orar y  Interr u pti o n of D osi n g 
la n g ua ge a n d clarif y disc o nti n uati o n 
criteria.  
A me n d me nt 1
2 0 J u ne 2 0 1 8
T he f oll o wi n g re visi o ns were ma de base d 


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o n V H P fee d bac k:
Clarifie d i n Sc he d ule of Acti vities 
Wee k
5 2 (f o ot n ote ii) a n d i n Secti o n 7. 3. 4 
t hat f oll o wi n g o ne ye ar of t otal e x p os ure t o 
st u d y dr u g si nce t he last t u berc ul osis ( T B) 
test, all s u bjects i n re gi o ns a b o ve a 
l o w-ris k f or T B (ie, > 1 0/ 1 0 0, 0 0 0 
pre vale nce) will u n der g o T B testi n g. 
Clarifie d i n Sc he d ule of Acti vities f o ot n ote 
h h a n d i n Secti o n 4. 2 E xcl usi o n Criteria 
# 1 8 t hat a c hest X -ra y is re q uire d u nless 
pre vi o usl y  perf or me d a n d d oc u me nte d 
wit hi n 1 2 wee ks pri or t o St u d y  D a y 1.
Re vise d Pr ot oc ol S u m mar y , Sc he d ule of 
Acti vities, Secti o n 3 a n d Secti o n 6. 3. 1 t o 
i n dicate t hat n o n-res p o nders at Wee k 1 2 
ma y  r oll o ver o nt o St u d y B 7 4 5 1 0 1 5 
pr o vi di n g t he y  re mai n eli gi ble.
Clarifie d i n t he Pr ot oc ol S u m mar y  a n d i n 
Secti o n 9. 1 t hat base d o n pri or data, a b o ut 
4 4 % of s u bjects w o ul d meet t he 
pr ot oc ol - defi ne d criteria t o be a res p o n der 
at W ee k 1 2, a p pr o xi matel y  1 3 7 0 s u bjects 
w o ul d nee d t o e nter t he o pe n la bel r u n -i n 
peri o d t o e ns ure t hat 6 0 0 s u bjects are 
a vaila ble f or ra n d o mizati o n. 
Secti o n 3 was re vise d t o i n dicate t hat all 
s u bjects w h o ha ve starte d was h-o ut of A D 
treat me nt i n t he scree ni ng peri o d will be 
all o we d t o e nter t he r u n-i n a n d treat me nt 
peri o ds pr o vi di n g all i ncl usi o n criteria a n d 
n o ne of t he e xcl usi o n criteria are met. 
Secti o n 4. 1 clarifie d I ncl usi o n Criteria # 3 
a n d Secti o n 7. 8. 1 t o i n dicate t he pr urit us 
N R S se verit y  sc ore will be use d o n t he da y  
of baseli ne visit t o deter mi ne m o derate t o 
se vere A D ( n ot t he fre q ue nc y of pr urit us 
sc ore). 
Secti o n 4. 2 re vise d E xcl usi o n Criteria t o 
a d d Criteria # 2 3 - k n o w n h y perse nsiti vit y  


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t o P F-0 4 9 6 5 8 4 2 or a n y st u d y  dr u g 
e xci pie nts.
Clarifie d Sec ti o n 4. 3 t o i n dicate 
ra n d o mizati o n is stratifie d b y a ge cate g or y, 
ie < 1 8 years a n d 1 8 ye ars.
Clarifie d i n Secti o n 5. 3 t hat i n vesti gat or is 
res p o nsi ble f or brea ki n g t he bli n d f or 
safety reas o ns w here k n o wle d ge of 
treat me nt is esse ntial.
Clarifie d i n Secti o n 5. 9. 1 t hat l o w d ose 
acet yl  salic ylic aci d (1 0 0 m g Q D) is 
per mitte d f or t he p ur p ose of car di o vasc ular 
pr o p h y la xis. 
Secti o n 6. 1 re vise d t o i n dicate t hat s u bjects 
n ot meeti n g e nr oll me nt criteria (scree n 
fail ures) s h o ul d be c o ntacte d q uic kly t o 
res u me/i nitiate A D treat me nts.
Ori gi nal pr ot oc ol
2 6 Fe br uar y  2 0 1 8
N ot a p plica ble ( N/ A)
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d i nstit uti o nal re vie w b oar ds (IR Bs)/et hics c o m mittees
( E Cs). 


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T A B L E O F C O N T E N T S
LI S T O F T A B L E S ................................................................................................................... 1 3
LI S T O F FI G U R E S ................................................................................................................. 1 4
A P P E N DI C E S ......................................................................................................................... 1 4
P R O T O C O L  S U M M A R Y....................................................................................................... 1 5
S C H E D U L E O F A C TI VI TI E S F O R R U N -I N A N D B LI ND E D T R E A T M E N T S ................ 2 4
S C H E D U L E O F A C TI VI TI E S F O R R E S C U E T R E A T M E N T – F L A R E A T 
S C H E D U L E D O R U N S C H E D U L E D VI SI T ..................................................................... 3 2
1. I N T R O D U C TI O N ............................................................................................................... 3 6
1. 1. Mec ha nis m of Acti o n/I n di cati o n............................................................................. 3 6
1. 2. Bac k gr o u n d a n d Rati o nale ...................................................................................... 3 7
1. 2. 1. Dr u g De vel o p me nt a n d Rati o nale ..............................................................3 7
1. 2. 2. At o pic Der matitis ........................................................................................ 3 7
1. 2. 3. N o n -Cli nical a n d P hase 1 Data ................................................................... 4 0
1. 2. 4. P hase 2 b i n A D ( B 7 4 5 1 0 0 6) ....................................................................... 4 0
1. 3. S u m mar y  of P F-0 4 9 6 5 8 4 2 Cli nical P har mac o ki netics ........................................... 4 1
1. 4. P o p ulati o n P har mac o ki netics .................................................................................. 4 2
1. 5. S u m mar y  of Be nefits a n d Ris ks.............................................................................. 4 2
1. 6. D ose Selecti o n Rati o nale ........................................................................................ 4 2
2. S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ....................................................................... 4 3
3. S T U D Y D E SI G N ................................................................................................................. 4 6
4. S U BJ E C T E LI GI BI LI T Y C RI T E R IA................................................................................. 4 9
4. 1. I ncl usi o n Criteria ..................................................................................................... 4 9
4. 2. E xcl usi o n Criteria ....................................................................................................5 1
4. 3. Ra n d o mi zati o n Criteria ........................................................................................... 5 6
4. 4. L ifest yle Re q uire me nts ........................................................................................... 5 6
4. 4. 1. C o ntrace pti o n ..............................................................................................5 7
4. 4. 2. Vacci ne a n d E x p os ure t o I nfecti o ns G ui deli nes ......................................... 5 9
4. 4. 2. 1. S u bject S pecific Rec o m me n dati o ns .......................................... 5 9
4. 4. 2. 2. G ui da nce Re gar di n g H o use h ol d C o ntact Vacci ne -Relate d 
E x p os ure ............................................................................................5 9
4. 4. 3. S ur ger y ........................................................................................................ 5 9
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4. 5. S p o ns or’s Q ualifie d Me dical Pers o n nel ..................................................................6 0
5. S T U D Y T R E A T M E N T S .....................................................................................................6 0
5. 1. All ocati o n t o Treat me nt ................................ ..........................................................6 1
5. 2. Resc ue Treat me nt ....................................................................................................6 1
5. 2. 1. G ui deli nes f or T o pical Resc ue Treat me nt ..................................................6 2
5. 3. Brea ki n g t he Bli n d ..................................................................................................6 3
5. 4 . S u bject C o m plia nce .................................................................................................6 3
5. 5. I n vesti gati o nal Pr o d uct S u p plies .............................................................................6 4
5. 5. 1. D osa ge F or m(s) a n d Pac ka gi n g ..................................................................6 4
5. 5. 2. Pre parati o n a n d Dis pe nsi n g ........................................................................6 4
5. 6. A d mi nistrati o n .........................................................................................................6 4
5. 7. I n vesti gati o nal Pr o d uct St ora ge ..............................................................................6 6
5. 8. I n vesti gati o nal Pr o d uct Acc o u nta bilit y................................ ...................................6 7
5. 8. 1. Destr ucti o n of I n vesti gati o nal Pr o d uct S u p plies........................................ 6 7
5. 9. C o nc o mita nt Treat me nt(s) .......................................................................................6 7
5. 9. 1. Per mitte d C o nc o mita nt Me dicati o ns.......................................................... 6 8
5. 9. 2. Pr o hi bite d M e dicati o ns a n d Treat me nts .....................................................6 8
6. S T U D Y P R O C E D U R E S................................ .....................................................................6 9
6. 1. Visit 1, Scree ni n g ....................................................................................................7 0
6. 2. R u n -In I n d ucti o n Treat me nt Peri o d ................................ ........................................7 2
6. 2. 1. Visit 2, Da y  1/ Wee k 0 ( Baseli ne)...............................................................7 2
6. 2. 2. Visit 3, Da y  8/ Wee k 1 (1 da y ).................................................................. 7 4
6. 2. 3. Visit 4, Da y  1 5/ Wee k 2 (1 da y )................................................................ 7 4
6. 2. 4. Visit 5, Da y  2 9/ Wee k 4 (2 da y s) ..............................................................7 5
6. 2. 5. Visit 6, Da y  4 3/ Wee k 6 (3 da y s) ..............................................................7 6
6. 2. 6. Visit 7, Da y  5 7/ Wee k 8 (3 da y s) ..............................................................7 7
6. 3. D o u ble- Bli n d Mai nte na nc e Treat me nt Peri o d ........................................................7 8
6. 3. 1. Visit 8, Da y  8 5/ Wee k 1 2 (3 da y s) Ra n d o mizati o n i nt o Mai nte na nce 
Treat me nt .........................................................................................................7 8
6. 3. 2. Visit 9, Da y  1 1 3/ Wee k 1 6 (3 da y s) ..........................................................8 0
6. 3. 3. Visit 1 0, Da y  1 9 7/ Wee k 2 8 (7 da y s) ........................................................8 1
6. 3. 4. Visit 1 1, Da y  2 8 1/ Wee k 4 0 (7 da y s) ........................................................8 2


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6. 3. 5. Visit 1 2, Da y  3 6 5/ Wee k 5 2 (3 da y s) E n d of Treat me nt ( E O T) or 
Earl y Ter mi nati o n ( E T) .................................................................................... 8 3
6. 4. F oll o w -u p Visit ....................................................................................................... 8 5
6. 4. 1. Visit 1 3, 4 Wee ks P ost E n d of Treat me nt/ Earl y  Ter mi nati o n - E n d of 
St u d y  ( ± 3 d a y s) ................................................................................................ 8 5
6. 5. Resc ue Treat me nt Peri o d ......................................................................................... 8 6
6. 5. 1. Resc ue Treat me nt - Flare Occ urri n g at a n U n pla n ne d Visit ( Resc ue 
Visit 1, Da y 1/ Wee k 0 ( 3 da y s)) .................................................................... 8 6
6. 5. 2. Resc ue Treat me nt – Visit 2, Da y  8/ Wee k 1 (1 da y )................................. 8 8
6. 5. 3. Resc ue Treat me nt – Visit 3, Da y  1 5/ Wee k 2 (1 da y )...............................8 8
6. 5. 4. Resc ue Treat me nt – Visit 4, Da y  2 9/ Wee k 4 (2 da y s) ............................. 8 9
6. 5. 5. Resc ue Treat me nt – Visit 5, Da y  4 3/ Wee k 6 (3 da y s) ............................. 9 0
6. 5. 6. Resc ue Treat me nt – Visit 6, Da y  5 7/Wee k 8 ( 3 da y s) ............................. 9 1
6. 5. 7. Resc ue Treat me nt - Visit 7, Da y  8 5/ Wee k 1 2 (3 da y s) E n d of 
Treat me nt ( E O T)/ Earl y Ter mi nati o n ( E T) .......................................................9 2
6. 5. 8. Resc ue Treat me nt - Visit 8, F oll o w - u p Visit a n d E n d of St u d y  
( ± 3 d a y s) .......................................................................................................... 9 4
6. 6. S u bject Wit h dra wal ................................................................................................. 9 5
7. A S S E S S M E N T S .................................................................................................................. 9 6
7. 1. Pre g na nc y  Testi n g................................................................................................... 9 7
7. 3. Safet y Assess me nts ................................................................................................. 9 9
7. 3. 1. V itals Si g ns................................................................................................. 9 9
7. 3. 2. Me dical Hist or y , P h ysical E xa mi nati o n, Hei ght, a n d Wei g ht .................... 9 9
7. 3. 3. C hest X -Ra y ..............................................................................................1 0 0
7. 3. 4. T u berc u l osis Testi n g................................................................................. 1 0 0
7 .3 . 5. Electr ocar di o gra m..................................................................................... 1 0 1
7. 3. 6. S pecial Safet y Assess me nt ....................................................................... 1 0 1
7. 4. S ki n T y pe Assess me nt .......................................................................................... 1 0 2
7. 5. A ssess me nt of S uici dal Ideati o n a n d Be ha vi or ..................................................... 1 0 2
7. 5. 1. C ol u m bia S uici de Se verit y  Rati n g Scale ( C-S S R S) .................................1 0 2
7. 5. 2. S uici dal Be ha vi ors Q uesti o n naire -Re vise d ( S B Q -R) ............................... 1 0 2
C CI


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7. 5. 3. Patie nt Healt h Q uesti o n naire – 8 ite ms ( P H Q - 8) ..................................... 1 0 2
7 . 6. Clin ical La b orat or y Tests......................................................................................1 0 3
7. 6. 1. Bl o o d V ol u me ...........................................................................................1 0 3
7. 6. 2. L a b orat or y Tests.......................................................................................1 0 3
7. 6. 2. 1. He patitis Testi n g ................................ .....................................1 0 5
7. 6. 2. 2. Varicella Z oster Vir us ( V Z V) I g G A nti b o d y ( A b) Testi n g ....1 0 5
7. 6. 2. 3. Baseli ne Viral Sc ree n ..............................................................1 0 6
7. 7. Efficac y  Assess me nts............................................................................................1 0 6
7. 7. 1. Rater Q ualificati o ns.................................................................................. 1 0 6
7. 7. 2. I n vesti gat or’s Gl o bal Assess me nt (I G A) ..................................................1 0 6
7. 7. 3. Ecze ma Area a n d Se verit y  In de x ( E A SI) .................................................1 0 7
7. 7. 3. 1. B o d y S urface A rea – Eff icac y ( B S A Efficac y)....................... 1 1 0
7. 7. 4. Sc ori n g At o pic Der matitis ( S C O R A D) ....................................................1 1 0
7. 8. Patie nt- Re p orte d O utc o mes ( P R Os) ......................................................................1 1 1
7. 8. 1. Pr urit us N u merical Rati n g Scale ( N R S)................................................... 1 1 2
7. 8. 2. Patie nt Gl o bal Assess me nt ( Pt G A)........................................................... 1 1 2
7. 8. 3. E ur o Q ol Q ualit y  of Life 5-Di me nsi o n 5 -Le vel Scale ( E Q - 5 D-5 L ) 
a n d E ur o Q ol Q ualit y of Life 5 - Di me nsi o n Y o ut h Scale ( E Q-5 D - Y i n 
select c o u ntries) .............................................................................................1 1 3
7. 8. 4. Der mat ol o g y  Life Q ualit y In d e x ( D L QI) a n d C hil dre n’s 
Der mat ol o g y  Life Q ualit y In de x ( C D L QI )....................................................1 1 3
7. 8. 5. Patie nt- Orie nte d Ecze ma Meas ure ( P O E M) .............................................1 1 3
7. 8. 6. H os pit al A n xiet y  a n d De pressi o n Scale ( H A D S).....................................1 1 3
7. 8. 7. Pr urit us a n d S y m pt o ms Assess me nt f or At o pic Der matitis ( P S A A D) .....1 1 4
7. 8. 8. S h ort F o r m-3 6 Healt h S ur ve y , Versi o n 2, Ac ute ( S F-3 6 v 2, Ac ute) ........1 1 4
7. 8. 9. F A CI T Fati g ue Scale ( F A CI T -F) a n d Pe diatric F A CI T -F 
( Pe ds-F A CI T -F) .............................................................................................1 1 4
7. 8. 1 0. Ast h ma C o ntr ol....................................................................................... 1 1 4
7. 9. P har m ac o ki netics ..................................................................................................1 1 5
7. 9. 1. Plas ma f or A nal ys is of P F-0 4 9 6 5 8 4 2 a n d Meta b olites ............................1 1 5
7. 9. 2. S hi p me nt of P har mac o ki netic Sa m ples ....................................................1 1 6
8. A D V E R S E E V E N T R E P O R TI N G ....................................................................................1 1 6
8. 1. R e q uire me nts .........................................................................................................1 1 6


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8. 1. 1. A d diti o nal Details o n Rec or di n g A d verse E ve nts o n t he C R F .................1 1 7
8. 1. 2. Eliciti n g A d verse E ve nt I nf or ma ti o n........................................................1 1 7
8. 1. 3. Wit h dra wal fr o m t he St u d y D ue t o A d verse E ve nts (see als o t he 
S u bject Wit h dra wal secti o n) ..........................................................................1 1 7
8. 1. 4. Ti me Peri o d f or C ollec tin g A E/ S A E I nf or mati o n ....................................1 1 8
8. 1. 4. 1. Re p orti n g S A Es t o Pfizer Safet y .............................................1 1 8
8. 1. 4. 2. Rec or di n g N o n -seri o us A Es a n d S A Es o n t he CR F ...............1 1 8
8. 1. 5. Ca usalit y  Assess me nt ...............................................................................1 1 8
8. 1. 6. S p o ns or’s Re p orti n g Re q uire me nts t o Re g ulat or y  A ut h orities................1 1 9
8. 2. Defi niti o ns................................ .............................................................................1 1 9
8. 2. 1. A d verse E ve nts .........................................................................................1 1 9
8. 2. 2. A b n or mal Test Fi n di n gs ...........................................................................1 2 0
8. 2. 3. Seri o us A d verse E ve nts ............................................................................1 2 0
8. 2. 4. H os pitalizati o n ..........................................................................................1 2 1
8. 3. Se verit y  Assess me nt ..............................................................................................1 2 2
8. 4. S pecial Sit uati o ns ..................................................................................................1 2 2
8. 4. 1. Pr ot oc ol- S pecifie d Seri o us A d verse E ve nts............................................. 1 2 2
8. 4. 2. P ote ntial Cases of Dr u g -I n d uce d Li ver I nj ur y..........................................1 2 2
8. 4. 3. E x p os ure t o t he I n vesti gati o nal Pr o d uct D uri n g Pre g na nc y  or 
Breastfee di n g, a n d Occ u pati o nal E x p os ure ...................................................1 2 4
8. 4. 3. 1. E x p os ure D uri n g Pre g na nc y ....................................................1 2 4
8. 4. 3. 2. E x p os ure D uri n g Breastfee di n g ..............................................1 2 5
8. 4 .3. 3. Occ u pati o nal E x p os ure ...........................................................1 2 5
8. 4. 4. Me dicati o n Err ors .....................................................................................1 2 6
8. 4. 4. 1. Me dicati o n Err ors ....................................................................1 2 6
9. D A T A A N A L Y SI S/ S T A TI S TI C A L  M E T H O D S.............................................................1 2 7
9. 1. Sa m ple Size Deter mi nati o n ...................................................................................1 2 7
9. 2. Efficac y  A nalys is ..................................................................................................1 2 7
9. 2. 1. A nal y sis Sets.............................................................................................1 2 7
9. 2. 2. Testi n g Pr oce d ure f or M ulti ple C o m paris o ns........................................... 1 2 8
9. 2. 3. A nal y sis of t he Pri mar y a n d Ke y Sec o n dar y E n d p oi nts...........................1 2 8
9. 2. 4. A nal y sis of Sec o n dar y E n d p oi nts.............................................................1 2 8
9. 3. Safet y A nal ys is......................................................................................................1 2 9


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9. 4. A nal y sis of P har mac o ki netic E n d p oi nts ...............................................................1 3 0
9. 5. E xter nal Data M o nit ori n g C o m mittee................................ ...................................1 3 0
9. 6. Safet y A dj u dicati o n C o m mittees ..........................................................................1 3 0
1 0. Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E............................................... 1 3 1
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G ...........................................................1 3 1
1 1. 1. Case Re p ort F or ms ( C R F)/ Data C ollecti o n T o ols ( D C Ts)/ Electr o nic Data 
Rec or d ......................................................................................................................1 3 1
1 1. 2. Rec or d Rete nti o n................................................................................................. 1 3 2
1 2. E T HI C S ............................................................................................................................1 3 2
1 2. 1. I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee ....................................................1 3 2
1 2 .2 . Et hical C o n d uct of t he St u d y ..............................................................................1 3 3
1 2. 3. S u bject I nf or mati o n a n d C o nse nt ........................................................................1 3 3
1 2. 4. Re p orti n g of Safet y I ss ues a n d Seri o us Breac hes o f t he Pr ot oc ol or I C H 
G C P .........................................................................................................................1 3 4
1 3. D E FI NI TI O N O F E N D O F T RI A L .................................................................................1 3 5
1 3. 1. E n d of Trial i n All Partici pati n g C o u ntries .........................................................1 3 5
1 4. S P O N S O R DI S C O N TI N U A TI O N C RI T E RI A ..............................................................1 3 5
1 5. P U B LI C A TI O N O F S T U D Y R E S U L T S ........................................................................1 3 5
1 5. 1 . C o m m u nicati o n of Res ults b y  Pfizer ..................................................................1 3 5
1 5. 2. P u blicati o ns b y  In vesti gat ors ..............................................................................1 3 6
1 6. R E F E R E N C E S ................................................................................................................1 3 8
L I S T O F T A B L E S
Ta ble 1.
O bjecti ves a n d E n d p oi nts .....................................................................................4 3
Ta ble 2.
I n vesti gati o nal Pr o d uct A d mi nistrati o n ................................................................6 5
Ta ble 3.
I n vesti gat or’s Gl o bal Assess me nt (I G A) Sc ore..................................................1 0 7
Ta ble 4.
Cli nical Si g n Se verit y  Sc ori n g Criteria f or t he Ecze ma Area a n d Se verity 
I n dex ( E A SI ).......................................................................................................1 0 8
Ta ble 5.
Ha n d pri nt Deter mi nati o n of B o d y S urface Area ( B S A) .....................................1 0 9
Ta ble 6.
Ecze ma Area a n d Se verit y I n de x ( E A SI) Area Sc ore Criteria...........................1 0 9
Ta ble 7.
Ecze ma Area a n d Se verit y I n de x ( E A SI) B o dy Re gi o n Wei g hti n g ...................1 0 9


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LI S T O F FI G U R E S
Fi g ure 1.
St u d y  Desi g n Sc he matic.......................................................................................4 7
A P P E N DI C E S
A p pe n di x 1. A b bre viati o ns ....................................................................................................1 4 2
A p pe n di x 2. Dia g n ostic Criteria f or At o pic Der matitis......................................................... 1 4 6
A p pe n di x 3. Pr o hi bite d C o nc o mita nt Me dicati o ns ................................................................1 4 7
A p pe n di x 4. G ui deli nes f or M o nit ori n g a n d Disc o nti n uati o n............................................... 1 4 9
A p pe n di x 5. Fitz patric k S ki n T y pe........................................................................................ 1 5 1
A p p en di x 6. Pr urit us Se verit y a n d Fre q ue nc y  ( Pr urit us N R S)..............................................1 5 2
A p pe n di x 7. Patie nt Gl o bal Assess me nt ( Pt G A) ...................................................................1 5 3
A p pe n di x 8. E ur o pea n Q u alit y of Life 5-Di me nsi o n 5 -Le vel Scale ( E Q -5 D -5 L ) a n d 
E ur o pea n Q ualit y  of Li fe 5-Di me nsi o n Y o ut h Scale ( E Q -5 D -Y i n select 
c o u ntries) ............................................................................................................1 5 4
A p pe n di x 9. Der mat ol o g y Life Q ualit y I n de x ( D L QI) a n d Ch il dre n’s Der mat ol o g y Life 
Q ualit y  In de x ( C D L QI ) ...................................................................................... 1 5 8
A p pe n di x 1 0. Patie nt- Orie nte d Ecze ma Meas ure ( P O E M) ...................................................1 6 1
A p pe n di x 1 1. H os pital A n x iet y a n d De pressi o n Scale ( H A D S) ...........................................1 6 2
A p pe n di x 1 2. Pr uri t us a n d S ym pt o ms Assess me nt f or At o pic Der matitis ( P S A A D; 
P S A A D S y m pt o m Diar y) ...................................................................................1 6 4
A p pe n di x 1 3. S h ort F or m -3 6 Versi o n 2 ( S F -3 6 v 2) ...............................................................1 6 8
A p pe n di x 1 4. F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y Fati g ue Scale 
( F A CI T-F) ...........................................................................................................1 7 4
A p pe n di x 1 5. C ol u m bia Se verit y  S uici de Rati n g Scale ( C-S S R S) f or Scree ni n g a n d 
Baseli ne Visits ....................................................................................................1 7 6
A p pe n di x 1 6. C ol u m bia Se verit y  S uici de Rati n g Scale ( C-S S R S) Si nce L ast Visit .............1 7 9
A p pe n di x 1 7. S uici de Be ha vi ors Q uesti o n naire – Re vise d ( S B Q -R) ....................................1 8 1
A p pe n di x 1 8. Patie nt Healt h Q uesti o n naire – 8 ite ms ( P H Q - 8)............................................1 8 2
A p pe n di x 1 9. Ast h ma C o ntr ol Q uesti o n naire ( A C Q) ............................................................1 8 3


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P R O T O C O L S U M M A R Y
B ac k gr o u n d a n d R ati o n ale:
At o pic der matitis ( A D), als o k n o w n as at o pic ecze ma, is a c o m m o n, c hr o nic, i nfla m mat or y
s ki n dis or der c haracterize d b y fla k y s ki n lesi o ns, i nte nse pr urit us, a n d a ge neral deteri orati o n
i n q ualit y of life.  O ver t he past 5 0 years, A D has bec o me m ore pre vale nt, es peciall y i n 
i n d ustrialize d, te m perate c o u ntries s uch as t h e U nite d St ates ( U S). 1 ,2  A D is o ne of t he m ost 
c om m o n, c hr o nic, rela psi n g c hil d h o o d der mat oses, i m pacti n g 1 5 -3 0 % of all c hil dre n i n t he 
U S a n d ma n y  ha ve disease t hat p ersists i nt o a d ult h o o d wit h a lifeti me pre vale nce of t h ose 
affecte d be yo n d c hil d h o o d re p orte d t o be 3 4 %. 8  Earlier re p orts i n dicate d t hat, i n u p t o 
7 0 % of cases, t he disease greatl y i m pr o ves or res ol ves b y  late c hil d h o o d, h o we ver m ore 
rece nt fi n di n gs s u g gest t hat disease acti vit y re mai ns ma nifest f or a pr ol o n ge d peri o d of ti me.  
Base d o n a t otal of 7 1 5 7 patie nts e nr olle d i n t he Pe diatric Ecze ma Electi ve Re gistr y  ( P E E R) 
st u d y, c o m prisi n g a t otal of 2 2, 5 5 0 pers o n - years, it was c o ncl u de d t hat sy m pt o ms ass ociate d 
wit h A D see m t o persist well i nt o t he sec o n d deca de of life a n d li kel y l o n ger. 3  At e ver y  a ge, 
m ore t ha n 8 0 % of P E E R st u d y  s u bjects ha d sy m pt o ms of A D a n d / or were usi n g me dicati o n 
t o treat t heir A D.
Of t he c urre ntl y a vaila ble t hera pies, n o ne offers a c ure; t heref ore, t he mai n ai ms of e xisti n g 
treat me nts are t o re d uce t he occ urre nce of ac ute flares, t o i ncrease t he ti me bet wee n rela pses, 
a n d to re d uce pr urit us a n d t he res ulti n g slee p dist ur ba nce. 5 ,6
N o n - me dicate d t o pical t hera pies i ncl u de e m ollie nts.  Me dicate d t o pical t hera pies f or 
m o derate t o se vere A D i ncl u de t o pical c ortic oster oi ds ( T C S ) (eg, beta met has o ne, cl o betas ol,
fl u oci n o ni de), t o pical calci ne uri n i n hi bit ors (T CI ) (e g, pi mecr oli m us, tacroli m us), a n d c oal 
tar pre parati o ns.  T C S are li mite d i n ter ms of t he treat me nt d urati o n (e g, c ortic oster oi d use is 
li mite d t o 2 t o 4 wee ks) a n d t he b o d y re gi o n of treat me nt, d ue t o c o nsiste nt s ki n t o xicities, as 
well as ha vi n g ris ks ass ociate d wit h t heir b r oa d i m m u n os u p pressi ve acti o ns. T CI  ha ve a 
li mite d r ole as a sec o n d-li ne treat me nt, d ue t o t heir li mitati o ns i n t he d urati o n a n d t he b o dy 
re gi o n of treat me nt, i n hi biti o n of t u m or s ur veilla nce i n t he s ki n, a n d safet y c o ncer ns wit h 
mali g na ncies.
C risa b or ole was a p pr o ve d as a t o pical me dicate d treat me nt i n Dece m ber 2 0 1 6 
b y  t he F o o d a n d Dr u g A d mi nistrati o n ( F D A ) f or use i n patie nts wit h mil d t o m o derate A D.  
A d diti o nal treat me nts ge nerall y reser ve d f or se vere A D i ncl u de p h ot ot hera p y (e g, ultra vi olet 
A li g ht [ U V A] wit h or wit h o ut ps orale n, ultra vi olet B li g ht [ U V B] narr o w ba n d or 
br oa d ba n d) a n d s ys te mic a ge nts (e g, c ortic oster oi ds, c ycl os p ori ne, rec o m bi na nt interfer o n 
ga m ma (I F N -), m yc o p he n olate m ofetil, met h otre xate [ M T X], azat hi o pri ne, i ntra ve n o us
i mm u n o gl o b uli n). 7
T here are a li mite d n u m ber of a p pr o ve d s ys te mic treat me nts a vaila ble f or m o derate t o se ve re 
A D, a n d, i n t he U nite d States of A meri ca ( U S A ), t he o nl y a p pr o ve d sys te mic dr u gs are 
c ortic oster oi ds a n d d u pil u ma b. D u pil u ma b , a n i njecta ble h u ma n m o n ocl o nal a nti b o d y 
tar geti n g i nterle u ki n (I L) -4 a n d - 1 3, was a p pr o ve d b y  t he F D A i n Marc h 2 0 1 7 a n d rece i ve d 
ma r keti n g a ut h orizati o n i n E ur o pe i n Se pte m ber 2 0 1 7, f or t he treat me nt of m o derate t o 
se vere A D. Treat me nt wit h s y ste mic c ortic oster oi ds has k n o w n a n d well d oc u me nte d 
a d verse effects. Treat me nt wit h d u pil u ma b has t he ris k of i njecti o n site reacti o ns , allergi c 
reacti o ns, e ye a n d e yeli d i nfla m mati o ns a n d c ol d s ores.  A n ot her li mitati o n of d u pil u ma b is 


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t he p ossi bilit y f or t he de vel o p me nt of a nti dr u g a nti b o dies, w hic h ma y res ult i n l oss of 
efficac y o ver ti me a n d t he de vel o p me nt of safety c o ncer ns s uc h as ser u m sic k ness-li ke 
reacti o ns. F urt her m ore, d u pil u ma b is deli vere d via s u bc uta ne o us i njecti o n, w hic h ma y  n ot 
be a met h o d of a d mi nistrati o n t olerate d well b y all patie nts.  D uri n g a 1 -ye ar, ra n d o mize d, 
d o u ble -bli n de d st u d y  wit h d u pil u ma b, i n t he d u pil u ma b 3 0 0 m g ev er y  2 wee ks ( mar kete d 
mai nte na nce d ose) pl us T C S gr o u p, t he esti mate d differe nce fr o m place b o of t he I n vesti gat or 
Gl o bal Assess me nt ( I G A) res p o nse rate a n d t he 7 5 % i m pr o ve me nt res p o nse rate i n t he 
Ecze ma Area a n d Se verit y I n de x (E A SI - 7 5) were 2 6 % a n d 4 6%, res pecti vel y.  T he pla ce b o 
res p o nse rate f or I G A a n d EA SI -7 5 was 1 2 % a n d 2 3 %. T he de vel o p me nt of p ote ntial 
treat ments wit h f urt her i m pr o ve me nts i n efficac y re mai ns desira ble. I n E ur o pe, c ycl os p ori ne 
is a p pr o ve d f or use i n patie nts wit h se vere AD w he n s yste mic t hera p y is re q uire d.  
C y cl os p ori ne use is ass ociate d wit h se veral u n desira ble si de effects a n d d ue t o its narr o w 
t hera pe utic i n de x, occasi o nal t hera pe utic dr u g m o nit ori n g is rec o m me n de d.  K n o w n a d verse 
effects i ncl u de i nfecti o ns, re nal t o xi cit y, h e pat ot o xicit y, s ki n mali gna ncies, l y m p h o ma a n d 
ot her mali g na ncies.
T he pre d o mi na nt u n met me dical nee d t he n is f or a n oral t hera p y wit h a n acce pta ble safet y 
pr ofile, f or l o n g-ter m use, w hic h is effecti ve f or m o derate t o se vere A D. Patie nts wit h 
m o d erate to se vere A D re q uire ot her s yste mic treat me nt o pti o ns be yo n d t h ose w hic h are 
c urre ntl y a p pr o ve d. P F -0 4 9 6 5 8 4 2 is a n oral ta blet, pr o vi di n g a m ore c o n ve nie nt r o ute of 
a d mi nistrati o n c o m pare d wit h t he s u bc uta ne o us i njecti o n re q uire d f or d u pil u ma b a n d s o it 
d o es n ot ha ve t he p ote ntial ris k of i njecti o n site reacti o ns.  T he l o n ger half- life of d u pil u ma b 
als o mea ns t hat it ma y ta ke a relati vel y l o n g peri o d of ti me f or s o me u n desira ble 
p har mac o d y n a mic effects (e g, treat me nt -relate d a d verse e ve nt [ A E]) t o s ubsi de after its 
disc o nti n uati o n . I n t his res pect, t he be nefit of a s h orter half-life wit h a ge nts s uc h as 
P F -0 4 9 6 5 8 4 2 is t hat a n A E ma y  p ote ntiall y res ol ve m ore ra pi dl y t ha n is t he case wit h 
d u pil u ma b.  U nli ke d u pil u ma b, P F -0 4 9 6 5 8 4 2 is a s mall m olec ule a n d t here is n o a ntici pate d 
i m m u n oge nicit y f or P F -0 4 9 6 5 8 4 2, a n d s o it is u nli kel y  t o ge nerate a nti dr u g a nti b o dies.
K e y c yt o ki nes i m plicate d i n t he pat h o p h ysi ol o g y of A D i ncl u de I L- 4, I L- 5, I L- 1 3, I L- 3 1,
a n d I F N -, re q uire Ja n us ki nase 1 (J A K 1) f or si g nal tra ns d ucti on ; t his s u g gests t hat selecti ve
J A K 1 i n hi bit ors t hat m o d ulate t he acti vit y of t hese c yt o ki nes re prese nt a c o m pelli n g
a p pr oac h t o t he treat me nt of i nfla m mat or y s ki n diseases s uc h as A D. 7
P F - 0 4 9 6 5 8 4 2 is a n orall y b ioa vaila ble s mall m olec ule t hat selecti vel y i n hi bits J A K 1 b y
bl oc ki n g t he a de n osi ne tri p h os p hate ( A T P) bi n di n g site. P F -0 4 9 6 5 8 4 2 has a hi g h de gree of
selecti vit y i n vitr o a gai nst ot her ki nases: 2 8-f ol d selecti vit y o ver Ja n us ki nase 2 (J A K 2), 
> 3 4 0 -f ol d o ver Ja n us ki nase 3 (J A K 3) a n d 4 3- f ol d o ver t yr osi ne ki nase 2 ( T Y K 2), as well as 
a g o o d selecti vit y pr ofile o ver t he br oa der ra n ge of h u ma n ki nases. T he selecti ve i n hi biti o n 
of J A K 1 will lea d t o m o d ulati o n of m ulti ple c y t o ki ne pat h wa ys i n v ol ve d i n t he 
pat h o p h ys i ol o g y of A D, i ncl u di n g I L-4, I L-5, I L -1 3, I L -3 1 a n d I F N -.  Data fr o m a P hase 2 b 
pr o of of c o nce pt ( P O C) st u d y  ( B 7 4 5 1 0 0 6) t hat e val uate d s u bjects wit h m o derate t o se vere 
A D ha ve s h o w n p ositi ve efficac y, as well as a n acce pta ble safet y pr ofile, s ufficie n t t o s u p p ort 
f urt her cli nical de vel o p me nt i n a lar ger P hase 3 pr o gra m.  St u d y  B 7 4 5 1 0 1 4 will i n vesti gate 
t he ti me t o l oss of res p o nse t o P F- 0 4 9 6 5 8 4 2 i n s u bjects wit h m o derate t o se vere A D 
f oll o wi n g a cli nical res p o nse t o o pe n-la bel i n d ucti o n treat ment wit h P F- 0 4 9 6 5 8 4 2.  S u bjects 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
w h o e x perie nce a l oss of res p o nse de n ote d as flare ( per pr ot oc ol defi niti o n) will recei ve 
resc ue treat me nt wit h P F-0 4 9 6 5 8 4 2 i n c o m bi nati o n wit h t o pical t hera p y per sta n dar d of care . 
O bjecti ves a n d E n d p oi nts 
Pri m ar y O bjecti v e:

T o e va l uate a n d c o m pare t he mai nte na nce of effect of t w o d oses of P F-0 4 9 6 5 8 4 2 
( 2 0 0 m g a n d 1 0 0 m g o nce dail y  [ Q D]) a n d place b o i n s u bjects a ge d 1 2 a n d a b o ve 
wit h m o derate t o se vere at o pic der matitis w h o res p o n d t o a n i nitial o pe n- la bel r u n-i n 
treat me nt of 2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D.
Sec o n d ar y O bjecti ves:

T o e val uate a n d c o m pare t he effect of P F -0 4 9 6 5 8 4 2 o n a d diti o nal efficac y  e n d p oi nts 
a n d patie nt -re p orte d o utc o mes o ver ti me i n s u bjects a ge d 1 2 years a n d ol der wit h 
m o derate t o se vere at o pic der matitis.

T o asse ss t he efficac y of o pe n-la bel resc ue treat me nt c o nsisti n g of 2 0 0 m g  
P F - 0 4 9 6 5 8 4 2 i n c o m bi nati o n wit h t o pical t hera p y per sta n dar d of care i n cases of 
flare ( per pr ot oc ol defi niti o n).
S afet y O bjecti ve:

T o ass ess t he safet y a n d t olera bilit y of P F -0 4 9 6 5 8 4 2 d ur i n g o pen- la bel a n d 
d o u ble -bli n d treat me nt i n s u bjects a ge d 1 2 a n d o ver wit h m o derate t o se vere A D.
P h ar m ac o ki netic O bjecti ve: 

T o e val uate t he p har mac o ki netics ( P K) of P F -0 4 9 6 5 8 4 2 a n d its meta b olites i n 
s u bjects a ge d 1 2 ye ars a n d ol der wit h m o derate t o se v ere at opic der matitis f oll o wi n g 
1 2 wee ks of mai nte na nce treat me nt.
 
 
Pri m ar y E n d p oi nt
1.
L oss of res p o nse re q uiri n g resc ue treat me nt will be e val uate d a n d c o m pare d a m o n g
gr o u p s d uri n g t he bli n de d treat me nt peri o d.  L oss of res p o nse is de n ote d as flare a n d 
is defi ne d as a l oss of at least 5 0 % of t he Ecze ma Area a n d Se verit y I n de x ( E A SI) 
res p o nse at Wee k 1 2 a n d a n I n vestigat or’s Gl o bal Assess me nt (I G A) sc ore of 2 or 
hi g her.
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
Ke y Se c o n d ar y E n d p oi nt
1.
L oss of res p o nse base d o n a n I G A sc ore of 2 or hi g her.
Sec o n d ar y E n d p oi nts
Cli nic al Effic ac y Assess me nts:
1.
Res p o nse base d o n t he I G A (sc ore of 0 or 1 a n d a re d ucti o n of ≥2 p oi nts) at all 
sc he d ule d ti me p oi nts. 
2.
Res p o nse base d o n E A SI t otal sc ore ( E A SI-5 0, E A SI -7 5, E A SI -9 0, a n d E A SI -1 0 0) at 
all sc he d ule d ti me p oi nts.
3.
Res p o nse base d o n ac hie vi n g 4 p oi nt i m pr o ve me nt i n t he se verit y  of pr urit us 
N u merical Rati n g Scale ( N R S) fr o m baseli ne at all sc he d ule d ti me p oi nts.
4.
Perce nt c ha n ge fr o m baseli ne i n perce nt B o d y S urface Area ( B S A) at all sc he d ule d 
ti me p oi nts.
5.
Perce nt c ha n ge fr o m baseli ne i n S C O Ri n g At o pic Der matitis ( S C O R A D) s u bjecti ve 
asses s me nts of itc h a n d slee p l oss at all sc he d ule d ti me p oi nts. 
6.
Res p o nse base d o n ac hie vi n g a 5 0 % a n d 7 5 % i m pr o ve me nt i n S C O R A D 
( S C O R A D-5 0, S C O R A D -7 5) fr o m baseli ne at all sc he d ule d ti me p oi nts.
Cli nic al Effic ac y Assess me nts i n S u bjects Re q uiri n g Resc ue Tre at me nt:
1.
Res p o nse base d o n t he I G A at t he e n d of resc ue t hera py. 
2.
Res p o nse base d o n t he E A SI  t otal sc ore at t he e n d of resc ue t hera p y. 
3.
Res p o nse base d o n ac hie vi n g 4 p oi nt i m pr o ve me nt i n t he se verit y  of pr urit us 
N u merical Rati n g Scale ( N R S) at t he e n d of r esc ue t hera p y relati ve t o t he start of 
resc ue t hera py baseli ne va l ue.
4.
Perce nt c ha n ge i n perce nt B o d y S urface Area ( B S A) at t he e n d of resc ue t hera p y 
relati ve t o t he start of resc ue t hera py baseli ne val ue .
5.
Perce nt c ha n ge i n S C O R A D s u bjecti ve assess me nts of itc h a n d slee p l oss at t he e n d 
of resc ue t hera p y rela ti ve t o t he start of resc ue t hera p y baseli ne val ue .
6.
Res p o nse base d o n ac hie vi n g a 5 0 % a n d 7 5 % i m pr o ve me nt i n S C O R A D 
( S C O R A D-5 0, S C O R A D- 7 5) at t he e n d of resc ue t hera p y relati ve t o t he start of 
resc ue thera p y baseli ne val ue .


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
P atie nt -Re p orte d O utc o mes i n All S u bjects:
1.
Res p o nse base d o n ac hie vi n g Pt G A sc ore of clear ( 0) or al m ost clear ( 1); a n d a 
re d ucti o n fr o m baseli ne of ≥2 p oi nts at all sc he d ule d ti me p oi nts (a m o n g s u bjects 
wit h a sc ore ≥2 at baseli ne) .
2.
C ha n ge fr o m baseli ne i n Der mat ol o g y  Life Q ualit y In de x ( D L QI) or C hil dre n’s 
D L QI ( C D L QI) at all sc he d ule d ti me p oi nts. 
3.
C ha n ge fr o m baseli ne i n H os pital A n xiet y  De pressi o n Scale ( H A D S) at all sc he d ule d 
ti me p oi nts.
4.
C ha n ge fr o m baseli ne i n Patie nt Orie nte d Ecze ma Meas ure ( P O E M) at all sc he d ule d 
ti me p oi nts.
5.
C ha n ge fr o m baseli ne i n t he Pr urit us a n d S y m pt o ms Assess me nt i n At o pic Der matitis 
( P S A A D) at all sc he d ule d ti me p oi n ts.
S afet y E n d p oi nts:
1.
I nci de nce of treat me nt e mer ge nt a d verse e ve nts.
2.
I nci de nce of Seri o us A d verse E ve nts ( S A E)s a n d A d verse E ve nts ( A E)s lea di n g t o 
disc o nti n uati o n.
3.
I nci de nce of cli nical a b n or malities a n d c ha n ge fr o m baseli ne i n cli nical la b orat or y  
val ues , electr ocar di o gra m ( E C G) meas ure me nts a n d vital si g ns.
P h ar m ac o ki netic E n d p oi nt:
1.
P o p ul ati o n P K c haracterizati o n i n s u bjects a ge d 1 2 ye ars ol d a n d a b o ve wit h 
m o derate t o se vere at o pic der matitis. 
 
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
St u d y Desi g n
T his is a ra n d o mize d, res p o n der-e nric he d, d o u ble- bli n d, place b o -c o ntr olle d , P hase 3 
wit h dra wal trial t o e val uate t he efficac y  a n d safet y of P F-0 4 9 6 5 8 4 2 m o n ot hera p y i n s u bjects 
a ge d 1 2 ye ars a n d ol der wit h m o derate t o se vere A D as defi ne d per t he i ncl usi o n criteria a n d 
a b o d y wei g ht 4 0 k g.  A d olesce nt s u bjects bel o w t he le gal a g e of maj orit y (legal 
a d ult h o o d), i n t he s u bject’s c o u ntr y  ca n o nl y e nr oll i n t his st u d y if i nstr ucte d b y t he s p o ns or 
a n d a p pr o ve d b y t he c o u ntr y’s re g ulat or y/ healt h a ut h orit y.  If t hese a p pr o vals ha ve n ot bee n 
gra nte d, o nl y s u bjects t he le gal a ge of maj ority (le ga l a d ulth o o d), i n t he s u bject’s c o u ntr y
are all o we d t o e nr oll.  F or s u bjects y o u n ger t ha n t his, t heir le gall y acce pta ble 
re prese ntati ve/pare nt(s) or le gal g uar dia n pr o vi de writte n c o nse nt a n d mi n or c hil dre n pr o vi de 
asse nt, acc or di n g t o l ocal re g ul ati o ns a n d r ules re gar di n g a bilit y t o gi ve asse nt a n d c o nse nt.  
After pr o vi di n g i nf or me d c o nse nt, s u bjects are assesse d f or st u d y eli gi bilit y at t he scree ni n g 
visit.  D uri n g t he scree ni n g peri o d, treat me nts f or A D are was he d o ut, as a p plica ble, 
acc or di n g t o eli gi bil it y re quire me nts.  -A baseli ne ( Da y 1) visit occ urs wit hi n 2 8 da y s after 
t he scree ni n g visit. 
S u bjects ma y  be re-scree ne d o nce if t he y fail t he scree ni n g e val uati o n f or reas o ns relate d t o 
i nci de ntal tra nsit or y c o n diti o ns.  S u bjects f or w h o m scree n fail ure is relate d t o faili n g t he 
dise ase se verit y (i ncl u di n g e xte nt of disease) i ncl usi o n criteri o n a n d w h o s u bse q ue ntl y 
e x perie nce w orse ni n g A D, w hic h i n t he i n vesti gat or’s j u d ge me nt w o ul d ma ke t he m eli gi ble 
f or partici pati o n, ma y be c o nsi dere d f or re-scree ni n g.  S uc h cases s h o ul d be disc usse d wit h 
t he Pfizer Me dical M o nit or ( or desi g nee) t o deter mi ne if re-scree ni n g is a p pr o priate.
T he trial c o nsists of a n o pe n -la bel r u n-in peri o d t o deter mi ne res p o n der stat us t o a n i nitial 
i n d ucti o n treat me nt wit h P F-0 4 9 6 5 8 4 2 ( 2 0 0 m g , Q D), a ra n d o mize d, place b o-c o ntr olle d, 
d o u ble -bli n de d P F - 0 4 9 6 5 8 4 2 mai nte na nce treat me nt peri o d, a n d a 4- wee k u ntreate d 
f oll o w-u p safet y peri o d.  S u bjects w h o meet t he pr ot oc ol defi niti o n of flare d uri n g bli n de d 
treat me nt e nter a n o pe n-label resc ue treat me nt peri o d.
E nr olle d s u bjects i nitiate t he 1 2 -wee k, o pe n -la bel r u n-i n peri o d t o i de ntif y res p o n ders w h o 
ha ve a p ositi ve cli nical res p o nse t o i n d ucti o n treat ment wit h 2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D.  
Res p o n der criteri a are defi ne d as a) ac hie vi n g a n I G A of clear ( 0) or al m ost clear ( 1) ( o n a 
5 - p oi nt scale), b) a re d ucti o n fr o m I G A baseli ne of 2 p oi nts, a n d c) reac hi n g a n E A SI - 7 5 
res p o nse c o m pare d t o baseli ne.  Baseli ne is defi ne d as t he I G A sc ore a n d E A SI sc ore 
o btai ne d pri or t o d osi n g o n Da y 1.  S u bjects meeti n g all of t he res p o n der criteria ma y  be 
eli gi ble f or ra n d o mizati o n. 
S u bjects w h o d o n ot reac h t he res p o nse t hres h ol d r e q uire d f or ra n d o mizati o n are declare d 
n o n -res p o n ders after c o m pleti o n of t he o pe n la bel r u n -i n peri o d.  N o n-res p o n ders are not 
eli gi ble f or ra n d o mizati o n i n t he B 7 4 5 1 0 1 4 st u d y , b ut ma y c h o ose t o e nr oll i nt o t he 
P F -0 4 9 6 5 8 4 2 L o n g Ter m E xte nsi o n ( L T E) st u d y  B 7 4 5 1 0 1 5 pr o vi di n g t he y  re mai n eli gi ble; 
ot h er wise t he y are per ma ne ntl y disc o nti n ue d fr o m treat me nt a n d e nter t he 4-wee k u ntr eate d 
f oll o w- u p peri o d i n B 7 4 5 1 0 1 4.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
S u bjects wit h a p ositi ve cli nical res p o nse t o P F- 0 4 9 6 5 8 4 2 i n d ucti o n treat me nt at t he e n d of 
t he 1 2 -wee k o pe n -la bel r u n-i n peri o d e nter a 4 0 wee k, d o u ble -bli n d, mai nte na nce treat me nt 
peri o d i n w hic h t he y are ra n d o mize d i n t o 1 of 3 treat me nt ar ms i n a 1: 1: 1 rati o: 
1.
1 0 0 m g P F -0 4 9 6 5 8 4 2 Q D;
2.
2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D; 
3.
Place b o.
Ra n d o mizati o n is stratifie d b y  a ge cate g or y, ie, < 1 8 years a n d 1 8 ye ars.  Eli gi ble s u bjects 
m ust ha ve a d oc u me nte d hist or y  of i na de q uate res p o nse wit h t o pical A D me dicati o ns or ha ve 
re q uire d sys te mic t hera pies f or c o ntr ol of t heir disease.
Me dicate d t o pic al a n d/ or s yste mic sta n dar d of care t hera pies are n ot all o we d d uri n g t he 
o pe n -la bel r u n-i n a n d bli n de d treat me nt peri o ds. Me dicate d t o pical t hera p y is defi ne d as a 
t o pical pr o d uct t hat c o ntai ns a n acti ve p har mace utical i n gre die nt i n dicate d f or t he treat me nt 
of A D (irres pecti ve of w het her it is a vaila ble as a n o ver- t he-c o u nter [ O T C] or prescri pti o n 
o nl y  pr o d uct).
F oll o wi n g c o m pleti o n of 4 0 wee ks of bli n de d tr eat me nt, all s u bjects are assesse d f or 
eli gi bilit y t o e nter t he P F-0 4 9 6 5 8 4 2 L T E st u d y  B 7 4 5 1 0 15.  If a s u bject disc o nti n ues 
pre mat urel y or is n ot eli gi ble or willi n g t o parti ci pate i n B 7 4 5 1 0 1 5, t he n t he s u bject e nters 
t he 4- wee k u ntreate d f oll o w-u p peri o d i n B 7 4 5 1 0 1 4.
D uri n g t he bli n de d treat me nt peri o d, s u bjects meeti n g t he pr ot oc ol defi niti o n of fl are e nter 
a n o pe n-la bel resc ue peri o d d uri n g w hic h t he y recei ve a n ot her 1 2-wee k c o urse of 2 0 0 m g  
P F - 0 4 9 6 5 8 4 2 Q D wit h t o pical t hera py per l ocal sta n dar d of care ( S O C).  I n t his st u d y, flare 
re q uiri n g resc ue treat me nt is defi ne d as a l oss of at least 5 0 % o f t he E A SI res p o nse at 
Wee k
1 2 a n d a n I G A sc ore of 2 or hi g her.  F or e xa m ple, if a s u bject has a t otal E A SI sc ore of 
4 0 at baseli ne a n d a sc ore of 1 0 at Wee k 1 2 (a c hie vi n g E A SI- 7 5 t o be a res p o n der at 
ra n d o mizati o n), t he E A SI res p o nse is -3 0.  T o meet t he defi niti o n of flare, t he t otal E A SI  
sc ore f or t his s u bject w o ul d ha ve t o g o u p by at least 1 5 ( 5 0 % of -3 0) fr o m Wee k 1 2, w hic h 
c o m p utes t o a t otal E A SI sc ore of at least 2 5, t his i n a d diti o n t o a n IG A sc ore of 2.
After c o m pleti n g t he f ull 1 2- wee k resc ue p eri o d, s u bjects ma y e nter t he L T E st u d y 
B 7 4 5 1 0 1 5, if eli gi ble.  S u bjects disc o nt i n ui n g earl y fr o m treat me nt or w h o are ot her wise 
i neli gi ble f or t he L T E st u d y e nter t he 4 wee k u ntreate d f oll o w - u p peri o d i n B 7 4 5 1 0 1 4.
A n i n vesti gat or ca n te m p oraril y i nterr u pt d osi n g f or u p t o a ma xi m u m of 2 8 c o nsec uti ve da ys 
f or a s u bject, f or safety rea s o ns or w hile m o nit ori n g a b n or mal la b orat or y tests if t he 
i n vesti gat or j u d ges t hat t his is necessar y. T he i n vesti gat or s h o ul d use t heir j u d ge me nt wit h 
re gar d t o u nsc he d ule d visits/la b orat or y/cli nical assess me nts re q uire d t o m o nit or t he s u bject 
d uri n g t his ti me-fra me. If wit hi n t his ti mefra me t he i n vesti gat or j u d ges t hat it is safe t o 
restart d osi n g, t he n t he s u bject ma y  restart i n vesti gati o nal pr o d uct. If t he i n vesti gat or j u dges 
t hat it is n ot safe t o restart d osi n g wit hi n t his ti mefra me t he n t he s u bject m ust be per ma ne ntl y 
disc o nti n ue d fr o m treat me nt, ha ve a n E n d of Treat me nt visit a n d e nter t he 4 -wee k f oll o w - u p 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
peri o d.  D oses n ot ta ke n f or t he reas o ns me nti o ne d a b o ve d o n ot c o nstit ute pr ot oc ol 
de viati o ns or me dicati o n err ors a n d s h o ul d n ot be c o nsi dere d d osi n g err ors, b ut s h o ul d be 
n ote d i n t he d osi n g l o g wit h t he reas o n f or re d uce d d r u g c o ns u m pti o n clearl y descri be d. 
La b orat or y  tests are perf or me d t hr o u g h o ut t his st u d y as detaile d i n t he Sc he d ule of Acti vities . 
I n vesti gat ors f oll o w t he i nstr ucti o ns f or m ore fre q ue nt m o nit ori n g i n A p pe n di x 4 if t he 
s pecifie d la b orat or y val ues reac h t he liste d t hres h ol ds.
T he t otal st u d y  d urati o n if a s u bject d oes n ot flare is 5 2 wee ks ( 1 2 wee ks o pe n -la bel 
in d ucti o n treat me nt + 4 0 wee ks bli n de d mai nte na nce treat me nt).  T he p ote ntial ma xi m u m
st u d y d urati o n is 6 4 wee ks.  T his w o ul d o nl y  be ac hie ve d if a s u bject flare d o n t he last da y of 
t he mai nte na nce treat me nt peri o d ( 5 2 wee ks + 1 2 wee ks resc ue).  If s u bjects d o n ot i nte n d t o 
e nr oll i n t he LT E st u d y , t he a b o ve d urati o ns are e xte n de d b y + 4 w e e ks of a n u ntreate d
f oll o w-u p safet y peri o d.
A t otal of a p pr o xi matel y  1 3 7 0 s u bjects will be e nr olle d fr o m a p pr o xi matel y 2 1 8 sites l ocate d 
gl o ball y.
St u d y Tre at me nts
All e nr o lle d s u bjects recei ve 1 2 wee ks of 2 0 0 m g  P F- 0 4 9 6 5 8 4 2 Q D d uri n g t he o pe n-la bel 
r u n-in i n d ucti o n peri o d.   At t he e n d of t he 1 2 wee ks, s u bjects res p o n di n g t o treat me nt as 
descri be d a b o ve are ra n d o mize d t o recei ve d o u ble- bli n d mai nte na nce treat me nt wit h 1 0 0 m g
P F -0 4 9 6 5 8 4 2 Q D, 2 0 0 m g  P F- 0 4 9 6 5 8 4 2 Q D, or place b o ( 1: 1: 1 ra n d o mizati o n rati o) f or 
4 0 -wee ks.  I n t he eve nt of flare d uri n g bli n de d treat me nt, s u bjects e nter a 1 2 -wee k o pe n -la bel 
resc ue peri o d a n d recei ve 2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D wit h c o nc o mita nt t o pical t hera p y  per 
S O C.
St atistic al Met h o ds
T he statistical o bjecti ve of t he st u d y  is t o c haracterize t he l oss of res p o nse wit h eac h 
ra n d o mize d gr o u p after ac hie vi n g res p o nse at Wee k 1 2 f oll o wi n g o pe n-la bel treat me nt wit h 
2 0 0 m g P F - 0 4 9 6 5 8 4 2 Q D.
A t otal of 6 0 0 s u bjects wit h 2 0 0 recei vi n g 1 0 0 m g P F -0 4 9 6 5 8 4 2 Q D, 2 0 0 recei vi n g 2 0 0 m g  
P F -0 4 9 6 5 8 4 2 Q D, a n d 2 0 0 recei vi n g plac e b o ( 1: 1: 1 ra n d o mizati o n rati o) will pr o vi de 
9 4 % p o wer t o detect a rati o of me dia n ti me t o flare of at least 1. 5 ti mes bet wee n eit her d ose 
of P F - 0 4 9 6 5 8 4 2 ( 1 0 0 m g or 2 0 0 m g) a n d place b o.  T he T y pe I err or rate is ass u me d t o be 
5 % ( 2-si de d).  Ass u mi n g base d o n pri or data, t hat a b o ut 4 4 % of s u bjects w o ul d meet t he 
pr ot oc ol -defi ne d criteria t o be a res p o n der at Wee k 1 2, a p pr o xi matel y  1 3 7 0 s u bjects w o ul d 
nee d t o e nter t he o pe n la bel r u n- i n peri o d of t he st u d y t o e ns ure t hat 6 0 0 s u bjects are 
a vaila ble f or ra n d o mi zati o n. 
T here are si x ke y  h yp ot heses t o be teste d f or eac h pair wise c o m paris o n bet wee n t w o 
P F -0 4 9 6 5 8 4 2 d oses ( 2 0 0 m g Q D a n d 1 0 0 m g Q D) a n d place b o, f or t he pri mar y  a n d ke y 
sec o n dar y e n d p oi nts.  F or t hese hy p ot heses, t he fa mil y wise T y pe-I err or rate will b e str o n gl y 
c o ntr olle d at 5 % usi n g a se q ue ntial, gate kee pi n g pr oce d ure. 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
F or a nal y sis of t he pri mar y a n d ke y sec o n dar y e n d p oi nt s, a c o m bi nati o n of gra p hical a n d 
a nal yt ical met h o ds will be use d.  T he ti me (i n wee ks) t o pr ot oc ol -defi ne d flare will be use d 
t o e val uate t he pri mar y e n d p oi nt w hile t he ti me (i n wee ks) t o ac hie ve a n I G A sc ore of 
2 will be use d f or t he ke y sec o n dar y  e n d p oi nt.  S u bjects w h o d o n ot rep ort a n e ve nt 
( pr ot oc ol-defi ne d flare or I G A 2) or disc o nti n ue t he st u d y  d uri n g t he d o u ble-bli n d 
ra n do mize d peri o d will ha ve t heir ti me t o e ve nt ce ns ore d at t heir last k n o w n visit i n t his 
peri o d.  Ka pla n -Meier c ur ves will be use d t o dis pla y  t he ti me t o e ve nt a n d re p ort t he me dia n 
ti me t o e ve nt a m o n g t he t hree ra n d o mize d treat me nt gr o u ps .  T he l o g-ra n k test will be use d 
t o c o m pare t hese c ur ves.  Pr o p orti o ns of s u bjects wit h an e ve nt a n d c o nfi de nce i nter vals will 
als o be re p orte d b y ra n d o mize d treat me nt gr o u p.
I n ge neral, bi nar y e n d p oi nts will be a nal yze d usi n g t he ( C oc hra n -Ma ntel -Hae nszel ) test 
a dj uste d b y  ra n d o mizati o n strata (a ge gr o u ps) a n d baseli ne disease se verit y.   T he differe nce 
bet wee n treat me nt gr o u ps i n t he pr o p orti o n of s u bjects ac hie vi n g a res p o n se al o n g wit h its 
9 5 % c o nfi de nce i nter val ( usi n g t he n or mal a p pr o xi mati o n f or t he d iffere nce i n bi no mial 
pr o p orti o ns) will be re p orte d. 
I n ge neral, f or c o nti n u o us e n d p oi nts, a mi xe d -effect m o del wit h re peate d meas ures ( M M R M) 
will be use d.  T his m o del will i ncl u de t he fact ors (fi xe d effects) f or treat me nt gr o u p, 
ra n d o mizati o n strata (a ge gr o u ps) a n d bas eli ne disease se verit y , visit, treat me nt-b y -visit 
i nteracti o n, a n d rele va nt baseli ne val ue.  Wit hi n t he fra me w or k of M M R M, differe nces 
bet wee n gr o u ps will be teste d usi n g esti mates fr o m t he M M R M m o del.
All s u bjects w h o recei ve i n vesti gati o n al pr o d uct (safe t y p o p ulati o n) will be i ncl u de d i n t he 
safety a nal yses.  All t he safet y data will be s u m marize d descri pti vel y t hr o u g h a p pr o priate 
data ta b ulati o ns, descri pti ve statistics, cate g orical s u m maries, a n d gra p hical prese ntati o ns.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
S C H E D U L E O F A C T I VI TI E S F O R R U N-I N AN D B LI N D E D T R E A T M E N T S
T he sc he d ule of acti vities ta ble pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures.  Refer t o t he S T U D Y P R O C E D U R E S a n d 
A S S E S S M E N T S secti o ns of t he pr ot oc ol f or detaile d i nf or mati o n o n eac h pr oce d ure a n d assess me nt re q uire d f or c o m plia nce wit h t he 
pr ot oc ol. 
T he i n vesti gat or ma y  sc he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d o n t he sc he d ule of acti vities ta ble, i n or der t o 
c o n d uct e val uati o ns or assess me nts re q uire d t o pr otect t he well -bei n g of t he s u bject.
Visit I de ntifier
D a y -2 8 a
Sc ree ni n g
D a y 1
Wee k 0
B aseli ne
D a y 8
Wee k 1
C all
D a y 1 5
Wee k 2
D a y 2 9
Wee k 4
D a y 4 3
Wee k 6
C all
D a y 5 7
Wee k 8
D a y 8 5
Wee k 1 2 
R a n d o mize
Res p o n ders
D a y 1 1 3 b
Wee k 1 6
D a y 
1 9 7 b
Wee k 
2 8
D a y 2 8 1 b
Wee k 4 0
D a y 3 6 5 b
Wee k 5 2 
E O T/ E T
E O S,
F oll o w -u p
Wee k 5 6/
4 Wee ks 
p ost E T
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visi t 9
Visit 1 0
Visit 1 1
Visit 1 2
Visit 1 3
Visit Wi n d o w
N o ne
N o ne
1 D a y 1 D a y 2 D a ys 3 D a ys 3 D a ys
3 D a ys
3 D a ys 7 D a ys
7 D a ys
3 D a ys
3 D a ys
E nr oll me nt Pr oce d ure
I nf or me d c o nse ntc
X
Re gister s u bject usi n g I R T 
s yste m
X
I ncl usi o n/ E xcl usi o n Criteria
X
X
X
C -S S R S d
X
X
X
X
X
X
X
X
X
S B Q -R d
X
P H Q -8 d
X
De m o gra p hics, Me dical 
Hi st or y, T o bacc o a n d Alc o h ol 
Hist or y, At o pic Der matitis 
Disease Hist or y e
X
Re vie w Pri or/ C o nc o mita nt 
Me dicati o ns & Tre at me nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Dis pe nse e -Diar y a n d i nstr uct 
s u bjects o n use
X
Pr o vi de Patie nt E mer ge nc y 
C o ntact Car d
X
Me dic al Pr oce d ures
C o m plete P h ysical E xa m f
X
X
X
X
Tar gete d P h ysical E xa m f
X
X
X
X
X
X
X
Vital Si g ns g
X
X
X
X
X
X
X
X
X
X
X
Wei g ht/ Hei g ht
d d
X
X
X
X


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
Visit I de ntifier
D a y -2 8 a
Sc ree ni n g
D a y 1
Wee k 0
B aseli ne
D a y 8
Wee k 1
C all
D a y 1 5
Wee k 2
D a y 2 9
Wee k 4
D a y 4 3
Wee k 6
C all
D a y 5 7
Wee k 8
D a y 8 5
Wee k 1 2 
R a n d o mize
Res p o n ders
D a y 1 1 3 b
Wee k 1 6
D a y 
1 9 7 b
Wee k 
2 8
D a y 2 8 1 b
Wee k 4 0
D a y 3 6 5 b
Wee k 5 2 
E O T/ E T
E O S,
F oll o w -u p
Wee k 5 6/
4 Wee ks 
p ost E T
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visi t 9
Visit 1 0
Visit 1 1
Visit 1 2
Visit 1 3
Visit Wi n d o w
N o ne
N o ne
1 D a y 1 D a y 2 D a ys 3 D a ys 3 D a ys
3 D a ys
3 D a ys 7 D a ys
7 D a ys
3 D a ys
3 D a ys
E C G ( 1 2 -lea d)k k
X
X
X
X
X
X
X
X
X
X
X
L a b or at or y Assess me nts h
He mat ol o g y i
X
X
X
X
X
X
X
X
X
X
X
C oa g ulati o n Pa nel j
X
X
X
X
X
X
X
X
X
X
X
Ser u m c he mistr y k
X
X
X
X
X
X
X
X
X
X
X
Uri nal ysis l
X
X
X
X
X
X
X
X
X
X
X
Li pi d Pa nel m
X
X
X
X
X
Ser u m F S H ( p ost -me n o pa usal) 
or Pre g na nc y Test n
X
Uri ne Pre g na nc y Test 
(c o n d ucte d at st u d y site)o
X
X  
X
X  
X  
X  
X  
X  
X  
X
HI V Testi n g q
X
He patitis B S urface A nti ge n 
( H Bs A g), He patitis B 
S urface A nti b o d y ( H Bs A b), 
He patitis B C ore A nti b o d y 
( H Bc A b), He patitis C 
A nti b o d y ( H C V A b), 
He patitis C Viral R N A ( H C V 
R N A) r
X
H B V D N A testi n g f or C hi na
a n d Tai wa n jj
X
X
X  
X  
X
Varic ella Z oster Vir us ( V Z V 
I g G A b) (a d olesce nts o nl y, if 
a p plica ble) s
X
T u berc ul osis Test t
X
X ii
C hest X -ra yh h
X
X ii
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
Visit I de ntifier
D a y -2 8 a
Sc ree ni n g
D a y 1
Wee k 0
B aseli ne
D a y 8
Wee k 1
C all
D a y 1 5
Wee k 2
D a y 2 9
Wee k 4
D a y 4 3
Wee k 6
C all
D a y 5 7
Wee k 8
D a y 8 5
Wee k 1 2 
R a n d o mize
Res p o n ders
D a y 1 1 3 b
Wee k 1 6
D a y 
1 9 7 b
Wee k 
2 8
D a y 2 8 1 b
Wee k 4 0
D a y 3 6 5 b
Wee k 5 2 
E O T/ E T
E O S,
F oll o w -u p
Wee k 5 6/
4 Wee ks 
p ost E T
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visi t 9
Visit 1 0
Visit 1 1
Visit 1 2
Visit 1 3
Visit Wi n d o w
N o ne
N o ne
1 D a y 1 D a y 2 D a ys 3 D a ys 3 D a ys
3 D a ys
3 D a ys 7 D a ys
7 D a ys
3 D a ys
3 D a ys
P h ar m ac o ki netic 
P har mac o ki netic Bl o o d 
Sa m pli n g ( P ost -d ose) u
X
Tri al Tre at me nt 
Ra n d o mizati o n 
X
Dr u g Dis pe nsi n g
X
X
X
X
X
X
X
I n vesti gati o nal Pr o d uct 
Acc o u nta bilit y 
X  
X
X  
X  
X  
X  
X  
X
I n vesti gati o nal Treat me nt 
A d mi nistrati o n v
X -------------------------------------------------------------------------------------------------------------------------- X
Re vie w e Diar y t o assess 
c o m pleti o n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Assess eli gi bilit y f or 
B 7 4 5 1 0 1 5 w
X
X
Cli nic al Assess me nts 
Fitz patric k S ki n T y pe 
Assess m e nt
X
I n vesti gat or’s Gl o bal 
Assess me nt (I G A)
X  
X
X  
X
X  
X  
X  
X  
X  
X  
X
S C O Ri n g At o pic Der matitis 
( S C O R A D)
X  
X
X  
X
X  
X  
X  
X  
X  
X  
X
Ecze ma Area a n d Se verit y 
I n de x ( E A SI)
X  
X
X  
X
X  
X  
X  
X  
X  
X  
X
T otal B o d y S urface Area 
( B S A fr o m E A SI) 
X  
X
X  
X
X  
X  
X  
X  
X  
X  
X
P atie nt -re p orte d O utc o me 
Pr urit us N u merical Rati n g 
Scale -e Diar y ( N R S) x
X ---------X  
X ---------------------X  
X
X  
X  
X  
X  
X  
X  
X
Patie nt Gl o bal Assess me nt 
( Pt G A)
X
X  
X
X  
X  
X  
X  
X  
X  
X
Der mat ol o g y Life Q ualit y 
I n de x ( D L QI or C D L QI)y
X
X  
X
X  
X  
X  
X  
X  
X  
X


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
Visit I de ntifier
D a y -2 8 a
Sc ree ni n g
D a y 1
Wee k 0
B aseli ne
D a y 8
Wee k 1
C all
D a y 1 5
Wee k 2
D a y 2 9
Wee k 4
D a y 4 3
Wee k 6
C all
D a y 5 7
Wee k 8
D a y 8 5
Wee k 1 2 
R a n d o mize
Res p o n ders
D a y 1 1 3 b
Wee k 1 6
D a y 
1 9 7 b
Wee k 
2 8
D a y 2 8 1 b
Wee k 4 0
D a y 3 6 5 b
Wee k 5 2 
E O T/ E T
E O S,
F oll o w -u p
Wee k 5 6/
4 Wee ks 
p ost E T
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visi t 9
Visit 1 0
Visit 1 1
Visit 1 2
Visit 1 3
Visit Wi n d o w
N o ne
N o ne
1 D a y 1 D a y 2 D a ys 3 D a ys 3 D a ys
3 D a ys
3 D a ys 7 D a ys
7 D a ys
3 D a ys
3 D a ys
Patie nt -Orie nte d Ecze ma 
Meas ure ( P O E M)
X
X  
X
X  
X  
X  
X  
X  
X  
X
H os pital A n xiet y a n d 
De pressi o n Scale ( H A D S)
X
X  
X
X  
X  
X  
X  
X  
X  
X
Pr u rit us a n d S y m pt o ms 
Assess me nt f or At o pic 
Der matitis - e Diar y ( P S A A D) z
X ---------X  
X ----------------------------------------------------------------------------------------------------------------------------------------X
E Q -5 D -5 L (a d ults) or 
E Q -5 D -Y (a ges 1 2 -1 7 years) aa
X
X  
X
X  
X  
X  
X  
X  
X  
X
S F -3 6 v 2, Ac ute b b (a d ults)
X
X
X
X
F A CI T -F (a d ults) or 
Pe ds -F A CI T -F ( a ges 1 2-1 7 
years )c c
X
X
X  
X
Ast h ma C o ntr ol Q uesti o n naire 
( A C Q) f or all s u bjects wit h a 
pri or dia g n osis of ast h ma 
X
X
X  
X
S af et y
Seri o us a n d n o n -seri o us 
a d verse e ve nt m o nit ori n g
X  
 
 
 
 
 
 
 
 
 
 
 

X
Assess f or prese nce of flare ee
X
X
X
X
C o ntrace pti o n C hec k ff
X
X
X
X
X
X
X
X
X
X
X
X
X
Ser u m Sa m ple f or Baseli ne 
Viral Scree n g g
X


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
A b bre viati o ns: A C Q = Ast h ma C o ntr ol Q uesti o n naire; B S A = b o d y s urface area; C D L QI = C hil dre n’s Der mat ol o g y Lif e Q ualit y I n de x ; C-S S R S = C ol u m bia 
S uici de Se verit y Rati n g Scale; D L QI = Der m at ol o g y Life Q ualit y I n de x; E A SI = Ecze m a Area a n d Se verit y I n de x ; E C G = electr ocar di o gra m; E O S = E n d of 
St u d y; E O T = E n d of Treat me nt; E T = earl y ter mi nati o n; E Q -5 D -5 L  = E ur o Q ol Q ualit y of Life 5-Di me nsi o n 5 -Le vel Scale; E Q -5 D -Y = E ur o Q ol Q ualit y of Life 
5- Di me nsi o n, Y o ut h Scale; F A CI T -F = F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y Fati g ue Scale; F S H = f ollicle sti m ulati n g h or m o ne; 
G G T = ga m ma -gl uta m yl tra nsferase; H A D S = H os pit al A n xiet y a n d De pressi o n Scale ; H Bs A g = he patitis B s urfac e a nti ge n; H Bs A b = he pati tis B s urface 
a nti b o d y; H Bc A b = he patitis B c ore a nti b o d y; H B V D N A = he patitis B vir us de o x yri b o n ucleic aci d; H C V A b = he patitis C a nti b o d y; H C V R N A = He patitis C 
Viral R N A; He p B = He pati tis B; HI V = h u ma n i m m u n o deficie nc y vir us; H S V -1 = her pes si m ple x vir us t y pe 1; H S V 2 = her pes si m ple x vir us t y pe 2; 
I G A = I n vesti gat or’s Gl o bal Assess me nt; I g E = I m m u n o gl o b uli n E; I R T = I nteracti ve Res p o nse S yste m; L D H = Lactate de h y dr o ge nase; L L Q = l o w er li mit of 
q ua ntificati o n; M C H = mea n c or p usc u lar he m o gl o bi n; M C H C = mea n c or p usc ular he m o gl o bi n c o nce ntrati o n; M C V = mea n c or p usc ular v ol u me; N K = Nat ural 
Killer; N R S = n u merical rati n g scale; Pe ds -F A CI T -F = Pe diatric F u ncti o nal Assess me nt of C hr o nic Ill nes s T hera p y Fati g ue Scale; P H Q-8 = Patie nt Hea lt h 
Q uesti o n naire 8 ite ms ; P O E M = Patie nt -Orie nte d Ecze ma Meas ure ; P S A A D = Pr urit us a n d S y m pt o ms Assess me nt f or At o pic Der matitis; Pt G A = Patie nt Gl o bal 
Assess me nt; R B C = Re d bl o o d cell; R N A = Ri b o n uc leic aci d; S B Q-R = S uici de Be ha vi ors Q uesti o n naire -Re vise d; S C O R A D = S C O Ri n g At o pic Der matitis; 
S F -3 6 v 2 = S h ort F or m -3 6 Healt h S ur ve y Versi o n 2; V Z V = varicella z oster vir us; V Z V I g G A b = varicella z oster vir us i m m u n o gl o b uli n G a nti b o d y.
a.
D a y  relati ve t o start of st u d y treat me nt ( Da y 1).
b.
Fr o m  Da y 8 6 t hr o u g h Da y 3 6 5, if t he s u bject flares as defi ne d b y pr ot oc ol, be gi n resc ue treat me nt peri o d.  See Sc he d ule of Acti vities f or Resc ue Treat me nt . 
c.
O btai n writte n i nf or me d c o nse nt; f or s u bjects a ge d u n der t he le gal a ge of maj orit y (le gal a d ult h o o d) i n t he s u bject’s c o u ntr y, o btai n writte n i nf or me d c o nse nt 
fr o m le gall y acce pta ble re prese ntati ve/pare nt(s) or le gal g uar dia n, a n d i nf or me d asse nt fr o m t he patie nt (if a ge a p pr o priate acc or di n g t o l ocal reg ulati o ns).
d.
Site staff is t o a d mi nister t he C -S S R S, S B Q -R a n d P H Q -8 t o all s u bjects at scree ni n g a n d sc ore i m me diatel y.  S u bjects w h o ha ve rece nt or acti ve s uici dal 
i deati o n or be ha vi or or cli nicall y si g nifica nt de pressi o n will be e xcl u de d fr o m t he st u d y or disc o nti n ue d fr o m t he st u d y per Se cti o n 4. 2 , Secti o n 7. 5. 1 , 
Secti o n 7. 5. 2 a n d Secti o n 7. 5. 3 .  S u bjects meeti n g e xcl usi o nar y res ults o n t he C- S S R S, S B Q -R a n d P H Q -8 s h o ul d be e xcl u de d fr o m partici pati o n; it is 
rec o m me n de d t he s u bject’s pri mar y care p h ysicia n ( P C P) s h o ul d be i nf or me d, a n d t he s u bject referre d t o a me ntal healt h pr ofessi o nal, eit her b y t he P C P or 
t he i n vesti gat or acc or di n g t o t heir us ual practice.  P ost -scree ni n g, if t here are “ yes” a ns wers o n ite ms 4, 5 or o n a n y be ha vi oral q uestio n of t he Si nce Last 
Visit C -S S R S a ris k assess me nt b y a q ualifie d me ntal healt h pr o fessi o nal (M H P ) s h o ul d be d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o nti n ue t o 
partici pate i n t he trial.
e.
At o pic Der matitis Disease Hist or y i ncl u des c ollecti o n of details of A D: A D dia g n osis a n d d urati o n, t he use of t o pical treat me nts, s yste m ic treat me nts an d 
ot her treat me nts f or A D. 
f.
C o m plete p h ysical e xa mi nati o ns m ust be perf or me d b y t he i n vesti gat or, s u b i n vesti gat or or a q ualifie d healt h pr ofessi o nal per l ocal g ui deli nes.   C o m plete 
p h ysical e xa mi nati o ns c o nsist of assess me nts of ge neral a p peara nce; s ki n; hea d, e yes, ears, n ose a n d t hr oat ( H E E N T); m o ut h, heart; l u n gs; breast ( o pti o nal); 
a b d o me n; e xter nal ge nitalia ( o pti o nal); e xtre mities; ne ur ol o gic f u ncti o n; a n d l y m p h n o de s.  Tar gete d p h ysical e xa mi nati o ns m ust be perf or me d b y t he 
i n vesti gat or, s u b-i n vesti gat or or a q ualifie d healt h pr ofessi o nal per l ocal g ui deli nes a n d s h o ul d i ncl u de s ki n, heart, l u n gs, a n d a b d o me n a n d e xa mi nati o n of 
b o d y s yste ms w here t here are s y m pt o m c o m p lai nts b y t he s u bject.
g.
Vital Si g ns i ncl u de sitti n g bl o o d press ure, p ulse, res pirat or y rate, a n d te m perat ure meas ure d after at least 5 mi n utes of rest. 
h.
La b orat or y tests wit h a b n or mal res ults ( per Secti o n 6. 1 a n d Secti o n 7. 6. 2 ) ma y be re peate d o nce d uri n g t he scree ni n g peri o d; t he last val ue will be use d t o 
deter mi ne eli gi bilit y.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
i.
H e m at ol o g y i ncl u des: He m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt a n d i n dices ( M C H, M C H C, M C V, R B C M or p h ol o g y), w hite bl o o d cells, ne utr o p hils 
( %, a bs ol ute), l y m p h oc ytes ( %, a bs ol ute), m o n oc ytes ( %, a bs ol ute), e osi n o p hils ( %, a bs ol ute), bas o p hils ( %, a bs ol ute), platel ets, retic ul oc yte c o u nt, 
ly m p h oc yte s u bse ts a n d mar kers ( T otal T cells [ C D 3 +], C D 4 + T cells [ C D 3 + C D 4 +], C D 8 + T cells [ C D 3 + C D 8 +], N K cells [ C D 3 - C D 1 6 + C D 5 6 +], 
B cells [ C D 3-C D 1 9 +) . 
j.
C oa g ulati o n pa nel i ncl u des: Acti vate d Partial T hr o m b o plasti n Ti me ( AP T T), Pr ot hr o m bi n Ti me/I nter nati o n al N or malize d Rati o ( P T/I N R).
k.
Ser u m c he mistr y i ncl u des: bl o o d urea nitr o ge n ( B U N), ser u m creati ni ne, creati ne p h os p h o ki nase, gl uc ose, Ca + +, Na +, K +, Cl -, t otal C O 2, as partate 
a mi n otra nsferase ( A S T), ala ni ne a mi n otra nsferase ( A L T), ga m ma-gl uta m yl tra nsfera se ( G G T), t otal, i n direct a n d direct bilir u bi n, al kali ne p h os p hatase, 
lactate de h y dro ge nase, uric aci d, al b u mi n a n d t otal pr otei n.
l.
Uri nal ysis i ncl u des: p H, Gl uc ose ( q ualitati ve), Pr otei n ( q ualitati ve), Bl o o d ( q ualitati ve ), Ket o nes, Nitrites, Le u k oc yte esterase, Micr osc o py a n d/ or c ult ure 
( perf or me d as a p pr o priate). 
m.
Li pi d Pa nel i ncl u des: t otal c h olester ol, l o w -de nsit y li p o pr otei n (L D L), hi g h -de nsit y li p o pr otei n ( H D L), a n d tri gl yceri des.  A mi ni m u m of 8-h o ur fasti n g is 
re q uire d f or li pi d pr ofile e val uati o n at D a y 1, Wee k 4, Wee k
1 2, Wee k 5 2 a n d E O S visits.
n.
Ser u m pre g na nc y testi n g at scree ni n g is re q uire d f or w o me n of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts a ge d 1 2 years a n d ol der re gar dless of w het her 
t he y ha ve e x perie nce d me narc he.  F ollicle sti m ulati n g h or m o ne ( F S H) test t o be perf or me d at Scree ni n g t o c o nfir m p ost me n o pa usal stat us i n fe male s u bjects 
w h o ha ve bee n a me n orr heic f or at least 1 2 c o nsec uti ve m o nt hs.
o.
Uri ne pre g na nc y test m ust be perf or me d at e ver y site visit pri or t o d osi n g wit h t he i n vesti gat i o nal pr o d uct f or fe male s u bjects of c hil d beari n g p ote ntial 
i ncl u di n g a d olesce nts a ge d 1 2 years a n d ol der re gar dless of w het her t he y ha ve e x perie nce d me narc he.
 
q.
S u bjects testi n g p ositi ve f or HI V will be scree n-faile d. 
r.
H Bs A b refle x testi n g will be perf or me d o nl y if H Bs A g ne gati ve b ut H Bc A b p ositi ve.  S u bj ects w h o are p ositi ve f or H C V A b a n d H C V R N A will be
scree n-faile d. 
s.
V Z V I g G a nti b o d y testi n g is re q uire d t o c o nfir m eli g i bilit y i n a d olesce nt s u bjects w h o ha ve n ot recei ve d at least o ne d ose of a varicella vacci ne.
t.
A d oc u me nte d T B test perf or me d wit hi n 1 2 we e ks pri or t o Da y 1 is acce pta ble.   S u bjects wit h a hist or y of t u berc ul osis ma y n ot re q uire T B testi n g as per t he 
pr ot o c ol e xcl usi o n criteria i n Secti o n 4. 2 .  Perf or m T B test pr oce d ure usi n g t he Q ua nti F E R O N-T B G ol d I n T u be Tes t ( or P urifie d Pr otei n Deri vati ve).  A 
ne gati ve P P D test ca n be s u bs tit ute d f or t he Q ua nti F E R O N-T B G ol d I n -T u be test o nl y if t he ce ntral la b orat or y is u na ble t o perf or m t he 
Q ua nti F E R O N -T B G ol d I n -T u be test or ca n n ot deter mi ne t he res ults t o be p ositi ve or ne gati ve a n d t he Pfizer Me dical M o nit or a p pr o ves it o n a 
case-b y -case basis.  I n a d diti o n t o pr ot oc ol re q uire d T B testi n g, sites s h o ul d f oll o w t heir l ocal sta n dar ds f or T B stat us deter mi nati o n, w hic h ma y i ncl u de 
c hest X -r a y.  See Secti o n 7. 3. 4 . 
u.
A P K bl o o d sa m ple will be c ollecte d at 2. 0 h o urs ( 3 0 mi n) p ost d ose of o pe n -la bel st u d y dr u g ( 2 0 0 m g) at t he Wee k 1 2 visit.  F or Earl y Ter mi nati o n ( E T) 
visits, if t he s u bject disc o nti n u es bef ore Wee k 4 , d o n ot c ollect a P K sa m ple.  If t he E T visit occ urs at or after Wee k 4 a n d bef ore Wee k 1 2, c ollect a P K 
sa m ple o nl y if t he s u bject ta kes t he i n vesti gati o nal pr o d uct at t he site visit.
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
v.
S u bjects s h o ul d ta ke t he me dicati o n fr o m st u d y Da ys 1 t o 3 6 5.  S u bjects will be e nc o ura ge d t o ta ke t he me dicati o n i n t he m or ni n g w he ne ver p ossi ble; 
h o we ver, at st u d y visit da ys, s u bjects are t o be i nstr ucte d t o refrai n fr o m d osi n g at h o me a n d are t o ta ke t he d ose i n t he cl i nic.  I nstr uct s u bjects re gar di n g 
pr o per st ora ge c o n diti o ns f or i n vesti gati o nal pr o d uct o n Da y 1. 
w.
S u bjects w h o are n o n res p o n ders b ut c o m plete t he 1 2 wee k r u n- i n treat me nt a n d s u bjects w h o are re p o n ders at E O T will be assesse d f or eli gi bilit y f or 
partici pati o n i n l o n g -ter m e xte nsi o n st u d y B7 4 5 1 0 1 5 as n ote d i n Secti o n 6. 3. 5 . 
x.
Pr urit us N u merical Rati n g Scale ( N R S) will be assesse d usi n g a n e Diar y dail y d uri n g t he scree ni n g peri o d a n d fr o m St u d y Da y 1 t o 1 5.  After Da y 1 5, t he 
Pr uri t us N R S will be c o mplete d o nl y o n st u d y visit da ys i n t he e Diar y.  At t he Scree ni n g v isit, site staff will dis pe nse t he electr o nic ta blet (e P R O de vice ) a n d 
re vie w i nstr ucti o ns f or c o m pleti o n of t he s u bject e Diar y f or t he N R S.  At e ver y visit, t he st u d y c o or di nat or will revie w t he e Diar y f or c o m plete ness a n d 
c o u nsel t he s u bject o n h o w t o co m p lete t he ite ms i n t he dail y e Diar y, if nee de d. 
y.
D L QI will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 1 2 -1 7 years of a ge will c o m plete t he C D L QI i nstea d.
z.
Pr urit us a n d S y m pt o ms Assess me nt f or At o pic Der matitis ( P S A A D) will be c o n d ucte d ( o nl y i n sel ecte d c o u ntries) t o assess t he se verit y a n d fre q ue nc y of 
pr urit us, s y m pt o ms a n d slee p c ollecte d dail y i n a s u bject e -diar y d uri n g t he scree ni n g peri o d a n d fr o m Da y 1 t hr o u g h t he E n d of St u d y  visit ( See 
Secti o n 7. 8. 7 ).  At t he Scree ni n g visit, site staff will dis pe nse t he e P R O de vice a n d re view i nstr ucti o ns f or c o m plet i o n of t he s u bject e Diar y f or t he P S A A D 
q uesti o n naire.  S u bjec ts will be as ke d t o rec or d t heir assess me nt i n t heir e Diar y o nce a day bef ore ta ki n g t he i n vesti gati o nal pr o d uct.  At e ver y visit, t he 
st u d y c o or di nat or will re view t he e Diar y f or c o m plete ness an d c o u nsel t he s u bject o n h o w t o c o m plete t he ite ms i n t he dail y e Diar y, if nee de d.
aa.
T he E ur o Q ol Q ualit y of Life 5 -Di me nsi o n 5 -Le ve l Scale ( E Q -5 D -5 L) will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 1 2 -1 7 y ears of a ge will 
c o m plete t he E ur o Q ol Q ualit y of Life 5 -Di me nsi o n, Y o ut h Scale ( E Q -5 D -Y) i n select c o u ntries.
b b. S F -3 6 v 2 will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 1 2 -1 7 y ears of a ge will n ot c o m plete t his assess me nt.
cc.
F A CI T -F will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 1 2 -1 7 y ears of a ge will c o m plete t he Pe ds -F A CI T -F i nstea d .
d d. Hei g ht is n ot re q uire d at t he baseli ne visit.  O nl y a d olesce nts ( 1 2 t o < 1 8 years o ld) re q uire re peate d hei g ht meas ure me nt at scree ni n g, Wee k 1 2, a n d E O T/ E T 
visits.  A d ults re q uire o ne hei g ht meas ure me nt at t h e scree ni n g visit.
ee.
Assess f or t he e mer ge nce of flare defi ne d as a l oss of at least 5 0 % of t he E A SI res p o nse at Wee k 1 2 a n d a n I G A o f 2 or hi g her.
ff.
T he c o ntrace pti o n c hec k is a n o p p ort u nit y t o c o nfir m t hat c o ntrace pti o n, if assi g ne d, is use d c o nsiste ntl y a n d c orrectl y.  It als o facilitates c o nti n ual 
reassess me nt of c hil d-beari n g p ote ntial i n w o me n.  T his all o ws f or i m ple me nti n g necessa ry c ha n ges t o c o ntrace pti o n; f or e xa m ple, i n vesti gat ors ma y nee d t o 
e ns ure alter nati ve c o ntrace pti ve met h o ds if ne w c o nc o mita nt disease c o ntrai n dicates a selecte d met h o d of c o ntrace pti o n, or if a s u bject is de m o nstra bl y n o 
l o n ger of c hil d-beari n g stat us (a s per pr ot oc ol) t he n t he y will n o l o n ger re q uire c o ntrace pti o n.  C o nti n ual reassess me nt of c o ntrace pti ve nee ds is i m perati ve.
g g. A ser u m sa m ple will be c ollecte d at baseli ne b ut a nal yze d o nl y if t he s u bject has s us pecte d varicella or her pes z oster.  I n t hat e v e nt, t he sa m ple w o ul d be 
a nal yze d f or H S V -1, H S V -2 a n d V Z V.
h h. C hest X -r a y or ot her a p pr o priate dia g n ostic i ma ge (ie, C T or M RI) ma y be perf or me d u p t o 1 2 we e ks pri or t o St u d y Da y 1.  C hest X- r a ys ( p osteri or-a nteri or 
a n d lateral vie ws) are re q uire d f or a d ult s a n d rec o m me n de d f or a d olesce nts as per l ocal g ui deli nes a n d sta n dar d of care.  Official rea di n g m ust be l ocate d a n d 
a vaila ble i n t he s o urce d oc u me ntati o n.
ii.
F oll o w i n g o ne year of t otal e x p os ure t o st u d y dr u g si nce t he last T B test, all s u bjects i n re gi o ns w hic h are a b o ve a l o w -ris k f or T u berc ul osis 
(ie, > 1 0/ 1 0 0, 0 0 0 pre vale nce) will u n der g o t u berc ul osis ( T B) testi n g.  A c hest X -ra y will be perf or me d t o ai d i n T B stat us deter m i nati o n f or all a d ults a n d 
rec o m me n de d f or a d olesce nts acc or di n g t o l ocal g ui deli nes a n d sta n dar d of care i n c o u ntries wit h a hi g h i nci de nce rate of T B. 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
jj.
I n C hi na a n d Tai wa n o nl y : S u bjects w h o are H Bs A g ne gati ve, H Bc A b p ositi ve, a n d H Bs A b p ositi ve at Scre e ni n g will ha ve refle x testi n g f or He patitis B 
Vir us ( H B V ) D N A. S u bjects w h o ha ve H B V D N A a b o ve t he l o w er li mit of q ua ntificati o n ( L L Q) will be e xcl u de d.  S u bjects w h o are H B V D N A ne gati ve 
or bel o w  L L Q ma y e nr oll b ut will ha ve H B V D N A testi n g re peate d at Wee ks
1 2, 2 8, 4 0 , 5 2, a n d earl y ter mi nati o n fr o m st u d y d uri n g a n y treat me nt peri o d. 
A si n gle p ositi ve H B V D N A test res ult a b o ve t he L L Q f or a s u bject re q uires i m me diate a n d per ma ne nt disc o nti n uati o n fr o m treat me nt.  Refer t o 
Secti o n 7. 6. 2. 1 .
k k. A si n gle 1 2 -Lea d E C G will be perf or m e d at scree ni n g a n d at all ot her pla n ne d o n -site visits a n d i nter prete d b y a ce ntral rea der.  Cli nicall y si g nifica nt or 
e xcl usi o nar y E C G fi n di n gs at t he scree ni n g or base li ne visits will re q uire scree n fail ure.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2
S C H E D U L E O F A C TI VI TI E S F O R R E S C U E T R E A T M E N T – F L A R E A T S C H E D U L E D O R U N S C H E D U L E D VI SI T
Visit I de ntifier
D a y 1
Wee k 0
D a y 8
Wee k 1
C all
D a y 1 5
Wee k 2
D a y 2 9
Wee k 4
D a y 4 3
Wee k 6
C all
D a y 5 7
Wee k 8
D a y 8 5
E O T/ E T
Wee k 1 2
E O S, F oll o w -u p
Wee k 1 6/
4 Wee ks p ost E T
Resc ue
Visit 1
Resc ue
Visit 2
Resc ue
Visi t 3
Resc ue
Visit 4
Resc ue
Visit 5
Resc ue
Visit 6
Resc ue
Visit 7
Resc ue
Visit 8
Visit Wi n d o w
3 D a ys
1 D a y
1 D a y
2 D a ys
3 D a ys
3 D a ys
3 D a ys
3 D a ys
E nr oll me nt Pr oc e d ure
R e vie w Pri or/ C o nc o mita nt 
Me dicati o ns & Treat me nts
X
X
X
X
X
X
X
X
Me d ic al Pr oce d ures
Tar gete d P h ysical E xa m a
X
X
X
X
X
C o m plete P h ysical E xa m a
X
Vital Si g ns b
X
X
X
X
X
X
Wei g ht/ Hei g ht
q
X
X
E C G ( 1 2 -lea d)
X
X
X
X
X
X
T u berc ul osis Test r
X
L a b or at or y Assess me nts 
He mat ol o g y c
X
X
X
X
X
X
C oa g ulati o n Pa nel d
X
X
X
X
X
X
Ser u m c he mistr y e
X
X
X
X
X
X
Uri nal ysis f
X
X
X
X
X
X
Li pi d Pa nel h
X
X
X
X
Uri ne Pre g na nc y Test 
(c o n d ucte d at st u d y site)i
X
X
X
X
X
X
H B V D N A testi n g f or C hi na
a n d Tai wa n s
X
Tri al Tre at me nt 
Dr u g Dis pe nsi n g
X
X
X
I n vesti gati o nal Pr o d uct 
Acc o u nta bilit y 
X
X
X
X
X
I n vesti gati o nal Treat me nt 
A d mi nistrati o n j
X ----------------------------------------------------------------------------------------------------------------------X
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3
Visit I de ntifier
D a y 1
Wee k 0
D a y 8
Wee k 1
C all
D a y 1 5
Wee k 2
D a y 2 9
Wee k 4
D a y 4 3
Wee k 6
C all
D a y 5 7
Wee k 8
D a y 8 5
E O T/ E T
Wee k 1 2
E O S, F oll o w -u p
Wee k 1 6/
4 Wee ks p ost E T
Resc ue
Visit 1
Resc ue
Visit 2
Resc ue
Visi t 3
Resc ue
Visit 4
Resc ue
Visit 5
Resc ue
Visit 6
Resc ue
Visit 7
Resc ue
Visit 8
Visit Wi n d o w
3 D a ys
1 D a y
1 D a y
2 D a ys
3 D a ys
3 D a ys
3 D a ys
3 D a ys
Re vie w e Diar y t o assess 
c o m pleti o n
X
X
X
X
X
X
X
X
Assess eli gi bilit y f or 
B 7 4 5 1 0 1 5 k
X
Cli nic al Assess me nt s
I n vesti gat or’s Gl o bal 
Assess me nt (I G A) 
X
X
X
X
X
X
S C O Ri n g At o pic Der m atitis 
( S C O R A D)
X
X
X
X
X
X
Ecze ma Area a n d Se verit y 
I n de x ( E A SI)
X
X
X
X
X
X
T otal B o d y S urface Area ( B S A 
fr o m E A SI) 
X
X
X
X
X
X
P atie nt -re p orte d O utc o me 
Pr urit us N u m erical Rati n g 
Scale -e Diar y ( N R S) l
X-------------------------------------- X
X
X
X
X
Patie nt Gl o bal Assess me nt 
( Pt G A)
X
X
X
X
X
X
Der mat ol o g y Life Q ualit y 
I n de x ( D L QI or C D L QI)m
X
X
X
X
X
X
Patie nt -Orie nte d Ecze ma 
Meas ure ( P O E M)
X
X
X
X
X
X
H os pital A n xiet y a n d 
De pressi o n Scale ( H A D S)
X
X
X
X
X
X
Pr urit us a n d S y m pt o ms 
Assess me nt f or At o pic 
Der matitis - e Diar y ( P S A A D) l
X ----------------------------------------------------------------------------------------------------------------------------------------------X
E Q -5 D -5 L (a d ults) or 
E Q -5 D -Y (a ges 1 2 -1 7 years) n
X
X
X
X
X
X
S F -3 6 v 2, Ac ute o (ad ults)
X
X
X
F A CI T -F (a d ults) or 
Pe ds -F A CI T - Fp (a ges 1 2- 1 7 
years o nl y )
X
X
X


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
Visit I de ntifier
D a y 1
Wee k 0
D a y 8
Wee k 1
C all
D a y 1 5
Wee k 2
D a y 2 9
Wee k 4
D a y 4 3
Wee k 6
C all
D a y 5 7
Wee k 8
D a y 8 5
E O T/ E T
Wee k 1 2
E O S, F oll o w -u p
Wee k 1 6/
4 Wee ks p ost E T
Resc ue
Visit 1
Resc ue
Visit 2
Resc ue
Visi t 3
Resc ue
Visit 4
Resc ue
Visit 5
Resc ue
Visit 6
Resc ue
Visit 7
Resc ue
Visit 8
Visit Wi n d o w
3 D a ys
1 D a y
1 D a y
2 D a ys
3 D a ys
3 D a ys
3 D a ys
3 D a ys
Ast h ma C o ntr ol Q uesti o n naire 
( A C Q) for all s u bjects wit h a 
pri or dia g n osis of ast h ma
X
X
X
S afet y
C -S S R S t
X
X
X
X
Seri o us a n d n o n -seri o us 
a d verse e ve nt m o nit ori n g
X 






X
C o ntrace pti o n C hec k
X
X
X
X
X
X
X
X
a.
C o m plete p h ysical e xa mi na ti o ns m ust be perf or me d b y t he i n vesti gat or, s u b i n vesti gat or or a q ualifie d healt h pr ofessi o nal per l ocal g ui deli nes.  C o m plete p h ysical 
e xa mi nati o ns c o nsist of assess me nts of ge neral a p peara nce; s ki n; hea d, e yes, ears, n ose a n d t hr oat ( H E E N T); m o ut h, heart; l u n gs; breast ( o pti o nal); a b d o me n; e xter nal 
ge nitalia ( o pti o nal); e xtre mities; ne ur ol o gic f u ncti o n; a n d l y m p h n o des.  Tar gete d p h ysical e xa mi nati o ns m ust be perf or me d b y t he i n vesti gat or, s u b -i n vesti gat or or a q ualifie d 
healt h pr ofessi o nal per l ocal g ui deli nes a n d s h o ul d i ncl u de s ki n, heart, l u n gs, a n d a b d o me n a n d e xa mi n ati o n of b o d y s yste ms w here t here are s y m pt o m c o m plai nts b y t he 
s u bject.
b.
Vital Si g ns i ncl u de sitti n g bl o o d press ure, p ulse, res pirat or y rate, a n d te m perat ure meas ure d aft er at least 5 mi n utes of rest.
c.
He mat ol o g y i ncl u des: He m o gl o bi n, he mat ocrit, re d bl o o d cells, w hite bl o o d cells, ne utr o p hils ( %, a bs ol ute), l y m p h oc ytes ( %, a bs ol ute), m o n oc ytes ( %, a bs ol ute), e osi n o p hils 
( %, a bs ol ute), bas o p hils ( %, a bs ol ute), platelets, retic ul oc yte c o u nt, R B C I n dices ( M C H, M C H C, M C V, R B C M or p h ol o g y), l y m p h oc yte s u bsets a n d mar kers ( T otal 
T cells [ C D 3 +], C D 4 + T cells [ C D 3 + C D 4 +], C D 8 + T cells [ C D 3 + C D 8 +], N K cells [ C D 3 -C D 1 6 + C D 5 6 +], B cells [ C D 3 -C D 1 9 +) .
d.
C oa g ulati o n pa nel i ncl u des: Acti vate d P artial T hr o m b o pl asti n Ti me ( A P T T), 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).
e.
Ser u m c he mistr y i ncl u des: bl o o d urea nitr o ge n ( B U N), ser u m creati ni ne, creati ne p h os p h o ki nase, gl uc ose, Ca + +, Na +, K +, Cl -, t otal C O 2, as partate a mi n otra nsferase (A S T), 
ala ni ne a mi n otra nsferase ( A L T), ga m ma-gl uta m yl tra nsferase ( G G T), t otal, i n dire ct a n d direct bilir u bi n, al kali ne p h os p hatase, lactate de h y dr o ge nase, uric aci d, al b u mi n a n d 
t otal pr otei n.
f.
Uri nal ysis i ncl u des: p H, Gl uc ose ( q ualitati ve), Pr otei n ( q ualit ati ve), Bl o o d ( q ualitati ve), Ket o ne s, Nitrites, Le u k oc yte esterase, Micr osc o p y a n d/ or c ult ure (perf or me d as 
a p pr o priate).
 
.
h.
Li pi d Pa nel i ncl u des: t otal c h olester ol, l o w -de n sit y li p o pr otei n (L D L), hi g h - de nsit y li p o pr otei n ( H D L), a n d tri gl yceri des.  A mi ni m u m of 8-h o ur fasti n g is re q uire d f or li pi d 
pr ofile e val uati o n at t he f oll o wi n g Resc ue Vi sits: Da y 1, Week 4, Wee k 1 2 a n d E O S visits.
i.
Uri ne pre g na nc y test m ust be perf or me d a t e ver y site visit pri or t o d osi n g wit h t he i n vesti gati o nal pr o d uct f or fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d o lesce nts 
a ge d 1 2 years a n d ol der re gar dless of w het her t he y ha ve e x perie nce d me narc he.
j.
S u bjects s h o ul d ta ke t he me dicati o n fr o m st u d y Da ys 1 t o 8 5 of t he resc ue treat me nt.  S u bjects will be e nc o ura ge d t o ta ke t he me dicati o n i n t he m or ni n g w he ne ver p ossi ble; 
h o we ver, at st u d y visit da ys, s u bjects are t o be i nstr ucted t o refrai n fr o m d osi n g at h o me a n d are t o ta ke t he d ose i n t he cli ni c.
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
k.
S u bjects w h o c o m plete E O T will be assesse d f or eli gi bilit y f or partici pati o n i n l o n g -ter m e xte nsi o n st u d y B 7 4 5 1 0 1 5 as n ote d i n Secti o n 6. 5. 7 . 
l.
Pr urit us N u merical Rati n g Scal e ( N R S) will be assesse d usi n g a n e Diar y, a n d will be c ollecte d dail y i n t he e Diar y fr o m St u d y D a ys 1- 1 5 d uri n g t he resc ue treat me nt a n d t he n 
o nl y o n st u d y visit da ys at t he i n vesti gati ve site t hereafter.  P S A A D will be c o m plete d dail y (i n selecte d c o u ntri es) i n t he e Diar y fr o m D a y 1 t hr o u g h t he E n d of St u d y ( E O S) 
visit d uri n g resc ue treat me nt.  At e ver y visit, t he st u d y c o or di nat or will re vie w t he e Diar y f or c o m plete ness a n d c o u nsel t he s u bject o n h o w t o c o m plete t he ite ms i n t he dail y 
e Diar y, if nee de d.
m.
D L QI will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 1 2 -1 7 years of a ge will c o m plete t he C D L QI i nstea d .
n.
T he E ur o Q ol Q ualit y of Life 5 -Di me nsi o n 5 -Le vel Scale ( E Q -5 D -5 L) will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 1 2 -1 7 ye ars of a ge will c o m plete t he E ur o Q ol 
Q ualit y of Life 5 - Di me nsi o n, Y o ut h Scale ( E Q-5 D -Y) i n select c o u ntries.
o.
S F - 3 6 v 2 will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 1 2-1 7 years of a ge will n ot c o m p lete t his assess me nt.
p.
F A CI T -F will be c o m plete d b y a d ult s u bjects o nl y .  A d olesce nts 1 2-1 7 years of a ge will c o m plete t he Pe ds- F A CI T -F i nstea d.
q.
C ollect wei g ht f or all s u bjects a n d hei g ht f or a d olesce nts o nl y ( 1 2 t o < 1 8 years ol d).
r.
F oll o wi n g o ne year of t ot al e x p os ure t o st u d y dr u g si nce t he last T B test, all s u bjects i n re g io ns w hic h are a b o ve a l o w -ris k f or T u berc ul osis (ie, > 1 0/ 1 0 0, 0 0 0 pre vale nce) will 
u n der g o t u berc ul osis ( T B) testi n g.  A c hest X-ra y will be perf or me d t o ai d i n T B stat us deter mi nati o n f o r all a d ults, a n d rec o m me n de d f or a d olesce nts acc or di n g t o l ocal 
g ui d eli nes a n d sta n dar d of care i n c o u ntries wit h a hi g h i nci de nce rate of T B. 
s.
I n C hi na a n d Tai wa n o nl y : F or s u bjects w h o ha d H B V D N A testi n g at Scree ni n g , H B V D N A testi n g is re peate d at Resc ue Wee k 1 2 or at a n earl y ter mi nati o n visit . A si n gle
p ositi ve H B V D N A test res ult a b o ve t he L L Q f or a s u bject re q uires i m me diate a n d per ma ne nt disc o nti n uati o n fr o m trea t me nt.  Refer t o Secti o n 7. 6. 2. 1 .
t.
P ost -scree ni n g, if t here are “ yes” a ns wers o n ite ms 4, 5 or o n a n y be ha vi oral q uesti o n of t he Si nce Last Visit C -S S R S a ris k assess me nt b y a q ualifie d me ntal healt h 
pr ofessi o nal ( M H P) s h o ul d be d o ne t o deter mi ne w het her it is sa fe f or t he s u bject t o c o nti n ue t o partici pate i n t he trial.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
1. I N T R O D U C TI O N
1. 1. Mec h a nis m o f Acti o n/I n dic ati o n
P F - 0 4 9 6 5 8 4 2 is a Ja n us ki nase 1 (J A K 1) i n hi bit or t hat is bei n g i n vesti gate d as a treat me nt f or 
patie nts wit h At o pic Der matitis ( A D). 
T he Ja n us ki nase (J A K) fa mil y, i ncl u din g J A K 1, J A K 2, J A K 3 a n d t y r osi ne ki nase 2 ( T Y K 2), 
is a gr o u p of c yt o plas mic t y r osi ne ki nases t hat me diate si g nal tra ns d ucti o n via i nteracti o ns 
wit h T y pe 1 a n d T y pe 2 c y t o ki ne rece pt ors critical f or le u k oc yte acti vati o n, pr oliferati o n, 
s ur vi val a n d f u ncti o n.  C yt o ki ne rece pt ors de m o nstrate restricte d ass ociati o n wit h J AK s s uc h 
t hat differe nt rece pt ors or rece pt or classes prefere ntiall y utilize a gi ve n J A K di mer or tri mer 
c o m bi nati o n t o tra ns d uce t heir si g nal.  J A K 1 pairs wit h J A K 3 t o me d iate -c o m m o n c yt o ki ne 
si g nali n g a n d als o wit h J A K 2 or T Y K 2 t o tra ns mit t he si g nals of a d diti o nal c yt o ki nes 
i m p orta nt i n i nfla m mati o n a n d i m m u ne res p o nses i ncl u di n g i nterle u ki n (I L) - 4, - 5, - 6, - 1 3,
- 2 1, - 3 1, i nterfer o n ga m ma (I F N-), a n d i nterfer o n al p ha (I F N-).  J A K 2 h o m o di mers are 
critical f or t he si g nali n g of he mat o p oietic c y t o ki nes an d h or m o nes i ncl u di n g er y t hr o p oieti n 
( E P O), t hr o m b o p oieti n ( T P O), I L-3, gra n ul oc y te-macr o p ha ge c ol o n y- sti m ulati n g fact or 
( G M-C S F) a n d pr olacti n. 
K e y c yt o ki nes i m plicated i n t he pat h o p h ys i olo g y of A D i ncl u de I L- 4, I L- 5, I L- 1 3, I L- 3 1,
a n d I F N -, re q uire J A K1 f or si g nal tra ns d ucti o n; t his s u g gests t hat selecti ve J A K 1 i n hi bit ors 
t hat m o d ulate t he acti vit y of t hese c yt o ki nes re prese nt a c o m pelli n g a p pr oac h t o t he 
treat me nt of i nfla m mat or y s ki n diseases s uc h as A D.7
I L-1 2 a n d I L - 2 3 are de pe n de nt o n T Y K 2 a n d J A K 2 f or tra ns mitti n g t heir si g nals.  F oll o wi n g 
c yt o ki ne acti vatio n, rece pt or -ass ociate d J A Ks are p h os p h or y late d a n d i n t ur n p h os p h or ylate 
s pecific sites o n t he rece pt or i ntracell ular d o mai n.  P h os p h or ylati o n of s pecific sites o n t he 
i ntracell ular d o mai n of t he rece pt or all o ws f or t he recr uit me nt of si g nal tra ns d ucers an d 
acti vat ors of tra nscri pti o n ( S T A Ts) t hat ca n s u bse q ue ntl y  be p h os p h or y late d b y  J A Ks.  
P h os p h or y late d S T A T m olec ules are release d fr o m t he rece pt or, tra nsl ocate t o t he n ucle us 
w here t he y  bi n d t o s pecific sites o n t he de o x yri b o n ucleic aci d ( D N A) a n d re g ulate ge ne 
tra nscri pti o n. 
P F -0 4 9 6 5 8 4 2 is a n orall y bi oa vaila ble s mall m olec ule that selecti vel y i n hi bits J A K 1 b y  
bl oc ki n g t he A T P bi n di n g site.  P F- 0 4 9 6 5 8 4 2 has a hi g h de gree of selecti vit y  i n vitr o a gai nst 
ot her ki nases: 2 8 -f ol d selecti vit y o ver J A K 2, > 3 4 0-f ol d o ver J A K 3 a n d 4 3-f ol d o ver T Y K 2, 
as well as a g o o d selecti vit y pr ofile o v er t he br oa der ra n ge of h u ma n ki nases. T he selecti ve 
i n hi biti o n of J A K1 will lea d t o m o d ulati o n of m ulti ple c yt o ki ne pat h wa ys i n v ol ve d i n t he 
pat h o p h y si ol o g y of A D, i ncl u di n g I L-4, I L-5, I L -1 3, I L -3 1 a n d I F N -.  Data fr o m a P hase 2 b 
pr o of of c o nce pt ( P O C) st u d y ( B 7 4 5 1 0 0 6) t hat e val uate d s u bjects wit h m o derate t o se vere 
A D ha v e s h o w n p ositi ve efficac y, as well as a n acce pta ble safety pr ofile, s ufficie nt t o s u p p ort 
f urt her cli nical de vel o p me nt i n a lar ger P hase 3 pr o gra m.  St u d y B 7 4 5 1 0 1 4 will i n vesti gate 
t he ti me t o l oss of res p o nse t o P F-0 4 9 6 5 8 4 2 i n s u bjects wit h m o derate t o s evere A D 
f oll o wi n g a cli nical res p o nse t o o pe n-la bel i n d ucti o n treat me nt wit h P F-0 4 9 6 5 8 4 2.  S u bjects 
w h o e x perie nce a l oss of res p o nse de n ote d as flare ( per pr ot oc ol def i niti o n) will recei ve 
resc ue treat me nt wit h P F-0 4 9 6 5 8 4 2 i n c o m bi nati o n wit h t o pical t he ra p y per sta n dar d of care.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
1. 2. B ac k gr o u n d a n d R ati o n ale
1. 2. 1. Dr u g De vel o p me nt a n d R ati o n ale
P F - 0 4 9 6 5 8 4 2 is bei n g devel o pe d as a n oral treat me nt f or patie nts wit h m o derate t o se ve re 
A D base d o n i ts mec ha nis m of acti o n, a n d t he cli nical res ults o btai ne d i n P hase 1 a n d
P hase 2 st u dies.  T he cli nical de vel o p me nt pr o gra m f or P F -0 4 9 6 5 8 4 2 i ncl u des healt h y  
v ol u nteers, s u bjects wit h ps oriasis a n d s u bjects wit h A D. 
A d diti o nal i nf or mati o n f or t his c o m p o u n d ma y  be f o u n d i n t he si n gle refere nce safety 
d oc u me nt ( S R S D), w hic h f or t his st u d y is t he I n vesti gat or’s Br oc h ure (I B). 
1. 2. 2. At o pic Der m atitis
At o pic der matitis, als o k n o w n as at o pic ecze ma, is a c o m m o n, c hr o nic, i nfla m mat or y s ki n 
dis or der c har acterize d b y flak y  s ki n lesi o ns, i nte nse pr urit us, a n d a ge neral deteri orati o n i n 
q uali ty of life.  O ver t he past 5 0 ye ars, A D has bec o me m ore pre vale nt, e s pecially i n 
i n d ustrialize d, te m perate c o u ntries s uc h as t he U S.1 ,2  A D is o ne of t he m ost c o m m o n,
c hr o nic, rela psi n g c hil d h o o d der mat oses, i m pacti n g 1 5 -3 0 % of all c hil dre n i n t he U S a n d 
ma n y  ha ve disease t hat persists i nt o a d ult h o o d wit h a lifeti me pre vale nce of t h o se affecte d 
be y o n d c hil d h o o d re p orte d t o be 3 4 %.8  Earlier re p orts i n dicate d t hat, i n u p t o 7 0 % of cases, 
t he disease greatly i m pr o ves or res ol ves b y l ate c hil d h o o d, h o we ver m ore rece nt fi n di n gs 
s u g gest t hat disease acti vit y remai ns ma nifest f or a pr ol o n ge d peri o d of ti me.  Base d o n a 
t otal of 7 1 5 7 patie nts e nr olle d i n t he Pe diatric Ecze ma Electi ve Re gistr y  ( P E E R) st u d y, 
c o m prisi n g a t otal of 2 2, 5 5 0 pers o n -ye ars, it was c o ncl u de d t hat s y m pt o ms ass ociate d wit h 
A D see m t o persist well i nt o t he sec o n d deca de of life a n d li kel y  l o n ger.3  At e ver y  a ge, m ore 
t ha n 8 0 % of P E E R st u d y s u bjects ha d sy m pt o ms of A D a n d/ or were usi n g me dicati o n t o treat 
t heir A D.  5 9 % of 8 3 3 A D patie nts w h o were a ge d 2 0 ye ars or ol der w he n t he y visite d t he 
cli nic a n d were 4 5 ye ars or older w he n t he y  c o m plete d a f oll o w u p q uesti o n naire, re p orte d 
t hat t he y ha d persiste nt A D at s o me ti me d uri n g t he last 1 2 m o nt hs. 9  
T he maj o rit y of st u dies c o n d ucte d acr oss m ulti ple a ge gr o u ps s u g gest a c o nti n ued decrease i n 
pre vale nce wit h ol der a ge. 1 0  A d ult- o nset A D d oes als o occ ur, t h o u g h it is less c o m m o n.  T he 
pre vale nce of A D i n a d ults is esti mate d t o be 1 0%. 1 1  Rece n t st u dies ha ve i n dicate d t hat 
a d ults wit h A D are m ore li kel y  t o s m o ke ci garettes, dri n k alc o h ol, a n d ha ve a se de ntar y 
lifest yle, p ote ntially ass ociate d wit h i ncrease d c o m or bi dities, s uc h as ast h ma a n d 
car di o vasc ular disease. 1 2
Alt h o u g h great stri des ha ve bee n ma de i n u n dersta n di n g t he ca uses, t he c o m ple x 
pat h o p h y si ol o g y of A D is still n ot c o m pletel y u n derst o o d.  It has bee n esta blis he d t hat t he 
pat h o p h y si ol o g y of A D i ncl u des a defecti ve s ki n barrier f u ncti o n, aller gic res p o nses, 
defecti ve a nti micr o bial i m m u ne defe nse, a n d a ge netic pre dis p ositi o n.  T he pre d o mi na nt 
s ym pt o m of A D, pr urit us a n d t he res ulti n g scratc hi n g, t y picall y s ets off a n a m plificati o n 
c ycle of at o pic s ki n i nfla m mati o n.  Acti vati o n of T l ym p h oc y tes, de n dritic cells, 
macr o p ha ges , kerati n oc ytes, mast cells, a n d e osi n o p hils res ults i n a release of n u mer o us 
pr o -i nfla m mat or y c yt o ki nes a n d c he m o ki nes.  T his a m plificatio n c y cle s ustai ns t he 
i nfla m mat or y res p o nses c haracteristic of t he A D lesi o ns.1 3


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
Ac ute A D lesi o ns ha ve bee n ass ociate d wit h t he T y p e 2 hel per T cell ( T H 2) p he n ot ype, 
s h o wi n g d o mi na nce of I L- 4, - 5, -1 3, a n d - 3 1 secreti o n.1 3 ,1 4 ,7  Rece nt researc h s h o we d t hat a 
s mall i ncrease of T ype 1 hel per T cell ( T H 1)-ass ociate d ge nes has bee n als o detecte d i n ac ute 
p hase. 1 5
W hile I L - 4-pr o d uci n g T H 2 cells ma y  dri ve t he de vel o p me nt of at o pic s ki n lesi o ns, c hr o nic 
lesi o ns s h o w eit her t he c oe xiste nce of b ot h I L- 4-pr o d uci n g T H 2 a n d I F N--pr o d uci n g T H 1 
cells or T H 1 d o mi na nce. 1 3  T his c oe xiste nce of T H 2 a n d T H 1 res p o nses or T H 1 d o mi na nce 
is m ore li kel y t o be t he u n derl yi n g i m m u n o pat h ol o g y i n a d ult patie nts w h o ha ve ha d A D 
c hr o nicall y or i nter mitte ntl y  si nce c hil d h o o d.  Rece nt e vi de nce als o s u p p orts I L-3 1’s r ol e i n 
pr urit us a n d i nfla m mati o n i n A D. 1 4 ,7  
N o n - me dicate d t o pical t hera pies i ncl u de e m ollie nts.  Me dicate d t o pical t hera pies f or 
m o derate t o se vere A D i ncl u de T C S (e g, beta met has o ne, cl o betas ol, fl uoci n o ni de), T CI 
(e g, pi mecr oli m us, tacr oli m us), a n d c oal tar pre parati o ns.  T C S are li mite d i n ter ms of t he 
treat me nt d urati o n (e g, c ortic oster oi d use is li mite d t o 2 t o 4 wee ks) a n d t he b o d y re gi o n of 
treat me nt, d ue t o c o nsiste nt s ki n t o xicities, as well as ha vi n g ris ks ass ociate d wit h t heir br oa d 
i m m u n os u p pressi ve acti o ns. T CI  ha ve a li mite d r ole as a sec o n d li ne treat me nt, d ue t o t heir 
li mitati o ns i n ter ms of t he d urati o n of treat me nt a n d t he b o d y re gi o n of treat me nt, i n hi biti o n 
of t u m or s ur veilla nce i n t he s ki n, a n d safet y c o ncer ns wit h mali g na ncies.  Crisa b or ole was 
a p pro ve d as a me dicate d t o pical treat me nt i n Dece m ber 2 0 1 6 b y  t he F D A f or use i n patie nts 
wit h mil d t o m o derate A D.   A d diti o nal treat me nts ge nerall y reser ve d f or se vere A D i ncl u de 
p h ot ot her a p y (e g, ultra vi olet A li g ht [ U V A] wit h or wit h o ut ps orale n, ultra vi olet B li g ht 
[ U V B] narr o w ba n d or br oa d ba n d) a n d sys te mic a ge nts (e g, c ortic oster oi ds, c ycl os p ori ne, 
rec o m bi na nt I F N-, myc o p he n olate m ofetil, met h otre xate [ M T X], azat hi o pri ne, i ntra ve n o us 
i m m u n o gl o b uli n).4  Of t he curre ntl y  a vaila ble t hera pies, n o ne offers a c ure; t heref ore, t he 
mai n ai ms of e xisti n g treat me nts are t o re d uce t he occ urre nce of ac ute flares , t o i ncrease t he 
ti me betwee n rela pses, r e d uce pr urit us a n d t he res ulti n g slee p dist ur ba nce. 5 ,6
T here are a li mite d n u m ber of a p pr o ve d s ys te mic treat me nts f or m o derate t o se vere A D, a n d 
i n t he U S A, t he o nl y a p pr o ve d s ys te mic dr u gs are c ortic oster oi ds a n d d u pil u ma b.
D u pil u ma b, an i njecta ble h u m a n m o n ocl o nal a nti b o d y tar geti n g i nterle u ki n (I L) -4 a n d - 1 3,
was a p pr o ve d b y t he F D A i n Marc h 2 0 1 7 a n d recei ve d mar keti n g a ut h orizati o n i n E ur o pe i n 
Se pte m ber 2 0 1 7, f o r t he treat me nt of m o derate t o se vere A D. Treat me nt wit h s y ste mic 
c ortic oster oi ds has k n o w n a n d well d oc u me nte d a d verse effects. Treat me nt wit h d u pil u ma b 
has t he ris k of i njecti o n site reacti o ns, aller gic reacti o ns, e y e a n d e yeli d i nfla m mati o ns an d 
c ol d s ores.  A n ot her li mitati o n of d u pil u ma b is t he p ossi bilit y f or de vel o p ment of a nti dr u g 
a nti b o dies, w hic h ma y res ult i n l oss of efficac y o ver ti me a n d t he de vel o p me nt of safety 
c o ncer ns s uc h as ser u m sic k ness -li ke reacti o ns. F urt her m ore, d u pil u ma b is deli vere d via 
s u bc uta ne o us i njecti o n, w hic h ma y n ot be a met h o d of a d mi nistrati o n t olerate d well by all 
patie nts. 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
D uri n g a 1 -ye ar, ra n d o mize d, d o u ble -bli n de d st u d y  wit h d u pil u ma b, i n t he d u pil u ma b 
3 0 0 m g e ver y  2 wee ks ( mar kete d mai nte na nce d ose ) pl us TC S gr o u p , t he esti mate d 
differe nce fr o m place b o of t he I G A res p o nse rate a n d E A SI- 7 5 res p o nse rate were 2 6 % a n d 
4 6 %, res pecti vel y .  T he place b o res p o nse rate f or I G A a n d E A SI-7 5 was 1 2 % a n d 2 3 %, 
res pecti vely.  T he de vel o p me nt of p ote ntial treat me nt s wit h furt her i m pr o ve me nts t o efficac y  
re mai ns desira ble.
I n E ur o pe, c ycl os p ori ne is ap pr o ve d f or use i n patie nts wit h se vere A D w he n s y ste mic 
t hera py is re q uire d.  C ycl os p ori ne use is ass ociate d wit h se veral u n desira ble si de effects a n d 
d ue t o its narr o w t hera p e utic i nde x, occasi o nal t hera pe utic dr u g m o nit ori n g is rec o m me n de d.  
K n o w n a d ve rse effects i ncl u de i nfecti o ns, re nal t o xicit y, he pat ot o xicit y, s ki n mali g na ncies, 
l ym p h o ma a n d ot her mali g na ncies.
T he pre d o mi na nt u n met me dical nee d t he n is f or a n ora l t hera py wit h a n acce pta ble safet y  
pr ofile, f or l o n g-ter m use, w hic h is effecti ve f or m o derate t o se vere A D. Patie nts wit h 
m o derate t o se vere A D re q uire ot her s ys te mic treat me nt o pti o ns be yo n d t h ose w hic h are 
c urre ntl y a p pr o ve d.
C urre ntl y  a vaila ble t herapies f or t he treat me nt of A D ha ve m ulti ple li mitati o ns.  T he 
me dicate d t o pical t hera pie s ha ve dra w bac ks relate d t o t he d urati o n of use d ue t o t he p ote ntial 
f or l ocal a n d sys te mic si de effects (e g, c ortic oster oi d use is li mite d t o 2 t o 4 wee ks) a n d t o 
t he bo d y  re gio ns of u se (e g, mi d-hi g h p ote nc y  c ortic oster oi ds are n ot a p pr o ve d f or use o n t he
face a n d/ or i ntertri gi n o us areas).  F or A D patie nts n ot res p o n di n g t o me dicate d t o pical 
t hera pies a n d p h ot ot hera p y, o n- a n d off -la bel use of s yste mic a ge nts, w hic h i ncl u de oral 
c orticoster oi ds or oral i m m u n os u p pressa nts, re mai n t he last via ble treat me nt o pti o n.  
S y ste mic t hera p y o pti o ns are ass ociate d wit h p ote ntiall y se vere a d verse effects a n d re q uire 
caref ul m o nit ori n g.  T he ris k of t o xicit y a n d si de effects re mai n a c o ncer n w he n s ys te mic 
a ge nts are use d.  F or t hese reas o ns t he use of t hese a ge nts is li m ite d t o s h ort c o urses or 
i nter mitte nt t hera p y. 
P F - 0 4 9 6 5 8 4 2 is a n oral ta blet, a m ore c o n ve nie nt r o ute of a d mi nistrati o n c o m pare d wit h 
s u bc uta ne o us i njecti o n re q uire d for d u pil u ma b a n d s o it d oes n ot ha ve t he p ote ntial ris k of 
i njecti o n site reacti o ns. T h e l o n ger half -life of d u pil u ma b als o mea ns t hat it ma y ta ke a 
relati vely l o n g peri o d of ti me f or s o me u n desira ble p har mac o d y n a mic effects 
(e g, treat me nt-relate d a d verse e ve nt [ A E]) t o s u bsi de after its disc o nti n uati o n.  I n t his res pect, 
t he be nefit of a sh orter half- life wit h a ge nts s uc h as P F-0 4 9 6 5 8 4 2 is t hat a n A E ma y  
p ote ntiall y  res ol ve m ore ra pi dl y t ha n is t he case wit h d u pil u ma b.  U nli ke d u pil u ma b, 
P F - 0 4 9 6 5 8 4 2 is a s mall m olec ule an d t here is n o a ntici pate d i m m u n o ge nicit y  f or 
P F -0 4 9 6 5 8 4 2, a n d s o it is u nli kel y  t o ge nerate a nti dr u g a nti b o dies.  
As me nti o ne d a b o ve, a variet y of pr o -i nfla m mat or y c yt o ki nes s uc h as I L-4, I L -1 3, I L - 2 2, 
I L-3 1 a n d I F N -, ha ve bee n s u g geste d t o ha ve a r ole i n t he pat h o ge nesis of A D.  Ma ny of 
t hese pat h o ge nic c yt o ki nes use t he JA K 1 f or si g nali n g.  T heref ore, J A K 1 is a n attracti ve 
t hera pe utic tar get f or A D as a n i n n o vati ve oral t hera pe utic a ge nt.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
1. 2. 3. N o n - Cli nic al a n d P h ase 1 D at a 
Data fr o m n o ncli n ical a n d P hase 1 pr o gra ms s u p p orts t he pla n ne d cli nical trials wit h 
P F -0 4 9 6 5 8 4 2 a n d f ur ther i nf or mati o n is i n t he c urre nt versi o n of t he I n vesti gat or’s Br oc h ure 
(I B).
1. 2. 4. P h ase 2 b i n A D ( B 7 4 5 1 0 0 6) 
B 7 4 5 1 0 0 6 was a P hase 2 b pr o of - of-c o nce pt trial i n a d u lts (a ges 1 8 -7 5) wit h m o d erate t o 
se vere A D i n vesti gati n g d oses of 1 0, 3 0, 1 0 0, a n d 2 0 0 m g P F - 0 4 96 5 8 4 2 or place b o ta ke n 
o nce dail y ( Q D) f or u p t o 1 2 wee ks.  T he pri mar y  e n d p oi nt i n t his st u d y was t he pr o p orti o n 
of s u bjects ac hie vi n g a n I G A sc ore of clear ( 0), or al m ost clear ( 1), a n d a 2- p oi nt 
i m pr o ve me nt fr o m baseli ne at Wee k 1 2.  T he baseli ne was d efi ne d as t he I G A sc ore o n 
D a y 1 pre -d ose. 
At Wee k 1 2, I G A res p o nse rates of P F -0 4 9 6 5 8 4 2 1 0 0 m g a n d 2 0 0 m g  d ose gr o u ps were 
si g nifica ntly greater t ha n place b o i n patients wit h m o derat e t o se vere A D.  T he I G A res p o nse 
rates of t he 2 0 0 m g  a n d 1 0 0 m g gr o u ps were 4 4. 5 % a n d 2 7. 8 %, res pecti vel y.  T he I G A 
res p o nse rate i n t he place b o gr o u p was 6. 3 % a n d t he esti mate d differe nces fr o m place b o i n 
t he 2 0 0 m g a n d 1 0 0 m g  gro u ps were 3 8. 2 % ( P = 0. 0 0 3 2 ) a n d 2 1. 5 % ( P = 0. 0 1 8 4), res pecti vel y.  
T he perce nt c ha n ge fr o m baseli ne ( % C ha n ge fr o m baseli ne ( C F B)) i n E A SI  sc ores at 
Wee k
1 2 were si g nifica ntl y  hi g her f or b ot h t he 2 0 0 m g a n d 1 0 0 m g  gr o u ps c o m pare d t o 
place b o.  T he esti mate d pe rce nt c han ge fr o m baseli n e i n E A SI sc ore was -3 5. 2 % i n t he 
place b o gr o u p, -8 2. 5 7 % i n t he 2 0 0 m g g r o u p a n d -5 9. 0 4 % i n t he 1 0 0 m g gr o u p.  At 
Wee k
1 2, t he pr o p orti o n of s u bjects ac hie vi n g E A SI -7 5 res p o nse was 1 5. 6 % i n t he place b o 
gr o u p, 6 3. 7 % i n t he 2 0 0 m g gr o u p a n d 4 1. 6 % i n t he 1 0 0 m g gr o u p.  T he differe nce fr o m 
place b o was 4 1. 8 % ( P = < 0. 0 0 0 1) f or t he 2 0 0 m g  gr o u p a n d 2 6. 0 % ( P = 0. 0 0 4 3) i n t he 1 0 0 m g 
gr o u p.  At Da y 1 5, t he pr o p orti o n of res p o nse base d o n ac hie vi n g at least 4 p oi nts 
i m pr o ve me nt i n t he se verit y of Pr urit us N u merical Rati n g Scale ( N R S) fr o m baseli ne 
( Pr urit us N R S 4) of P F -0 4 9 6 5 8 4 2 1 0 0 m g a n d 2 0 0 m g d ose gr o u ps was greater t ha n place b o.  
T he esti mate d pr o p orti o n of Pr urit us N R S 4 res p o nses at Da y 1 5 were 6 9. 8 %, 4 1. 1 % a n d 
1 5. 7 % f or 2 0 0 m g , 1 0 0 m g a n d p lace b o gro u ps, res pecti ve l y.
P F -0 4 9 6 5 8 4 2 de m o nstrate d a ra pi d o nset of acti o n.  I n t he 2 0 0 m g g ro u p, I G A a n d E A SI 
sc ores i m pr o ve d u ntil W ee k 4 a n d W ee k 6, res pecti vel y , a n d mai ntai ne d t heir effect t hr o u g h 
1 2 wee ks of treat me nt.  Res p o nse rates at Wee k
1 2 f or t he 1 0 m g  a n d 3 0 m g g r o u ps were n ot 
si g nifica ntly differe nt fr o m place b o.  A ke y differe ntiati n g feat ure f or t his J A K 1 i n hi bit or 
was ra pi d res ol uti o n of itc h ass ociate d wit h A D.  Si g nifica nt se parati o n fr o m place b o was 
ac hie ve d f or t he Pr urit us N R S sc ore as ear l y as 2 d a y s after i nitiati o n of treat me nt f or t he 
2 0 0 m g d ose gr o u p.
O verall, t he res u lts de m o nstrate d d ose-de pe n de nt i ncreases i n res p o nses at Wee k 1 2 f or ke y  
efficac y e n d p oi nts (I G A, E A SI a n d pr urit us N R S sc ore).


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1
P F - 0 4 9 6 5 8 4 2 a p peare d generall y safe a n d well t olerate d i n t his st u d y .  O verall, a d verse 
e ve nts ( A Es) a n d seri o us a d verse e ve nts ( S A Es) were n u merically hi g her i n s u bjects 
recei vi n g P F-0 4 9 6 5 8 4 2 c o m pare d t o place b o, b ut di d n ot a p pear t o i ncrease wit h d ose.  T he 
m ost c o m m o n A Es we re i n t he i nfectio ns a n d i nfestat i o ns, s ki n a n d s u bc uta ne o us tiss ue 
dis or ders a n d gastr oi ntesti nal dis or d ers s ys te m or ga n class, a n d t he maj orit y of t he A Es were 
mil d.  T here were 2 cases of her pes z oster, o ne i n t he 1 0 m g gr o u p ( n ot treat me nt relate d), 
a nd o ne i n t he 3 0 m g gr o u p (treat me nt relate d).  T here were d ose -de pe n de nt decreases i n 
platelet c o u nts o b ser ve d i n t he st u d y, w hic h platea ue d at Wee k 4.  F urt her details of t he 
cli nical P hase 2 de vel o p me nt pr o gra m ca n be f o u n d i n t he I B.
1. 3. S u m m ar y of P F - 0 4 9 6 58 4 2 Cli nic al P h ar m ac o ki netics 
P F -0 4 9 6 5 8 4 2 was ra pi dl y  a bs or be d f oll o wi n g si n gle d ose oral s ol uti o n/s us pensi o n 
a d mi nistrati o n o ver t he d ose ra n ge 3 m g  t o 2 0 0 m g  wit h ti me t o ma xi m u m a bs or pti o n ( Tma x ) 
ra n gi n g bet wee n 0. 5 5 t o 0. 7 7 h o urs ( B 7 4 5 1 0 0 1).  Me dia n Tma x at d oses of 4 0 0 m g a n d 
8 0 0 m g were 1. 5 a n d 3. 9 h o urs, res pecti vel y , w hic h i n dicate d t he sl o wer a bs orp ti o n 
c o m pare d t o l o wer d oses.  P F - 0 4 9 6 5 8 4 2 s h o we d a m o n o p hasic decli ne at d ose < 1 0 0 m g  wit h 
bi p hasic pr ofiles at d oses 1 0 0 m g.  O bser ve d pea k plas ma P F- 0 4 9 6 5 8 4 2 c o nce n trati o ns 
( Cma x ) f oll o wi n g t he si n gle-d ose a d mi nistrati o n ge nerall y i ncrease d i n pr o p ort io n t o t he d ose 
fr o m 3 m g t o 8 0 0 m g .  I n c o ntrast, b ot h area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m 
ti me zer o e xtra p olate d t o i nfi nit y ( A U Ci nf) a n d area u n der t h e plas ma c o nce nt rati o n ti me 
pr ofile fr o m ti me zer o t o t he last q ua ntifia ble c o nce ntrati o n ( A U C last) were d ose pr o p orti o nal 
i n t he ra n ge of 3 m g  t o 2 0 0 m g, w hile a greater t ha n pr o p orti o nal i ncrease was o bser ve d at 
d oses of 4 0 0 a n d 8 0 0 m g. T he arit h metic m ea n ter mi nal p hase half-life (t½ ) was 1. 9 t o 
4. 9 h o urs.
F oll o wi n g o nce dail y ( Q D) a d mi n istrati o n o ver t he d ose ra n ge 3 0 m g  t o 4 0 0 m g a n d 1 0 0 m g  
a n d 2 0 0 m g t wice a da y ( BI D) f or 1 0 d a y s, me dia n Tma x ra n ge d bet wee n 0. 5 0 t o 0. 7 7 h o urs 
( B 7 4 5 1 00 1).  After attai n me nt of C ma x , the dis p ositi o n of P F -0 4 9 6 5 8 4 2 was c o nsiste nt wit h 
t hat o bser ve d f oll o win g si n gle - d ose a d mi nistrati o n, s h o wi n g a bi p hasic decli ne f oll o wi n g all 
b ut t he l o west d ose a n d a n arit h metic mea n ter mi nal p hase t ½ bet wee n 2. 8 t o 5. 0 h o urs.  
Alt h o u g h C ma x ge nerall y  increase d i n pr o p orti o n t o t he d ose u p t o 1 0 0 m g gi ve n t wice dail y 
( BI D), it i ncrease d m ore t ha n t he d ose i ncrease d at 4 0 0 m g Q D a n d 2 0 0 m g BI D.  T he sa me 
tre n d was als o o bser ve d f or area u n der t he plas ma c o nce ntrati o n-ti me c ur ve ( A U C ta u) o ver 
t he d osi n g i nter val (ta u = 1 2 or 2 4 h o urs).  T he o bser ve d acc u m ulati o n rati o ( R ac) fo ll o wi n g 
2 0 0 m g BI D was 2. 0 a n d 2. 5 f or A U C ta u a n d C ma x , res pecti vely.  R ac was 1. 1 t o 1. 5 at ot her 
d oses.  T heref ore, t he res ults s h o we d t hat dr u g c o nc e ntrati o n acc u m ul ati o n is mi ni mal after 
re peate d oral a d mi nistrati o n at l o wer d oses c o nsiste nt wit h t he p re dicti o n fr o m t½ .  Uri nar y 
rec o ver y of P F-0 4 9 6 5 8 4 2 was l o w, wit h < 5 % of t he d ose rec o vere d u nc ha n ge d i n uri ne 
acr oss all d oses a n d re gi me ns i n all c o h orts.
At a si n gle 8 0 0 m g d ose, t h e ge o metric mea n perce nt c oefficie nt of variati o n ( % C V) C ma x
( n g/ m L) was si milar i n Wester n ( n = 5; 3 8 1 9 ( 2 6)) a n d Ja pa nese s u bjects ( n = 1 0; 3 6 6 0 ( 4 8)).  
H o we ver, ge o metric mea n A U C i nf ( n g * hr/ m L) was 2 6 % hi g her i n Wester n s u bjects ( n = 5; 
2 7 5 4 0 ( 3 5)) t ha n t hat o bser ve d i n Ja pa nese s u bjects ( n = 9; 2 1 8 6 0 ( 4 3)) ( B 7 4 5 1 0 0 1).  
Ge o metric m ea n ( % C V) C ma x a n d A U C ta u f oll o wi n g m ulti ple-d ose a d mi nistrati o n of 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
2 0 0 m g BI D were 1 7 % a n d 5 6 % hi g her, res pecti vel y , i n t he Wester n s u bjects ( n = 5) t han i n 
Ja pa nese s u bjects ( n = 6). 
C o -a d mi nistrati o n of 4 0 0 m g ( 4 x 1 0 0 m g) of t he ta blet wit h f o o d res ulte d i n e q ui vale nt 
ge o metric mea n A U C i nf bet wee n faste d a n d fe d c o n diti o ns a n d a s mall mea n decrease 
( < 5 %) i n Cma x .  T he ma g nit u de of decrease i n Cma x was n ot c o nsi dere d t o be cli nicall y  
i mp orta nt.  O verall, P F - 0 4 9 6 5 8 4 2 ca n be a d mi nistere d wit h or wit h o ut f o o d.
Plas ma pr ofili n g fr o m t he [ 1 4C] P F -0 4 9 6 5 8 4 2 h u ma n mass bala nce st u d y  ( B 7 4 5 1 0 0 8) 
i n dicate d pare nt as t he m ost pre vale nt circ ulati ng s pecies ( 2 6 %), wit h 3 maj or a n d m ore p olar 
m o n o -h y dr o x y late d meta b olites i de ntifie d: P F - 0 6 4 71 6 5 8 ( 3 -h y dr o x y pr o p yl , 1 1 %), 
P F - 07 0 5 5 0 8 7 ( 2 -h y dr o x y pr o p y l, 1 2 %), a n d P F-0 7 0 5 4 8 7 4 ( p y rr oli di n o ne p yri mi di ne, 1 4 %).
1. 4. P o p ul ati o n P h ar m ac o ki netics
P o p ulati o n p har mac o ki netic ( P K) a nal ysis was c o n d ucte d b y p o oli n g data fr o m t w o P hase 1 
st u dies ( B 7 4 5 1 0 0 1, first-i n-h u ma n st u d y , a n d B 7 4 5 1 0 0 4, relati ve bi oa vaila bilit y st u d y) i n 
healt h y  s u bjects a n d t he pr o of- of-c o nce pt st u d y ( B 7 4 5 1 0 0 6) i n A D patie nts.  Baseli ne b o d y
wei g ht, race, a ge a n d se x were teste d as c o vari ates o n cleara nce a n d di d n ot a p pear t o i m pact 
t he P K of P F- 0 4 9 6 5 8 4 2. 
1. 5. S u m m ar y of Be nef its a n d Ris ks
T here was cli nicall y mea ni n gf ul be nefit de m o nstrate d i n t he P hase 2 b Pr o of of C o nce pt st u d y  
i n a d ult patie nts wit h m o derate t o se vere A D.  T he p ote ntial ris ks of treat me nt i ncl u de t h ose 
t hat were n ote d i n P hase 2 b a n d/ or t h ose base d o n t he p h ar mac ol o g y of J A K i n hi bit ors a n d 
i ncl u de viral reacti vati o n, seri o us a n d o p p ort u nistic i nfecti o ns, he mat o p oietic effects
(i ncl u di n g re d uce d platelet c o u nt), a n d mali g nan c y  a n d i m m u n o proliferati ve dis or ders. 
F urt her i nf or mati o n is a vaila ble i n t he I n vesti g at or’s Br oc h ure (I B).  A p pr o priate ris k 
e val uati o n a n d miti gati o n strate gies ha ve bee n i nc or p orate d i nt o t his pr ot oc ol.
O verall, t here is a fa v ora ble be nefit -ris k pr ofile t o s u p p ort t he c o nti n ue d de vel o p me nt i nt o 
P hase 3 of P F -0 4 9 6 5 8 4 2 i n t he treat me nt of patie nts, 1 2 years of a ge a n d ol der, wit h A D f or 
b ot h t he 1 0 0 m g a n d 2 0 0 m g d ose.
1. 6. D ose Selecti o n R ati o n ale
D ose selecti o n f or P hase 3 was base d o n efficac y  a n d safet y of P F - 0 4 9 6 5 8 4 2 fro m a 
d ose -ra n gi n g P hase 2 b st u d y , B 7 4 5 1 0 0 6 t hat e val uate d a 2 0-f ol d d ose ra n ge ( 1 0 m g t o 
2 0 0 m g Q D) i n a d ult s u bjects wit h A D.  T he 2 0 0 m g Q D d ose as a m o n ot hera p y  is e x pecte d 
t o pr o vi de efficac y si milar t o t hat of c urre ntl y a p pr o ve d s yste mic treat me nts (eg c y cl os p ori ne, 
s yste mic c ortic oster oi ds a n d d u pil u ma b) i n m o derate t o se vere A D, base d o n d ose-res p o nse 
m o deli n g of I G A res p o nse i n t he P hase 2 st u d y , a n d was t heref ore selecte d as t he hi g h dose 
f or e val uati o n i n P hase 3 st u dies.  A d diti o n all y, a d ose of 1 0 0 m g Q D was als o selecte d f or 
P hase 3 e val uati o n. T he 1 0 0 m g d ose is e x pecte d t o differe ntiate fr o m t he hi g her d ose i n 
ter ms of e x pecte d efficac y, safety a n d s ys te mic e x p os ure.  B ot h 1 0 0 m g a n d 2 0 0 m g Q D 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3
d oses de m o nstrate d acce pta ble saf et y a n d t olera bi lit y i n t he P hase 2 st u d y .  F urt her details 
are a vaila ble i n t he I B. 
Si nce b o d y  wei g ht di d n ot a p pear t o be a si g nifica nt deter mi na nt of P K acr oss t he wei g ht 
ra n ge e val uate d i n t he P hase 2 b st u d y, a d olesce nts a ge d 1 2 ye ars a n d ol der wei g hin g 4 0 k g or 
m ore will be a d mi nistere d t he sa me d ose as t he a d ults (ie, 1 0 0 m g Q D a n d 2 0 0 m g Q D.)  
(See Secti o n 1. 3 P o p ulati o n P har mac o ki netics) .  T he P K efficac y  a n d safet y data c ollecte d i n 
a dolesce nts wil l be m o n it ore d peri o dicall y b y a n e xter nal data m o nit ori n g c o m mittee 
( E-D M C ) t o e ns ure acce pta ble be nefit ris k f or t his patie nt p o p ulati o n.
 
 
 
 
 
2. S T U D Y O B J E C TI V E S A N D E N D P OI N T S
St u d y  o bjecti ves a n d c orres p o n di n g e n d p oi nts are pr o vi de d i n Ta ble 1. 
T a ble 1.
O bjecti ves a n d E n d p oi nts
Pri m ar y O bjecti ve:
Pri m ar y E n d p oi nt:

T o e val uate a n d c o m pare 
t he mai nte na nce of effect of 
t wo d oses of P F -0 4 9 6 5 8 4 2 
( 2 0 0 m g a n d 1 0 0 m g o nce
dail y ( Q D)) a n d place b o i n 
s u bjects a ge d 1 2 a n d a b o ve 
wit h m o derate t o se vere 
at o pic der matitis w h o 
res p o n d t o i nitial o pe n-la bel 
r u n-i n treat me nt of 2 0 0 m g 
P F -0 4 9 6 5 8 4 2 Q D.
1.
L oss of res p o nse re q uiri n g resc ue treat me nt will be e val uate d a n d 
c o m pare d a mo n g gr o u ps d uri n g t he bli n de d treat me nt peri o d.  L oss 
of res p o nse is de n ote d as flare a n d is defi ne d as a l oss of at least 
5 0 % of t he Ecze ma Area a n d Se verit y I n de x ( E A SI) re s p o nse at 
Wee k
1 2 a n d a n I n vesti gat or’s Gl o bal Assess me nt (I G A) sc ore of 
2 o r hi g her.
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4
S ec o n d ar y O bjecti ves:
Sec o n d ar y E n d p oi nts:

T o e val uate a n d c o m pare 
t he effect of P F-0 4 9 6 5 8 4 2 
o n a d diti o nal efficac y 
e n d p oi nts a n d 
patie nt -re p orte d o utc o mes 
o ver ti me i n s u bjects a ge d 
1 2 years a n d ol der w it h 
m o derate t o se vere at o pic 
der matitis;

T o assess the efficac y of 
o pe n la bel resc ue treat me nt 
c o nsisti n g of 2 0 0 m g 
P F -0 4 9 6 5 8 4 2 i n 
c o m bi nati o n wit h t o pical 
t hera p y per sta n dar d of care 
i n cases of flare ( per 
pr ot oc ol def i niti o n). 
K e y Sec o n d ar y E n d p oi nt
1.
L oss of res p o nse base d o n a n I G A sc ore of 2 or hi g her.
Cli nic al Effic ac y Assess me nts:
1.
Res p o nse base d o n t he I G A (sc ore of 0 or 1 a n d a re d ucti o n of 
≥2 p oi nts ) at all sc he d ule d ti me p oi nts. 
2.
Res p o nse base d o n E A SI t otal sc o re ( E A SI-5 0, E A SI -7 5, E A SI -9 0, 
a n d E A SI -1 0 0) at all sc he d ule d ti me p oi nts.
3.
Res p o nse bas ed o n ac hie vi n g ≥4 p oi nt i m pr o ve me nt i n t he se verit y 
of pr urit us N u merical Rati n g Scale ( N R S) fr o m baseli ne at all 
sc he d ule d ti me p oi nts.
4.
Perce nt c ha n ge fr o m baseli ne i n perce nt B o d y  S urface Area ( B S A) at 
all sc he d ule d ti me p oi nts.
5.
Perce nt c ha n ge fr o m baseli ne i n S C O Ri n g At o pic Der matitis 
( S C O R A D) s u bjecti ve assess me nts of itc h a n d slee p l oss at all 
sc he d ule d ti me p oi nts. 
6.
Res p o nse base d o n ac hie vi n g a 5 0 % a n d 7 5 % i mpr o ve me nt i n 
S C O R A D ( S C O R A D -5 0, S C O R A D -7 5) fr o m baseli ne a t all 
sc he d ule d ti me p oi nts.
Cli n ic al Effic ac y Assess me nts i n S u bjects Re q uiri n g Resc ue 
Tre at m e nt:
1.
Res p o nse base d o n t he I G A at t he e n d of resc ue t hera p y. 
2.
Res p o nse ba se d o n t he E A SI t otal sc ore at t he e n d of resc ue t hera p y. 
3.
Res p o nse base d o n ac hie vi n g ≥4 p oi nt i m pr o ve me nt i n t he se verit y 
of pr urit us N u merical Rati n g Scale ( N R S) at t he e n d of resc ue 
t hera p y relati ve t o t he start of resc ue t hera p y baseli ne val ue .
4.
Perce nt c ha n ge i n perce nt B o d y S urface Area ( B S A) at t he e n d of 
resc ue t hera p y relati ve t o t he start of resc ue t hera p y baseli ne val ue .
5.
Perce nt c ha n ge i n S C O R A D s u bjecti ve assess me nts of itc h a n d slee p 
l oss at t he e n d of resc ue t hera p y relati ve t o t he start of resc ue t hera p y
baseli ne val ue .
6.
Res p o nse base d o n ac hie vi n g a 5 0 % a n d 7 5 % i mpr o ve me nt i n 
S C O R A D ( S C O R A D -5 0, S C O R A D -7 5) at t he e n d of resc ue t hera p y 
relati ve t o t he start of resc ue t hera p y baseli ne val ue .
P atie nt -Re p orte d O u tc o mes i n All Su bjects :
1.
Res p o nse base d o n ac hie vi n g Pt G A sc ore of clear ( 0) or al m ost clear 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5
(1); a n d a re d ucti o n fr o m baseli ne of ≥2 p oi nts at all sc he d ule d ti me 
p oi nts ( a mo n g s u bjects wit h a sc ore ≥2 at baseli ne) .
2.
C ha n ge fr o m ba seli ne i n Der mat ol o g y Life Q ualit y I n de x ( D L QI) or 
C hil dre n’s D L QI ( C D L QI) at all sc he d ule d ti me p oi nts. 
3.
C ha n ge fr o m ba seli ne i n H os pital A n xiet y De pressi o n Scale 
( H A D S) at all sc he d ule d ti me p oi nts.
4.
C ha n ge fr o m baseli ne i n Patie nt Orie nte d Ecze m a Meas ure ( P O E M) 
at all sc he d ule d ti me p oi nts.
5.
C ha n ge fr o m baseli ne i n t he Pr urit us a n d S y m pt o ms Assess me nt i n 
At o pic Der matitis ( P S A A D) at all sc he d ule d ti me p oi nts.
S afet y O bjecti ve:
S afet y E n d p oi nts:

T o assess t he safet y a n d 
t olera bilit y of P F-0 4 9 6 5 8 4 2 
d uri n g o pe n la bel a n d 
d o u ble bli n d treat me nt i n 
s u bjects a ged 1 2 a n d o ver 
w it h m o derate t o se vere 
A D.

I nci de nce of treat me nt em er ge nt a d verse e ve nts.

I nci de nce of Seri o us A d verse E ve nts ( S A E)s a n d A d verse E ve nts 
( A E)s lea di n g t o disc o nti n uati o n.

T he i nci de nce of cli nical a b n or malities a n d c ha n ge fr o m baseli ne i n 
cli nical la b orat or y val ues, electr ocar di o gra m ( E C G) meas ure me nts, 
a nd vital si g ns.
P h ar m ac o ki netic O bjecti ve:
P h ar m ac o ki netic E n d p oi nt :

T o e val uate t he P K of 
P F -0 4 9 6 5 8 4 2 a n d its 
meta b olites i n s u bjects a ge d 
1 2 years a n d ol der w it h 
m o derate t o se vere at o pic
der matitis f ol l o wi n g 
1 2 we e ks of m ai nte n a nce
treat me nt.
1.
P o p ulati o n P K c haracterizati o n i n s u bjects a ge d 1 2 years ol d a n d 
a b o ve wit h m o derate t o se vere at o pic der matitis.
 
 
 
 
 
 
  
 
A D = At o p ic der matitis; A E = A d verse E ve nt; B S A = B o d y S urface Area; C D L QI = C hil dre n’s Der mat ol o g y 
Life Q ualit y I n de x; D L QI = D er m at ol o g y Life Q ualit y I n de x; E A SI = Ecze ma Area a n d Se verit y I n de x; 
E C G = Electr ocar di o gra m; H A D S = H os pital A n xiet y a n d De pressi o n Sca le; I G A = I n vesti gat or’s Gl o bal 
Assess me nt ; N R S = pr urit us n u merical rati n g scale; P K = p har m ac o ki netics; S C O R A D = Sc ori n g At o pic 
Der m atitis; P O E M = Patie nt -Orie nte d Ecze ma Meas ure ; Pt G A = Patie nt Gl o bal Assess me nt; P S A A D
= Pr urit us a n d S y m pt o ms Assess me nt f or At o pic Der matitis; Q D = O nce Dail y; S A E = Seri o us A d verse 
E ve nt.
C CI
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6
3. S T U D Y D E SI G N
T his is a ra n d o mize d, res p o n der-e nric he d, d o u ble- bli n d, place b o -c o ntr olle d, P hase 3 
wit h dra wal tria l t o e val uate the efficac y  a n d safet y of P F-0 4 9 6 5 8 4 2 m o n o t hera py i n s u bje cts 
a ge d 1 2 ye ars a n d ol der wit h c hr o nic m o derate t o se vere A D as defi ne d per t he i ncl usi o n 
criteria a n d a b o d y wei g ht 4 0 k g.  A d olesce nt s u bjects bel o w t he le gal a ge of maj orit y  (legal 
a d ult h o o d) i n t he s u bject’s c o u ntr y ca n be e nr oll i n t his st u d y if i nstr ucte d b y t he s p o ns or a n d 
a p pr o ve d b y t he c o u ntr y ’s re g ulat or y/ healt h a ut h orit y.  If t hese a p pr o vals ha ve n ot bee n 
gra nte d, o nl y s u bjects t he le gal a ge of maj ority (le gal a d ult h o o d) i n t he s u bje ct’s c o u ntr y
are all o we d t o e nr oll.  F or s u bjects y o u n ger tha n t his, t heir le gall y acce pta ble 
re prese ntati ve/pare nt(s) or le gal g uar dia n pr o vi de writte n c o nse nt a n d mi n or c hil dre n pr o vi de 
asse nt, acc or di n g t o l ocal re g ulati o ns a n d r ules re ga r di n g a bilit y to gi ve asse nt a n d c o nse nt.   
After pr o vi di n g i nf or me d c o nse n t, s u bjects are assesse d f or st u dy eli gi bilit y at t he scree ni n g 
visit.  D uri n g t he scree ni n g peri o d, treat me nts f or A D are was he d - o ut, as a p plica ble, 
acc or di n g t o eli gi bilit y re q uireme nts.  A baseli ne ( Da y 1) visit is t o occ ur wit hi n 2 8 da y s 
after the scr e e ni n g visit. 
S u bjects ma y  be re-scree ne d o nce if t he y fail t he scree ni n g e val uati o ns f or reas o ns relate d t o 
i nci de ntal tra nsit or y c o n diti o ns.  S u bjects f or w h o m scree n fail ure is relate d t o faili n g t he 
dis ease se verit y (i ncl u di n g e xte nt of disease) i ncl usi o n criteri o n a n d w h o s u bse q ue ntl y 
e x perie nce w orse ni n g A D, w hic h i n t he i n vesti gat or’s j u d ge me nt w o ul d ma ke t he m eli gi ble 
f or partici pati o n, ma y be c o nsi dere d f or re-scree ni n g.  S uc h cases s h o ul d be disc usse d wit h 
t he Pfizer Me dical M o nit or y ( or desi g nee) t o deter mi ne if re-scree ni n g is a p pr o priate.
T he trial c o nsists of a n o pe n -la bel r u n-i n peri o d t o deter mi ne res p o n der stat us t o a n i nitial 
i n d ucti o n treat me nt wit h 2 0 0 m g P F-0 4 9 6 5 8 4 2 Q D, a ra n d o mize d, plac e b o-c o ntr olle d,
d o u ble -bli n de d P F -0 4 9 6 5 8 4 2 mai nte n a nce treat me nt peri o d, a n d a 4 wee k u ntreate d 
f oll o w-u p safet y peri o d.  S u bjects w h o meet t he pr ot oc ol defi niti o n of flare d uri n g bli n de d 
treat me nt e nter a n o pe n-la bel resc ue treat me nt peri o d.  A st u d y desig n sc he matic is prese nte d 
i n Fi g ure 1 . 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7
Fi g ure 1 .
St u d y Desi g n Sc he m atic
E nr olle d s u bjects i nitiate t he 1 2 -wee k, o pe n -la bel r u n-i n peri o d t o i de ntif y res p o n ders w h o 
ha ve a p os iti ve cli nical res p o nse t o i n d ucti o n treat me nt wi t h 2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D.  
Res p o n der criteri a are defi ne d as a) ac hie vi n g a n I G A of clear ( 0) or al m ost clear ( 1) ( o n a 
5 - p oi nt scale), b) a re d ucti o n fr o m I G A baseli ne of 2 p oi nts, a n d c) reac hi n g a n E A SI - 7 5 
res p o nse c o m pare d t o baseli ne.  Baseli ne is defi ne d as t he I G A sc ore a n d E A SI sc ore 
o btai ne d pri or t o d osi n g o n Da y  1.  S u bjects meeti n g all res p o n der criteria ma y be eli gi ble f or 
ra n d o mizati o n.  S u bjects w h o d o n ot reac h t he res p o nse t hres h ol d re q uire d f or ra n d o mizati o n 
are declare d n o n-res p o nders after c o m pleti o n of t he o pe n la bel r u n- i n peri o d. 
N o n -res p o n ders are n ot eli gi ble f or ra n d o mizati o n i n t his st u d y b ut ma y ch o ose t o e nr oll i nt o 
t he P F-0 4 9 6 5 8 4 2 L o n g Ter m E xte nsi o n ( L T E) st u d y  B 7 4 5 1 0 1 5 pr o vi din g t he y  re mai n 
eli gi ble; ot her wise, t he y are per mane ntl y disc o nti n ue d fr o m treat me nt a n d e nter t he 4 -wee k 
u ntreate d f oll o w -u p peri o d i n t his st u d y .
Res p o n ders at t he e n d o f t he 1 2-wee k o pe n -la bel r u n-i n peri o d e nter t he 4 0 wee k, 
d o u ble - bli n d, mai nte na nce treat me nt peri o d i n w hic h t he y are ra n d o mize d i nt o 1 of 
3 treat me nt ar ms i n a 1: 1: 1 rati o: 
1.
1 0 0 m g P F -0 4 9 6 5 8 4 2 Q D;
2.
2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D; 
3.
Place b o.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8
All s u bjects w h o ha ve s tarte d was h-o ut of A D treat me nt i n t he scree ni n g peri o d will be 
all o we d t o e nter t he r u n-i n a n d treat me nt peri o ds pr o vi di n g all i ncl usio n criteria a n d n o ne of 
t he e xcl usi o n criteria are met. Ra n d o mizati o n is stratifie d b y a ge cate g or y, ie , < 1 8 years a n d 
1 8 ye ars.  Eli gi ble s u bjects m ust ha ve a d oc u me nte d hist or y  of i na de q uate res p o nse wit h 
t o pical A D me dicati o ns or ha ve re q uire d s yste mic t hera pies f or c o ntr ol of t heir disease. 
Me dicate d t o pical a n d/ or s y ste mic sta n dar d of care t hera pies are n ot all o we d d uri n g t he 
o pe n -la bel r u n-i n a n d bli n de d treat me nt peri o ds. 
Me dicate d t o pical t hera p y is defi ne d as a 
t o pical pr o d uct t hat c o ntai ns a n acti ve p har mace utical i n gre die nt i n dicate d f or t he treat me nt 
of A D (irres pecti ve of w het her it is a n o ver -t he-c o u nter [ O T C ] or prescri pti o n o nl y pr o d uct).
F oll o wi n g c o m pleti o n of t he 4 0 -wee ks of bli n de d tre at me nt, all s u bjects are assesse d f or 
eli gibilit y  to e nter t he P F -0 4 9 6 5 8 4 2 L T E st u d y  B 7 4 5 1 0 1 5.  If a s u bject disc o nti n ues 
pre mat urel y or is n ot eli gi ble/ willi n g t o partici p ate i n B 7 4 5 1 0 1 5, t he n t he s u bject e nters t he 
4 - wee k u ntreate d f oll o w-u p peri o d.
D uri n g t he bli n de d treat me nt peri o d, s u bjects m eeti n g the pr ot oc ol defi niti o n of fl are e nter 
a n o pe n-la bel resc ue peri o d d uri n g w hic h t he y recei ve a n ot her 1 2-wee k c o urse of 2 0 0 m g  
P F - 0 4 9 6 5 8 4 2 Q D wit h t o pical t hera py per l ocal sta n dar d of care ( S O C).  I n t his s t u d y, flare 
re q uiri n g resc ue treat me nt is defi ne d as a l oss of at least 5 0 % of t he E A SI res p o nse at 
Wee k
1 2 a n d a n I G A sc ore of 2 or hi g her.  F or e xa m ple, if a s u bject h as a t otal E A SI sc ore of 
4 0 at baseli ne a n d a sc ore of 1 0 at Wee k 1 2 (ac hie vi n g E A SI - 7 5 t o be a res p o n der at 
ra n d o mizati o n), t he EA SI res p o nse is - 3 0.  T o meet t he defi niti o n of flare, t he t otal E A SI  
sc ore f or t his s u bject w o ul d ha ve t o g o u p by at least 15 ( 5 0 % of -3 0) fr o m Wee k 1 2, w hic h 
c o m p utes t o a t otal E A SI sc ore of at least 2 5, t his i n a d diti o n t o a n IG A sc ore of 2. 
After c o m pleti n g t he 1 2 -wee k resc ue peri o d, s u bjects ma y  e nter t he L T E st u d y B 7 4 5 1 0 1 5, if 
eli gi ble.  S u bjects disc o nti n ui n g earl y fr om treat me nt, or w h o are ot her wise i neli gi ble f or t he 
L T E st u d y e nter a 4 wee k f oll o w - u p peri o d i n B 7 4 5 1 0 1 4.
A n i n vesti gat or ca n te m p orari ly i nterr u pt d osi n g f or u p t o a ma xi m u m of 2 8 c o nsec uti ve da ys 
f or a s u bject, f or safety reas o ns or w hile m o nit ori n g a b n or mal la b orat or y  tests if t he 
i n vesti gat or j u d ges t hat t his is necessar y. T he i n vesti gat or s h o ul d use t heir j u d ge me nt wit h 
re gard t o u n sc he d ule d visits/la b orat or y/cli nical assess me nts re q uire d t o m o nit or t he s u bject 
d uri n g t his ti me- fra me. If wit hi n t his ti mefra me t he i n vesti gat or j u d ges t hat it is safe t o 
restart d osi n g, t he n t he s u bject m a y  restart i n vesti gati o nal pr o d uct. If the i n ve sti gat or j u d ges 
t hat it is n ot safe t o restart d osi n g wit hi n t his ti mefra me t he n t he s u bject m ust be per ma ne ntly 
disc o n ti n ue d fr o m treat me nt, ha ve a n E n d of Treat me nt visit a n d e nter t he 4-wee k f oll o w - u p 
pe ri o d.  D oses n ot ta ke n f or t he reas o ns me nti o ne d ab o ve d o n ot c o nstit ute pr ot oc ol 
de viati o ns or me dicati o n err ors a n d s h o ul d n ot be c o nsi dere d d osi n g err ors, b ut s h o ul d be 
n ote d i n t he d osi n g l o g wit h t he reas o n f or re d uce d dr u g c o ns u m pti o n clearl y  descri be d.
La b orat or y  tests are perf or me d t hr o u g h out t his st u d y as detaile d i n t he Sc he d ule of Acti vities
a n d i n vesti gat ors will f oll o w t he i n str ucti o ns f or m ore fre q ue nt m o nit ori n g i n A p pe n di x 4 if 
t he s pecifie d la b orat or y val ues reac h t he liste d th res h ol ds.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9
T he t otal st u d y  d urati o n if a s u bject d oes n ot flare is 5 2 wee ks ( 1 2 wee ks o pe n -la bel 
treat me nt + 4 0 wee ks bli n de d treat me nt).  T he ma xi m u m st u d y  d urati o n is u p t o 6 4 wee ks.  
T his w o ul d o nl y  be achie ve d if a s u bject flare d o n t he last da y  of t he mai nte na nce treat me nt 
peri o d ( 5 2 wee ks + 1 2 wee ks resc ue) .  If s u bjects d o n ot i nte n d t o e nr oll i n t he L T E st u d y, t he 
a b o ve d urati o ns are e xte n de d b y  + 4 wee ks of a n u ntreate d f oll o w -u p peri o d.  A t otal of 
a ppr o xi matel y  1 3 7 0 s u bjects will be e nr olle d fr o m a pp r o xi matel y 2 1 8 sites l ocate d gl o ball y. 
4. S U B J E C T E LI GI BI LI T Y C RI T E RI A
T his st u d y  ca n f ulfill its o bjecti ves o nl y if a p pr o priate s u bjects are e nr olle d.  T he f oll o wi n g 
eli gi bilit y criteria are desi g ne d t o select s u bjects f or w h o m partici pati o n i n t he st u d y is
c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n m e dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n deci di n g w het her a partic ular s u bject is s uita ble f or t his pr ot oc ol. 
S u bject eli gi bilit y  s ho ul d be re vie we d a n d d oc u me nte d b y  a n a p pr opriate m e m ber of t he 
i n vesti gat or’s st u dy tea m (t hat is lice nse d t o practice me dici ne i n t he state/ pr o vi nce or 
c o u ntr y w here t he st u d y is bei n g c o n d ucte d or by a n ot her healt hcare practiti o ner as per mitte d 
b y  l ocal la w) bef ore s u bjects are i ncl u de d i n t he st u d y.  Initial s u bject eli gi bilit y  m ust be 
c o nfir me d a n d d oc u me nte d pri or t o s u bjects recei vi n g a d ose of i n vesti gati o nal pr o d uct (I P). 
4. 1. I ncl usi o n Criteri a
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteri a t o be eli gi ble f or e nr oll me nt i nt o t he 
stu d y :
1.
E v ide nce of a pers o nall y  si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n dicati n g t hat 
t he s u bject, or his/ her le gall y acce pta ble re prese ntati ve/pare nt(s) or le gal g uar dia n if a 
mi n or, ha ve bee n i nf or me d of all perti ne nt as pects of t he st u d y . 
2.
Male or fe male s u b jects of 1 2 ye ars of a ge or ol der, at t he ti me of i nf or me d c o nse nt 
a n d b o d y wei g ht 4 0 k g.  A d olesce nt s u bjects bel o w t he le gal a ge of maj orit y  (le gal 
a d ult h o o d) i n t he s u bject’s c o u ntr y  will o nl y be e nr olle d i n t his st u d y if i nstr ucte d b y 
t he s p o ns or a n d a p pr o ve d b y t he c o u ntr y’s re g ulat or y/ healt h a ut h orit y. If t hese 
a p pr o vals ha ve n ot bee n gra nte d, o nl y s u bjects t he le gal a ge of maj ority (le gal 
a d ult h o o d) i n t he s u bject’s c o u ntr y  will be e nr olle d.
3.
Meet
all t he f oll o wi n g at o pic der matitis criter ia:

Cli n ical dia g n osis of c hr o nic at o pic der matitis (als o k n o w n as at o pic ecze ma) f or 
at least 1 ye ar pri or t o Da y 1 a n d has c o nfir me d at o pic der matitis at t he scree ni n g 
a n d baseli ne visits acc or di n g t o Ha nifi n a n d Raj ka criteria of A D 4 3 (see 
A p pe n di x 2 ).

D oc u me nte d rece nt hist or y  ( wit hi n 6 m o nt hs bef ore t he scree ni n g v isit) of 
i na de q uate res p o nse t o treat me nt wit h me dicate d to pical t hera p y f or A D f or at 
least 4 wee ks, or w h o ha ve re q uire d s y ste mic t hera pies f or c o ntr ol of t heir 
disease.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0
N O T E: Me dicate d t o pical t hera p y is defi ne d as a t o pical pr o d uct t hat c o ntai ns a n 
acti ve p har mace utical i n gre die nt i n dicate d f or t he treat me nt of A D (irres pecti ve of 
w het her it is a n o ve r-t he-c ou nter [ O T C] or prescri pti o n o nl y pr o d uct).

M o derate t o se vere A D (affecte d B S A 1 0 %, I G A 3, E A SI  1 6 a n d pr urit us 
N R S se verit y  4 o n t he da y  of t he baseli ne visit).
4.
Willi n g a n d a ble t o c o m pl y  wit h sc he d ule d visits, treat me nt pla n, la b orat or y tests a n d 
ot h er st u d y pr oce d ures.
5.
Fe male s u bjects w h o are of c hil d- beari n g p ote ntial ( w hic h i ncl u des a d olesce nts a ge d 
1 2 ye ars a n d ol der re gar dless of w het her t h e y  ha ve e x perie nce d me narc he) m ust n ot 
be i nte n di n g t o be c o me pre g na nt, c urre ntl y pre g na nt, or lacta ti n g.  T he f oll o wi n g 
c o n diti o ns a p pl y:
a.
Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a c o nfir me d ne gati ve 
pre g na nc y  test pri or t o treat me nt wit h i n vesti gati o nal pr o d uct;
b.
Fe male s u bjects of c hil d beari n g p ote n tial m ust a gree t o use a hi g hly effecti ve 
m et h o d of c o ntrace pti o n (as per Secti o n 4. 4. 1 ) f or t he d urati o n of t he acti ve 
treat me nt peri o d a n d f or at least 2 8 d a y s after t he last d ose of i n vesti gati o nal 
pr o d uct.
N O T E: Se x ual a bsti ne nce, d efi ne d as c o m pletely a n d persiste ntl y refrai ni n g fr o m all 
heter ose x ual i nterc o urse (i ncl u di n g d uri n g t he e ntire peri o d of ris k ass ociate d wit h 
st u d y treat me nts) ma y o b viate t he nee d f or c o ntrace pti o n O N L Y if t his is t he 
preferre d a n d us ual lifest y le of t he s u bject. 
6.
Fe male s u bjects of n o n -c hil d beari n g p ote ntial m ust meet at least 1 of t he f oll o wi n g 
criteria: 

Ha ve u n der g o ne a d oc u me nte d h y sterect o m y a n d/ or bilateral o o p h orect o m y;

Ha ve me dicall y  c o nfir me d o varia n fail ure; or

Ac hie ve d p ost me n o pa usal stat us, d efi ne d as f oll o ws: cessati o n of re g ular me nses 
f or at least 1 2 c o nsec uti ve m o nt hs wit h n o alter nati ve pat h ol o gical or 
p h y si ol o gical ca use a n d ha ve a ser u m f ollicle-sti m ulati n g h or m o ne ( F S H) le vel 
c o nfir mi n g t he p ost me n o pa usal state.
All ot her fe male s u bjec ts (i nclu di n g fe male s u bjects wit h t u bal li gati o ns) are 
c o nsi dere d t o be of c hil d beari n g p ote ntial.
7.
M ust a gree t o a v oi d pr ol o n ge d e x p os ure t o t he s u n a n d n ot t o use ta n ni n g b o ot hs, s u n 
la m ps or ot her ultra vi olet li g ht s o urces d uri n g t he st u d y.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1
4. 2. E xcl usi o n Cr iteri a
S u bjects wit h a n y of t he f oll o wi n g c haracteristics/c o n diti o ns will n ot be i ncl u de d i n t he 
st u d y:
1.
Ot her ac ute or c hr o nic me dical or ps yc hi atric c o n diti o n i ncl u di n g rece nt ( wit hi n t he 
past y ear) or acti ve s ui ci dal i deati o n or be ha vi or or la b orat or y  a bn or mali ty t hat ma y 
i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or i n vesti gati o nal pr o d uct 
a d mi nistrati o n or ma y i nterfere wit h t he i nter pretati o n of st u d y res ults a n d, i n t he 
j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he s u bject i na p pr o priate f or e ntr y in t o t his 
st u d y.
2.
A n y  psyc hiatric c o n diti o n i ncl u di n g rece nt or acti ve s uici dal i deat i o n or be ha vi or t hat 
meets a n y of t he f oll o wi n g criteria: 

S uici dal i deati o n ass ociate d wit h act ual i nte nt a n d a met h o d or pla n i n t he past 
ye ar: “ Yes” a ns wers o n items 4 or 5 of t he C ol u m bia s uici de se verit y rati n g scale 
( C-S S R S) ( A p pe n di x 1 5 );

Pre vi o us hist or y  of s uici dal be ha vi ors i n t he past 5 years: “ Yes” a ns wer (f or 
e ve nts t hat occ urre d i n t he past 5 years) t o a n y of the s uic idal be ha vi or ite ms of 
t he C-S S R S;

A n y  lifeti me hist or y of seri o us or rec urre nt s uici dal be ha vi or;

S uici dal be ha vi ors q uesti o n naire – re vise d ( S B Q-R) t otal sc ore 8 ( A p pe n di x 1 7 );

Cli nicall y  si g nifica nt de pressi o n: patie nt health q uesti o n naire – 8 ite ms ( P H Q -8) 
t otal sc ore 1 5 ( A p pe n di x 1 8 );

T he prese nce of a n y c urre nt maj or ps yc hiatric dis or der t hat is n ot e x plicitl y 
per mitte d i n t he i ncl usi o n/e xcl usi o n criteria;

I n t he o pi ni o n of t he i n vesti gat or or P fizer ( or desi g nee) e xcl usi o n is re q uire d.
3.
A c urre nt or past me dical hist or y  of c o n diti o ns ass ociate d wit h t hr o m b oc yt o pe nia, 
c oa g ul o pat h y or platelet d ysf u ncti o n.
4.
Recei vi n g a nti -c oa g ula nts or me dicati o ns kn o w n t o ca use t hr o m b oc y t o pe nia ( u nless 
c o nsi dere d safe t o st o p a n d was h o ut f o r t he d urati o n of t he st u d y).
5.
C urre ntl y  ha ve acti ve f or ms of ot her i nfla m mat or y s ki n diseases, ie, n ot A D or ha ve 
e vi de nce of s ki n c o n diti o ns (e g, ps oriasis, se b orr heic der matitis , L u p us) at t he ti me of 
D a y 1 t hat w o ul d i nterfere wit h e val uati o n of at o pic der matitis or res p o nse t o 
treat me nt.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
6.
Vacci nate d or e x p ose d t o a li ve or atte n uate d vacci ne wit hi n t he 6 wee ks pri or t o t he 
first d ose of i n vesti gati o nal pr o d uct, or is e x pecte d t o be vacci nate d or t o ha ve 
h o use h ol d e x p os ure t o t h ese vacci nes d uri n g treat ment or d uri n g t he 6 wee ks 
f oll o wi n g disc o nti n uati o n of i n vesti gati o nal pr o d uct.
7.
A d olesce nt s u bjects 1 2 t o < 1 8 ye ars ol d wit h o ut d oc u me nte d e vi de nce of ha vi n g 
recei ve d at least o ne d ose of t he varicel la vacci ne i n c o u ntries w here t he vacci ne is 
a p pr o ve d a n d sta n dar d of care or t h ose w h o d o n ot ha ve e vi de nce of pri or e x p os ure t o 
varicella z oster vir us ( V Z V) base d o n ser ol o gical testi n g (ie, varicella z oster vir us 
i m m u n o gl o b uli n G a ntib o d y  [ V Z V I g G A b]) at scree ni n g.
8.
S u bjects w h o ha ve recei ve d pri or treat me nt wit h a n y J A K i n hi bit ors.
9.
Partici pati o n i n ot her st u dies i n v ol vi n g i n vesti gati o nal dr u g(s) wit hi n 8 wee ks or 
wit hi n 5 half -li ves (if k n o w n) w hic he ver is l o n ger, pri or t o st u d y e ntr y a n d/ or d uri n g 
st u dy partici pati o n.
N ote: A n y  i n vesti gati o nal or e x peri me ntal t hera py ta ke n or pr oce d ure perf or me d f or 
A D, ps oriasis, ps oriatic art hritis or r he u mat oi d art hritis i n t he pre vi o us 1 ye ar s h o ul d 
be disc usse d wit h t he Pfizer Me dical M o nit or ( or desi g nee).  S u bjec ts ca n n ot 
partici pate i n st u die s of ot her i n vesti gati o nal or e x peri me ntal t hera pies or pr oce d ures 
at a n y ti me d uri n g t heir partici pati o n i n t his st u d y .
1 0. Ha ve recei ve d a n y of t he f oll o wi n g treat me nt re gi me ns s pecifie d i n t he ti mefra mes 
o ut li ne d bel o w:
Wit hi n
1 ye ar of first d ose of i n vest igati o nal pr o d uct:

Pri or treat me nt wit h n o n B cell -s pecific ly m p h oc yte de pleti n g a ge nts/t hera pies 
(e g, ale mt uz u ma b [ C A M P A T H ], al k ylati n g a ge nts [e g, c ycl o p h os p ha mi de or 
c hl ora m b ucil], t otal l ym p h oi d irra di ati o n, etc.).  S u bj ects w h o ha ve recei ve d 
rit u xi mab or ot her selecti v e B l y m p h oc y te de pleti n g a ge nts (i ncl u di n g 
e x peri me ntal a ge nts) are eli gi ble if t he y  ha ve n ot recei ve d s uc h t hera p y f or at 
least 1 ye ar pri or t o st u d y baseli ne a n d ha ve n or mal cl uster of differe ntiati o n ( C D ) 
1 9/ 2 0 + c o u nts b y  fl u oresce nce-acti vate d cell s or ti n g ( F A C S) a nal ysis.
Wit hi n 1 2 wee ks of first d ose of i n vesti gati o nal pr o d uct:

Ot her bi ol o gics: wit hi n 1 2 wee ks of first d ose of i n vesti gati o nal pr o d uct or 
5 half -li ves (if k n o w n), w hic h e ver is l o n ger.
Wit hi n 6 wee ks of first d ose of i nv esti gati o nal pr o d uct:

Use of d u pil u ma b.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
Wit hi n 4
wee ks of first d ose of i n vesti gati o nal pr o d uct: 

Use of oral i m m u n os u p pressi ve dr u gs (e g, c ycl os p ori n A [ Cs A], azat hi o pri ne, 
met h otre xate, s y ste mic c ortic oster oi ds, m yc o p he n olate-m ofetil, I F N -) wit hi n 
4 we eks of first d ose of i n vesti gati o nal pr o d uct or wit hi n 5 half -li ves (if k n o w n), 
w hic he ver is l o n ger; 

P h ot ot hera p y  narr o w ba n d U V B (N B -U V B) or br oa d ba n d p h ot ot hera p y;

Re g ular use ( m ore t ha n 2 visits per wee k) of a ta n ni n g b o o t h/ parl or;

Her bal me dicati o ns wi t h u n k n o w n pr o perties or k n o w n be neficial effects f or A D.
Wit hi n 1 wee k of first d ose of i n vesti gati o nal pr o d uct:

A nti- platelet dr u gs. 
N ote: l o w d ose acet y l salic ylic aci d (1 0 0 m g  Q D) is per mitte d, f or the p ur p ose of 
car di o vasc ular pr o p h yl a xis, at t he d iscreti o n of t he i n vesti gat or.
Wit hi n 7 2 h o urs of first d ose of i n vesti gati o nal pr o d uct:

T o pical treat me nts t hat c o ul d affect at o pic der matitis (e g, c ortic oster oi ds, 
calci ne uri n i n hi bit ors, tars, a nti bi otic crea ms, t o pical a n ti hista mi nes);
N ote: C ortic os teroi d i n halers a n d i ntra nasal s pra ys are all o we d f or sta ble ast h ma 
a n d/ or aller gic r hi nitis patie nts.
1 1. Ha ve a hist or y  of a n y ly m p h o pr oliferati ve dis or der s uc h as E pstei n Barr Vir us ( E B V) 
relate d ly m p h o pr olife rati ve dis or der, hist or y of l y m p h o ma, le u ke mia, or si g ns or 
s ym pt o ms s u g gesti ve of c urre nt l y m p hatic or l y m p h oi d disease.
1 2. I nfecti o n Hist or y:
a.
Ha ve a hist or y  of s yste mic i nfecti o n re q uiri n g h os pitalizati o n, pare nteral 
a nti micr o bial t hera p y, or as ot her wise j u d ge d cli nicall y  sig nifica nt b y t he 
i n vesti gat or wi t hi n 6 m o nt hs pri or t o Da y 1.
b.
Ha ve acti ve c hr o nic or ac ute s ki n i nfecti o n re q uiri n g treat me nt wit h s y ste mic 
a nti bi otics, a nti virals, a nti parasitics, a nti pr ot oz oals, or a ntif u n gals wit hi n 2 wee ks 
pri or t o D a y 1 , or s u perficial s ki n i nfecti o ns wit hi n 1 we e k pri or t o Da y 1.
c.
A s u bject k n o w n t o be i nfecte d wit h H u ma n I m m u n o deficie nc y Vir us ( HI V), 
He patitis B, or He patitis C ( Secti o n 7. 6. 2 ).


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F or C hi n a a n d T ai w a n o nl y :
S u bjects w h o are he patitis B s u rface a nti ge n (H Bs A g ) ne gati ve, he patitis B c ore 
a nti b o d y (H Bc A b ) p ositi ve, a n d he patitis B s urface a nti b o d y  (H Bs A b ) p ositi ve at 
Scree ni n g will ha ve refle x testi n g f or h e patitis B vir us ( H B V ) D N A. S u bjects
w h o ha ve H B V D N A a b o ve t he l o wer li mit of q ua ntif icati o n ( L L Q) will be
e xcl u de d.  S u bjects w h o are H B V D N A ne gati ve or bel o w L L Q ma y  e nr oll b ut 
will ha ve H B V D N A tes ti n g re peate d at Wee ks 1 2, 2 8, 4 0, 5 2 , Resc ue Wee k
1 2 , 
a n d earl y ter mi nati o n fr o m st u d y  d uri n g a ny treat me nt peri o d .
d.
Ha ve a hist or y  (si n gle e pis o de) of disse mi nate d her pes z oster or disse mi nate d 
her pes si m ple x, or a rec urre nt ( m ore t ha n o ne e pis o de of) l ocalize d, der mat o mal 
her pes z oster.
1 3. Ha ve a hist or y  of alc o h ol or s u bsta nce a b use wit hi n 6 m o nt hs pri or t o Da y 1 t hat i n 
t he o pi ni o n of t he i n vesti gat or will precl u de partici pati o n i n t he st u d y .
1 4. A Scree ni n g 1 2 -lea d E C G t hat de m o nstrates cli nicall y si g nifica nt a b n or malities 
re q uiri n g treat me nt (e g, ac ute m yocar dial i nfarcti o n, seri o us tac h y - or 
br a d y- arr h yt h mias) or t hat are i n dicati ve of seri o us u n derl y i n g heart disease 
(e g, car di o m yo pat h y , maj or c o n ge nital heart disease, l o w v olta ge i n all lea ds, 
W olff - Par ki ns o n-W hite s y n dr o me) or criteria ass ociate d wit h Q wa ve i nter val 
( Q T)/ Fri dericia-c orrecte d Q wa ve ( Q Tc F) a b n o r malities i ncl u di n g:

A mar ke d p rol o n gati o n of Q Tc F i nter val ( > 4 5 0 millisec o n ds [ ms]) o n t he 
scree ni n g E C G;

A hist or y  of a d ditio nal ris k fact ors f or T orsa de de P oi ntes ( T d P) (e g, heart fail ure, 
h y p o kale mia, fa mil y hist or y of L o n g Q T S y n dr o me);

Use of c o nc o m ita nt me dicati o ns t hat pr ol o n g the Q T/ Q Tc F i nter val.
1 5. Ha ve a k n o w n i m m u n o deficie nc y  dis or der or a first-de gree relati ve wit h a here ditar y  
i m m u n o deficie nc y.
1 6. Ha ve a n y m ali g na ncies or ha ve a hist or y of mali g na ncies wit h t he e xce pti o n of 
a de quatel y treate d or e xcise d n o n -metastatic basal cel l or s q ua m o us cell ca ncer of t he 
s ki n, or cer vical carci n o ma i n sit u.
1 7. Re q uire treat me nt wit h pr o hi bite d c o nc o mita nt me dicati o n(s) ( Secti o n 5. 9. 2 a n d 
A p pe n di x 3 ) or ha ve recei ve d a pr o hi bite d c o nc o mita nt me dicati o n wit hi n t he 
s pecifie d ti me fra me pri or t o t he first d ose of st u d y me dicati o n.
1 8. Ha ve e vi de nce of acti ve or late nt or i na de q uate l y treate d i nfecti o n wit h 
M y c o bacteri u m t u berc ul os is ( T B) as e vi de nce d b y a ny of t he f oll o wi n g:


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
A p ositi ve Q ua nti F E R O N -T B G ol d ( Q F T -G) I n -T u be test or p ositi ve 
Ma nt o u x/ P urifie d Pr otei n Deri vati ve ( P P D) t u berc uli n s ki n test perf or me d at or 
wit hi n t he 1 2 we e ks pri or t o Da y 1.

It is rec o m me n de d t hat s u bjects wit h a hist or y of Bacille Cal mette G uéri n ( B C G) 
vacci nati o n be teste d wit h t he Q F T -G test si nce t he Ma nt o u x/ P P D t u berc uli n s ki n 
test ma y be p ositi ve d ue t o vacci nati o n.  See Secti o n 7. 3. 4 f or re q uire me nts f or 
Ma nt o u x/ P P D t u berc uli n s ki n testi n g. 

A ne gati ve Q F T -G or Ma nt o u x/ P P D t u berc uli n s ki n test is re q uire d u nless t he 
s u bject has pre vi o usly recei ve d a d oc u me nte d a de q uate c o urse of t hera p y f or 
eit her late nt ( 9 m o nt hs of is o niazi d i n a l ocal e w here rates of pri mar y  m ulti-dr u g 
T B resista nce are < 5 % or a n acce pta ble alter nati ve re gi me n) or acti ve (acce pta ble 
m ulti -dr u g re gi me n) T B i nfecti o n.  If t he c urre nt i nci de nce rates of m ulti-dr u g 
resista nt T B i nfecti o n i n the l ocale are u na vaila ble, a n a d e q uate treat me nt re gi me n 
s h o ul d be defi ne d as t he re gi me n rec o m me n de d b y t he healt h mi nistr y or e x pert 
pa nel i n t he l ocale;

C hest ra di o gra p h ( or c hest C o m p ute d T o m o gra p h y ( C T) sca n, if a vaila ble) ta ke n 
at scree ni n g wit h c ha nges s u g gesti ve of acti ve t u berc u l osis ( T B) i nfecti o n as 
deter mi ne d b y a q ualifie d ra di ol o gist.  A c hest X -ra y is re q uire d f or a d ults a n d 
rec o m me n de d f or a d olesce nts per l ocal sta n dar d/ g ui deli nes, u nless pre vi o usl y 
perf or me d a n d d oc u me nte d wit hi n 1 2 wee ks p ri or t o St u d y D a y 1.

A hist or y  of eit her u ntreate d or i na de q uatel y treate d late nt or acti ve T B i nfecti o n;

A s u bject w h o is c urre ntl y bei n g treate d f or acti ve T B i nfecti o n is t o be e xcl u d e d.
1 9. A N Y of t he f oll o wi n g a b n or malities i n cli nical la b orat or y tests at scree ni n g, as 
assesse d b y t he st u d y-s pecific la b orat or y a n d c o nfir me d b y a si n gle re peat, if dee me d 
necessar y :

A bs ol ute ne utr o p hil c o u nt of < 1. 2 x 1 0 9/ L ( < 1 2 0 0/ m m3);

He m o gl o bi n < 1 0. 0 g/ d L  or he mat ocrit < 3 0 %;

Platelet c o u nt of < 1 5 0 x 1 0 9/ L ( < 1 5 0, 0 0 0/ m m3);

A bs ol ute l y m p h oc y te c o u nt of < 0. 5 0 x 1 0 9 / L ( < 5 0 0/ m m3);

Esti mate d Creati ni ne Cleara nce < 4 0 m L / mi n base d o n t he a ge a p pr o priate 
calc ulati o n, or ser u m creati ni ne > 1. 5 ti mes t he u p per li mit of n or mal ( U L N);

As partate a mi n otra nsferase ( A S T) or ala ni ne a mi n otra nsferase ( A L T) val ues 
> 2 ti mes the U L N;


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
T otal bilir u bi n 1. 5 ti mes t he U L N; s u bjects wit h a hist or y of Gil bert's sy n dr o me 
ma y  ha ve a direct bilir u bi n meas ure d a n d w o ul d be eli gi ble f or this st u d y  
pr o vi de d t he direct bilir u bi n is U L N.
2 0. I n t he o pi ni o n of t h e i n vesti gat or or s p o ns or, ha ve a n y u nc o ntr olle d cli nicall y 
si g nifica nt la b orat or y a b n or malit y t hat w o ul d affect i nter pretati o n of st u dy data or t he 
s u bject’s partici pati o n i n t he st u d y.
2 1. Ha ve u n der g o ne si g nifica nt tra u ma or maj or s ur ger y wit hi n 1 m o nt h of t he first d ose 
of i n vesti gati o n al pr o d uct.
2 2. I n vesti gat or site staff me m bers directly i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir 
fa mil y me m bers, site staff me m bers ot her wise s u per vise d b y  t he i n vesti gat or, or 
s u bjects w h o are Pfizer e mpl o y ees, i ncl u di n g t heir fa mil y me m bers, directl y in v ol ve d 
i n t he c o n d uct of t he st u d y. 
2 3. Ha ve k n o w n h y p erse nsiti vit y t o P F-0 4 9 6 5 8 4 2 or t o a n y  of t he e xci pie nts of t he st u d y 
dr u g.
4. 3. R a n d o miz ati o n Criteri a 
S u bjects will be e nr olle d i nt o t he o pe n -la bel, r u n-i n peri o d of t he st u d y pr o vi de d t he y or t heir 
le gally acce pta ble re prese ntati ve /pare nt(s) or le gal g uar dia n if a mi n or, ha ve si g ne d a n 
i nf or me d c o nse nt d oc u me nt at scree ni n g t o partici pate i n t he st u d y, have u n der g o ne all 
scree ni n g pr oce d ures, a n d ha ve met all i ncl usi o n a n d n one of t he e xcl usi o n criteria f o r
partici pati o n i n t he st u d y  at Da y 1.  S u bjects w h o c o m plete t he r u n-i n peri o d a n d res p o n d t o 
o pe n -la bel treat me nt will be ra n d o mize d t o o ne of t hree treat me nt ar ms a n d e nter t he 
d o u ble -bli n d peri o d of t he trial (see Secti o n 3 ).  Ra n d o mizati o n is stratifie d b y a ge cate g or y, 
ie, < 1 8 years a n d 1 8 ye ars.  A c o m p uter- ge nerate d ra n d o mizati o n sc he d ule will be use d t o 
assi g n s u bjects t o t he treat me nt gr o u ps usi n g a n I nt eracti ve Res p o nse Tec h n ol o g y (IR T). 
4. 4. Lifest yle Re q uire me nts 
I n or der t o partici pate i n t he st u d y, s u bjects m ust be a ware of t he f oll o wi n g lifestyl e
g ui deli nes a n d restricti o ns t hat a p pl y d uri n g a n d after t he treat me nt peri o d.

O n st u d y  visit da ys: Da y 1, W ee ks 4, 1 2, 5 2 a n d E n d of St u d y ( E O S) a n d 
c orres p o n di n g visits if a s u bject e nters t he resc ue treat me nt peri o d, s u bjects m ust 
c o m pl y wit h fasti n g re q uire me nt f or at least 8 h o urs pri or t o t he visit.  Water a n d 
per mitte d n o n -st u d y me dicati o ns are all o we d (see Secti o n 5. 9. 1 ).

O n st u d y  visit da ys, s u bjects m ust n ot s m o ke or i n gest caffei ne d uri n g t he 3 0 mi n utes 
pri or t o bl o o d press ure a n d heart rate meas ure me nts.

O n st u d y  visit da ys, s u bjects m ust n ot ta ke t he d o se of i n vesti gatio nal pr o d uct u ntil 
i nstr ucte d t o d o s o b y t he i n vesti gat or or desi g nate d st u d y site staff.


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
O n st u d y  visit da ys, s h o weri n g or bat hi n g is per mitte d pri or t o atte n di n g t he st u d y 
visit, b ut s u bjects m ust n ot m oist urize or a p pl y  e m ollie nt.  N o n-me dicate d e m oll ie nt 
is all o we d after t he visit.  Disc o nti n ue a n d a v oi d usi n g certai n me dicati o ns a n d 
treat me nts (Secti o n 4. 2 , Secti o n 5. 9. 2 , a n d A p pe n di x 3 ).

A gree t o use o ne hi g hl y  effecti ve met h o d of c o ntrace pti o n (as s pecifie d i n 
Secti o n 4. 4. 1 , as a p plica ble.
4. 4. 1. C o ntr ace pti o n
T he c o ntrace pti o n c hec k is a n o p p ort u nit y t o c o nfir m t hat c o ntrace pti o n, if assi g ne d, is use d 
c o nsiste ntl y a n d c orrectl y.  It als o facilitates c o nti n ual reassess me nt of c hil d-beari n g p ote ntial 
i n w o me n.  T his all o ws f or i m ple me nti n g necessary c ha n ges t o c o ntrace pti o n; f or e xa m ple, 
i n vesti gat ors ma y nee d t o e ns ure alter nati ve c o ntrace pti ve met h o ds if ne w c o nc o mita nt 
disease c o ntrai n dicates a selecte d met h o d of c o ntrace pti o n, or if a s u bject is de m o nstra bl y  n o 
l o n ger of c hil d-beari n g stat us (as per pr ot oc ol) t he n t he y  will no l o n ger re q uire c o ntrace pti o n.  
C o nti n ual reassess me nt of c o ntrace pti ve nee ds is i m perati ve.
All fe male s u bjects w h o are of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts a ge d 1 2 ye ars 
a n d ol der re gar dless o f w het her t he y ha ve e x perie nce d me narc he, w h o are, i n t he o pi ni o n of 
t he i n vesti gat or, se x uall y acti ve a n d at ris k f or pre g na nc y wit h t heir part ner(s) m ust a gree t o 
use a hi g hl y effecti ve met h o d of c o ntrace pti o n c o nsiste ntl y  a n d c orrectl y f or t he d urati o n of 
t he acti ve treatme nt peri o d a n d f or at least 2 8 d a y s after t he last d ose of i n vesti gati o nal 
pr o d uct. 
T he i n vesti gat or or his or her desi g nee, i n c o ns ultati o n wit h t he s u bject, will c o nfir m t hat t he 
s u bject has selecte d a n a p pr o priate met h o d of c o ntracepti o n f or t he i n di v id ual s u bject a n d her 
part ner f ro m t he per mitte d list of c o ntrace pti o n met h o ds (see bel o w) a n d will c o nfir m t hat t he 
s u bject has bee n i nstr ucte d i n its c o nsiste nt a n d c orrect use.  At ti me p oi nts i n dicate d i n t he 
Sc he d ule of A cti vities , t he i n vesti gat or or desi g nee will i nf or m t he s u bject of t he nee d t o use 
hi g hl y effecti ve c o ntrace pti o n c o nsiste ntl y  a n d c orrectly a n d d oc u me nt t he c o n versati o n a n d 
t he s u bject’s affir mati o n i n t he s u bject’s c hart (s u bjects nee ds t o affir m t hei r c o nsiste nt a n d 
c orrect use of at least 1 of t he selecte d met h o ds of c o ntrace pti o n).  I n a d diti o n, t he 
i n vesti gat or or desi g nee will i nstr uct t he s u bject t o call i m me diatel y if t he selecte d 
c o ntrace pti o n met h o d is disc o nti n ue d or if pre g na nc y  is k n o w n or s us pecte d i n t he s u bject or 
t he part ner. 
Hi g hl y effecti ve met h o ds of c o ntrace pti o n are t h ose t hat, al o ne or i n c o m bi nati o n, res ult i n a 
fail ure rate of less t ha n 1 % per ye ar w he n use d c o nsiste ntl y a n d c orrectl y (ie, perfect use) a n d 
i ncl u de t he f oll o wi n g:
1.
E sta blis he d use of h or m o nal meth o ds of c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n (e g, oral, i nserte d, i njecte d, i m pla nte d, tra ns der mal) pr o vi de d t he s u bject 
pla ns t o re mai n o n t he sa me treat me nt t hr o u g h o ut t he e ntire st u d y  an d has bee n usi n g 
t hat h or m o nal c o ntrace pti ve f or an a de q uate peri o d of ti me t o e ns ure effecti ve ness.
2.
C orrectl y place d c o p per -c o ntai ni n g i ntra uteri ne de vice (I U D). 


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3.
Male c o n d o m or fe male c o n d o m use d WI T H a se parate s per mici de pr o d uct (ie, f oa m, 
gel, fil m, crea m, or s u p p osit o r y).  F or c o u ntries w here s per mici de is n ot a vaila ble or 
c o n d o m pl us s per mici de is n ot acce pte d as hi g hl y effecti ve c o ntrace pti o n, t his o pti o n 
is n ot a p pr o priate.
4.
Male sterilizati o n wit h a bse nce of s per m i n t he p ost- vasect o m y ejac ulate. 
N ote: Vasect o mize d p art ner is a hi g hl y effecti ve b irt h c o ntr ol met h o d pr o vi de d t hat 
part ner is t he s ole se x ual part ner of t he w o ma n of c hil d beari n g p ote ntial ( W O C B P) 
trial partici pa nt a n d t hat t he vasect o mize d part ner has recei ve d me dical assess me nt of 
the s ur gical s uccess .
5.
Bilateral t u bal li gati o n/ bilat eral sal pi n gect o m y or bilateral t u bal occl usi ve pr oce d ure 
( pr o vi de d t hat occl usi o n has bee n c o nfir me d i n acc or da nce wit h t he de vice’s la bel).
N O T E: Se x ual a bsti ne nce, defi ne d as c o m pletel y a n d persiste ntl y refrai ni n g fr o m all 
heter ose x ual i nterc o urse (i nc lu di n g d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y  
treat me nts) ma y o b viate t he nee d f or c o ntrace pti o n O N L Y if t his is t he preferre d a n d us ual 
lifest yle of t he s u bject. 
T he c o ntrace pti o n c hec k is a n o p p ort u nit y to c o nfir m t hat c o ntrace pti o n, if assi g ne d, is use d 
c o nsiste ntl y a n d c orrectl y. 
F or c o u ntries i n t he E U:
Hi g hl y effecti ve met h o ds of c o ntrace pti o n are t h ose t hat, al o ne or i n c o m bi nati o n, res ult i n a 
fail ure rate of less t ha n 1 % per ye ar w he n use d c o nsis tentl y  a n d c orrectl y (ie, perfect use) a n d 
i ncl u de t he f oll o wi n g:
1.
Esta blis he d use of h or m o nal met h o ds of c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n (e g, oral, i nserte d, i njecte d, i m pla nte d, tra ns der mal) pr o vi de d t he s u bject 
pl a ns t o re mai n o n t he sa me treat me nt t hr o u g h o ut t he e ntire st u d y a n d has bee n usi n g 
t hat h or m o nal c o ntrace pti ve f or a n a de q uate peri o d of ti me t o e ns ure effecti ve ness.
2.
C orrectl y place d c o p per -c o ntai ni n g i ntra uteri ne de vice (I U D).
3.
Male sterilizati o n wit h a bs e nce of s per m i n t he p ost -vasect o m y ejac ulate.
N ot e: Vasect o mize d part ner is a hi g hl y effecti ve birt h c o ntr ol met h o d pr o vi de d t hat 
part ner is t he s ole se x ual part ner of t he W O C B P trial partici pa nt a n d t hat t he 
vasect o mize d part ner has recei ve d me dical asse ss me nt of t he s urgi cal s uccess.
4.
Bilateral t u bal li g ati o n/ bilateral sal pi n gect o m y or bilateral t u bal occl usi ve pr oce d ure 
( pr o vi de d t hat occl usi o n has bee n c o nfir me d i n acc or da nce wit h t he de vice’s la bel).


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N O T E: Se x ual a bsti ne nce, defi ne d as c o m pletel y a n d persiste ntl y refrai ni n g fr o m all 
heter ose x ual i nter co urse (i ncl u di n g d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y  
treat me nts) ma y o b viate t he nee d f or c o ntrace pti o n O N L Y if t his is t he preferre d a n d us ual 
lifest yle of t he s u bject.
4. 4. 2. V acci ne a n d E x p os ure t o I nfec tio ns G ui deli nes
4. 4. 2. 1. S u bject S pecific Rec o m me n d ati o ns
It is rec o m me n de d t hat all s u bjects s h o ul d be u p-t o-date wit h res pect t o sta n dar d of care 
vacci nati o ns (as defi ne d b y  t heir c o u ntr y healt h mi nistr y) or A D g ui deli nes.  Vacci nati o n of 
s u bjects wit h li ve atten u ate d vacci nes is pr o hi bite d wit h i n t he 6 wee ks pri or t o first d ose of 
i n vesti gati o nal pr o d uct.  A d olesce nt s u bjects wit h o ut d oc u me nte d e vi de nce of ha vi n g 
recei ve d at least o ne d ose of t he varicella vacci ne or t h ose w h o are wit h o ut e vi de nce of 
pre vi o us va ricella z oster e x p os ure as c o nfir m e d b y V Z V I g G A b ser ol o gical testi n g are 
e xcl u de d.
4. 4. 2. 2. G ui d a nce Re g ar di n g H o use h ol d C o nt act V acci ne - Rel ate d E x p os ure
C urre nt r o uti ne h o use h ol d c o ntact wit h c hil dre n a n d ot hers w h o ha ve bee n vacci nate d wit h a 
li ve atte n uate d va cci ne ma y p ose a ris k d uri n g treatme nt a n d f or 6 wee ks f oll o wi n g 
c o m pleti o n of t he st u d y.  S o me of t hese vacci nes i ncl u de varicella (“c hic ke n p o x”) vacci ne, 
oral p oli o vacci ne, a n d t he i ntra nasal fl u vacci ne.  F oll o wi n g vacci nati o n wit h li ve atte n uate d 
vacc i nes, t he vir us ma y be s he d i n b od il y fl ui ds, i ncl u di n g st o ol, a n d t here is a p ote ntial ris k 
t hat t he vir us ma y be tra ns mitte d.  Ge neral g ui deli nes f or i m m u n os u p presse d s u bjects 
s u g gest t hat e x p os ure (t hr o u g h r o uti ne c o ntact) s h o ul d be a v oi de d f oll o wi n g vacci nati o n ( of 
ot hers) wit h t hese v acci nes f or t he state d ti me peri o d:
a.
Varicella or atte n uate d t y p h oi d fe ver vacci nati o n f or 4 wee ks f oll o wi n g vacci nati o n.
b.
Oral p oli o vacci nati o n f or 6 wee ks f oll o wi n g vacci nati o n.
c.
Atte n uate d r ota vir us vacci ne f or 1 0 d a y s f ollo wi n g vacci nati o n.
d.
Fl u Mist (i ntra nasal fl u vacci ne) f or 1 wee k f oll o wi n g vacci nati o n.
S u bjects s h o ul d a v oi d e x p os ure t o vacci nate d or i nfecte d pers o ns a n d c o ntact t he i n vesti gat or 
pr o m ptl y s h o ul d t he y  de vel o p si g ns or sy m pt o ms of i nfect i o ns.
4. 4. 3. S ur ger y
D uri n g t he st u d y , n o electi ve s ur gery s h o ul d occ ur wit h o ut first c o ns ulti n g wit h t he Pfizer 
Me dical M o nit or or desi g nee.  Prefera bl y, electi ve s ur ger y  s h o ul d occ ur bef ore t he st u d y or 
be dela y e d u ntil partici pati o n i n t he st u d y is c o m plete d.
T he Pf izer Me dical M o nit or or desi g nee s h o ul d be n o tifie d if a s u bject re q uires s ur ger y 
(i ncl u di n g de ntal s ur ger y) d uri n g t he st u d y t o deter mi ne w het her t he s u bject s h o ul d 
disc o nti n ue fr o m t he st u d y a n d/ or disc o nti n ue i n vesti gati o nal pr o d uct pri or t o t he s ur gica l 
pr oce d ure. I n ge neral, pla n ne d s ur gical pr oce d ures s h o ul d n ot be perf or me d u nless t he 


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i n vesti gati o nal pr o d uct has bee n disc o nti n ue d f or at least 2 8 d a y s ( u nless ot her wise a d vise d 
b y  t he Pfizer Me dical M o nit or or desi g nee).  T he Pfizer Me dical M o nit or or desi g nee s h o ul d 
be n otifie d as s o o n as p ossi ble if a s u bject u n der g oes a s ur gical pr oce d ure wit h o ut first 
i nf or mi n g t he st u dy staff.
4. 5. S p o ns or’s Q u alifie d Me dic al Pers o n nel
T he c o ntact i nf or mati o n f or t he s p o ns or's a p pr o priatel y  q ualifie d me dical perso n nel f or t he 
st u d y is d oc u me nte d i n t he st u d y c o ntact list l ocate d i n t he c o or di nat or’s ma n ual a n d i n t he 
st u d y p ortal.
T o facilitate access t o a p pr o priatel y q ualifie d me dical pers o n nel o n st u d y- relate d me dical 
q uesti o ns or pr o ble ms, s u bjects are pr o vi de d wit h a c o ntact car d.  T he c o ntact car d c o ntai ns, 
at a mi ni m u m, pr ot oc ol a n d i n vesti gati o nal pr o d uct i de ntifiers, s u bject st u d y  n u m bers, 
c o ntact i nf or mati o n f or t he i n vesti gat or site, a n d c o ntact details f or a c o ntact ce nter i n t he 
e ve nt t hat t he i n vesti gat or site staff ca n not be reac he d t o pr o vi de a d vice o n a me dical 
q uesti o n or pr o ble m ori gi nati n g fr o m a n ot her healt hcare pr ofessi o nal n ot i n v ol ve d i n t he 
s u bject’s partici pati o n i n t he st u d y.  T he c o ntact n u m ber ca n als o be use d b y i n vesti gat or 
staff if t hey are see ki n g a d vice o n me dical q uesti o ns or pr o bl ems; h o we ver, it s h o ul d be use d 
o nl y  i n t he e ve nt t hat t he esta blis he d c o m m u nicati o n pat h wa ys bet wee n t he i n vesti gat or site 
a n d t he st u d y tea m are n ot a vaila ble.  It is t heref ore i nte n de d t o a u g me nt, b ut n ot re place, t he 
establis he d c o m m u nicati o n pat h wa y s b et wee n t he i n vesti gat or site a n d t he st u d y tea m f or 
a d vice o n me dical q uesti o ns or pr o ble ms t hat ma y arise d uri n g t he st u d y.  T he c o ntact 
n u m ber is n ot i nte n de d f or use b y t he s u bject directl y , a n d if a s ubject , t heir le gally 
acce pta ble re prese ntati ve /par e nt(s) or le gal g uar dia n calls t hat n u m ber, he or s he will be 
directe d bac k t o t he i n vesti gat or site.
5. S T U D Y T R E A T M E N T S 
F or t his st u d y , t he i n vesti gati o nal pr o d ucts are P F-0 4 9 6 5 8 4 2 a n d place b o.  E nr olle d s u bjects
recei ve 1 2 w ee ks i n d ucti o n treat me nt of 2 0 0 m g  P F-0 4 9 6 5 8 4 2 Q D d uri n g a n o pe n -la bel 
r u n-i n peri o d.  At t he e n d of t he 1 2 wee ks, s u bjects res p o n di n g t o treat me nt as descri be d i n 
Secti o n 3 are ra n d o mize d i nt o t he d o u ble- bli n d e d, mai nte nance treat me nt peri o d d uri n g 
w hi ch t he y  recei ve 2 0 0 m g P F-0 4 9 6 5 8 4 2 Q D, 1 0 0 m g P F -0 4 9 6 5 8 4 2 Q D, or place b o 
( 1: 1: 1 ra n d o mizati o n rati o) f or 4 0-wee ks.  T he last d ose of o pe n la bel r u n- i n treat me nt 
( 2 0 0 m g) is a d mi nistere d at t he Wee k 1 2 visit ; s u bjects i nitiate a d mi nistrati o n of ra n d o mize d 
b li n de d treat me nt t he da y after t he Wee k 1 2 visit.   I n t he e ve nt of l oss of res p o nse d uri n g 
bli n de d treat me nt de n ote d as flare, defi ne d as a l oss of at least 5 0 % of t he E A SI  res p o nse at 
Wee k
1 2 a n d a n I G A sc ore of 2 or hi g her, s u bjects will e nter a 1 2- wee k op e n -la bel resc ue 
peri o d a n d recei ve 2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D wit h c o nc o mita nt t o pical t hera p y  per S O C.
A n i n vesti gat or ca n te m p oraril y i nterr u pt d osi n g f or u p t o a ma xi m u m of 2 8 c o nsec uti ve da ys 
f or a s u bject f or safety reas o ns or w hile m o nit ori n g a b n or mal l ab orat or y  tests if t he 
i n vesti gat or j u d ges t hat t his is necessar y (A p pe n di x 4 ). T he i n vesti gat or s h o ul d use t heir 
j u d ge me nt wit h re gar d t o u nsc he d ule d visits/la b orat or y /cli nical assess me nts re q uire d t o 
m o nit or t he s u bject d uri n g t his ti me -fra me. If wit hi n t his ti mefra me t he i n vesti gat or j u d ges 
t hat it is safe t o restart d osi n g, t he n t he s u bject ma y restart i n vesti gati o nal pr o d uct. If t he 


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i n vesti gat or j u d ges t hat it is n ot safe t o restart d osi n g wit hi n t his ti mefra me, t he n t he s u bject 
m ust be per ma ne ntl y disc o nti n ue d fr o m treat me nt, ha ve a n E n d of Treat me nt visit a n d e nter 
t he 4-wee k f oll o w -u p peri o d.  D oses n ot ta ke n f or t he reas o ns me nti o ne d a b o ve d o n ot 
c o nstit ute pr ot oc ol de viati o ns or me dicat i o n err ors a n d s h o ul d n ot be c on si dere d d osi n g 
err ors, b ut s h o ul d be n ote d i n t he d osi n g l o g wit h t he reas o n f or re d uce d dr u g c o ns u m pti o n 
clearl y descri be d.
F or t he p ur p oses of t h is st u d y, a n d per I nter nati o nal C o nfere nce o n Har m o nisati on (I C H) 
g ui deli nes, i n vesti gati o nal pr o d uct is define d as 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/c o m parat or i n a cli nical trial, 
i ncl u di n g a pr od uct wit h a mar keti n g a ut h orizati o n 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 the a p pr o ve d f or m, or w he n use d f or a n u na p pr o ve d 
i n dicati o n, or w he n use d t o gai n f urt her i nf or mati o n a b o ut a n a p pr o ve d use (IC H E 6 1. 3 3). 
5. 1. All oc at i o n t o Tre at me nt
All ocati o n of s u bjects t o treat me nt gr o u p s will pr ocee d t hr ou g h t he use of a n I nteracti ve 
Re s p o nse Tec h n ol o g y (I R T) s yste m.  T he site pers o n nel (st u d y c o or di nat or or s pecifie d 
desi g nee) will be re q uire d t o e nter or select i nf or mati o n i ncl u di n g b ut n ot li mi te d t o t he 
user’s i de ntificati o n (I D) a n d pass w or d, pr ot oc ol n u m ber, t he s u bject n u m ber a n d t he date of 
birt h of t he s u bject.  T he site pers o n nel will t he n be pr o vi de d wit h a treat me nt assi g n me nt 
a n d dis pe nsa ble u nit ( D U) or c o ntai ner n u m ber w he n i n vesti ga ti o nal pr o d uct is bei n g 
s u p plie d via t he I RT.  T he I R T s ys t em will pr o vi de a c o nfir mati o n r ep ort c o ntai ni n g t he 
s u bject n u m ber a n d D U or c o ntai ner n u m ber assi g ne d.  T he c o nfir mati o n re p ort m ust be 
st ore d i n t he site’s files. 
T here is a 2 4 h o ur a da y , 3 6 5 da y s a year I R T hel p des k a vaila ble f or a n y  q uesti o ns or issues.  
T he st u d y  s pecific I R T refere nce ma n ual will pr o vi de t he c o ntact i nf or mati o n a n d f urt her 
details o n t he use of t he I R T. 
N ote: T he I R T is t he s o urce of t he s u bject n u m ber.  T he I R T s y ste m will pr o vi de t he s u bject 
n u m ber at t he e n d of t he first I R T s u bject tra nsacti o n.
5. 2. Resc ue Tre at me nt
S u bjects will be i nstr ucte d t o c o ntact t he site if t he y e x perie nce a si g nifica nt w orse ni n g of 
t heir at o pic der matitis, s uc h as a rec urre nce of pr urit us, d uri n g t he d o u ble-bli n d treat me nt 
peri o d.  Site staff will deter mi ne if t he s u bject s h o ul d ret ur n to t he site f or a n u nsc he d ule d 
(see Secti o n 6. 5. 1 ) or re g ularl y sc he d ule d visit (see Secti o n 6. 3 ). S u bject will be re mi n de d 
n ot t o ta ke st u d y dr u g o n t he da y of t he site visit.  At t he visit (re g ular or u n pla n ne d) t he 
s u bject will be assesse d f or flare, defi ne d as a l oss of at least 5 0 % of t he E A SI  res p o nse at 
Wee k
1 2 a n d a n I G A of 2 or hi g her.  S u bjec ts w h o meet t he defi niti o n of flare are t o recei ve 
resc ue treat me nt t hat da y a n d e nter a n o pe n -la bel resc ue peri o d d uri n g w hic h t he y recei ve 
1 2 -wee ks of 2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D wit h c o nc o mita nt t o pical t hera p y per S O C.  See 
S ecti o n 5. 2. 1 f or g ui da nce o n t o pical t hera pies. 


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After c o m pleti n g t he resc ue peri o d, s u bjects ar e all o we d t o e nter t he L T E st u d y  B 7 4 5 1 0 1 5, if 
eli gi ble.  If a s u bject disc o nti n ues pre mat urel y or is n ot eli gi b le or willi n g t o partici pate i n 
B 7 4 5 1 0 1 5, t he n t he s u bject e nters t he 4- wee k, u ntreate d f oll o w- u p safety peri o d.  Refer t o 
Sc he d ule of Acti vities f or Resc ue Treat me nt .
S u bjects n ot meeti n g t he defi niti o n of flare will c o n ti n ue o n t heir bli nde d treat me nt.  
P h y sicia ns ma y co nti n ue t o cli nicall y  e val uate f or flare usi n g t he E A SI a n d I G A assess me nts 
at t heir discreti o n.
5. 2. 1. G ui deli nes f or T o pic al Resc ue Tre at me nt
Starti n g o n Da y  1 of resc ue treat me nt, all s u bjects will i nitiate t opical treat me nt a n d c o nti n ue 
a t o pical re gi me n as lo n g as nee de d d uri n g t he resc ue peri o d.  T hree classes of treat me nt 
re gi me ns, s pecificall y, t o pical c ortic oster oi ds, t o pical calci ne uri n i n hi bit ors, a n d a 
p h os p h o diesterase i n hi bit or 4 ( P D E -4) i n hi bit or, a re all o we d al o ne or i n c o m bi nati o n d uri n g 
t he rescu e peri o d.  I n vesti gat ors are t o use t hese t hree treat me nt classes acc or di n g t o t heir 
us ual practice . 
Rec o m me n de d t o pical treat me nts c o ul d i ncl u de:
T o pic al C ortic oster oi ds:
T o pical c ortic oster oi ds ( T C S) ca n be use d acc or di n g t o t he i n vesti gat or’s us ual practice.  T he 
f oll o wi n g use of T C S is s u g geste d f or t his st u d y:

A p pl y  me di u m p ote nc y T CS (e g, Tria mci n ol o ne acet o ni de 0. 1 % crea m or 
fl u oci n ol o ne acet o ni de 0. 0 2 5 % oi nt me nt) o nce dail y t o areas wit h acti ve lesi o ns.

After lesi o ns are u n der c o ntr ol (clear or al m ost clear), treat o nce dail y f or 7 da ys, 
t he n st o p;

If lesi o ns ret ur n d uri n g t he rescue peri o d, res u me treat me nt wit h me di u m p ote nc y  
T C S, b ut use t he a p pr oac h descri be d a b o ve u p o n lesi o n res ol uti o n.

L o w p o te nc y T C S (ie, h y droc ortis o ne 1 % crea m) ca n be use d o nce dail y  o n areas of 
t hi n s ki n (face, nec k, i ntertri gi n o us, a n d ge nital areas, areas of s ki n atr o p h y, etc.).

Hi g h or s u per -hi g h p ote nc y  T C S ma y be use d f or lesi o ns persisti n g or w orse ni n g 
u n der o nce dai l y treat me nt wit h me di u m p ote nc y T C S, u nless hi g her p ote nc y  T C S 
are c o nsi dere d u nsafe.
S u bject s h o ul d be m o nit ore d f or si g ns of l ocal or s yste mic T C S t o xicit y a n d st o p T C S 
treat me nt as necessar y.  T C S treat me nt is n ot e x pecte d t o last l o n ger t ha n 4 wee ks.


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Ot her T o pic al Tre at me nts:
T he use of t o pical calci n e uri n i n hi bit ors (e g, tacr oli m us, pi mecr oli m us) or a 
p h os p h o diesterase 4 ( P D E -4) i n hi bit or (crisa b or ole) ca n be use d acc or di n g t o l ocall y  
a p pr o ve d la bel at t he i n vesti gat or’s discreti o n base d o n pri or res p o nse or i nt olera nce t o t hese 
me dicati o ns. 
I n cases w here t he desire d t o pical treat me nt re gi me n differs si g nifica ntl y  fr o m t he a b o ve 
g ui deli nes, t he Pfizer me dical m o nit or s h o ul d be c o ntacte d f or g ui da nce.
5. 3. Bre a ki n g t he Bli n d
I n vesti gat ors, s u bjects a n d t he s p o ns or st u d y tea m will be bli n de d as t o treat me nt gr o u p.  At 
all ti mes, treat me nt a n d ra n d o mizati o n i nf or mati o n will be ke pt c o nfi de nt ial a n d will n ot be 
release d t o t he i n vesti gat or, t he st u d y staff, or t he s p o ns or’s st u d y tea m u ntil f oll o wi n g t he 
c o nclusi o n of t he st u d y , wit h t he e xce pti o n descri be d i n t his secti o n. 
At t he i nitiati o n of t he st u d y , t he st u d y site will be i nstr ucte d o n pr oce d ures f or brea ki n g t he 
bli n d.  Bli n di n g c o des s h o ul d o nl y  be br o ke n i n e mer ge nc y sit uati o ns f or reas o ns of s u bject 
safety.  T he i n vest i gat or is res p o nsi ble f or a n d m ay brea k t he bli n d f or safet y  reas o ns w here 
t he k n o wle d ge of act ual treat me nt is esse ntial f or f urt her ma na ge me nt of t he s u bject.  T he 
met h o d will be a n electr o nic pr ocess.  W he n t he bli n d f or a s u bject has bee n br o ke n, t he 
reas o n m ust be f ull y d oc u me nte d an d e ntere d o n t he Case Re p ort F or m ( C R F).  W he ne ver 
p ossi ble, t he i n vesti gat or s h o ul d c o ntact Pfizer bef ore brea ki n g t he bli n d.  If t he bli n d is 
br o ke n, t he i n vesti gat or s h o ul d pr o m ptl y i nf or m t he Pfizer C li nicia n or Me dical M o nit or.  
T he s u bject f or w h o m t he bli n d has bee n br o ke n will be disc o nti n ue d fr o m t he st u d y a n d 
u n der g o t he early t er mi nati o n ( E T) pr oce d ures. 
5. 4. S u bject C o m pli a nce
F or self -a d mi nistrati o n of t he i n vesti gati o nal pr o d uct at h o me, ti me of d ose will be ca pt ur e d 
a n d c o m plete d b y t he s u bject .  S u bjects will be iss ue d a n electr o nic d osi n g diar y  (e Diar y) a n d 
will be e d ucate d t o rec or d t he ti me of dail y d osi n g o nce t he y ha ve ta ke n t he i n vesti gati o nal 
pr o d uct.   W he n i n vesti gati o nal pr o d uct is a d ministere d at t he res earc h facilit y, it will be 
a d min istere d u n der t he s u per visi o n of st u d y pers o n nel.
C o m plia nce wit h t he d osi n g of i n vesti gati o nal pr o d uct will be m o nit ore d a n d verifie d b y 
dele gate d site pers o n nel t hr o u g h a c o m bi nati o n of t he acc o u nti n g of u n use d i n vesti gati o nal 
pr o d uct ret ur ne d b y t he s u b ject at t he st u d y visits, re vie w of t he d osi n g diar y, a n d disc ussi o n 
wit h t he s u bject w hic h will be d oc u me nte d i n t he s o urce d oc u me nts. 
S u bjects s h o ul d ta ke t he i n vesti gati o nal pr o d uct fr o m st u d y  Da y 1 u n til i nstr ucte d ot her wise 
b y  t he site staff (e g, tem p orar y  i nterr u pti o n t o d osi n g).  I n vesti gati o nal pr o d uct s h o ul d be 
ta ke n i n t he m or ni n g w he ne ver it is p ossi ble; h o we ver at st u d y visit da ys, s u bjects are t o be 
i nstr ucte d t o refrai n fr o m d osi n g at h o me, an d are t o ta ke t he d ose i n t he cli nic.  S u bjects 
s ho ul d be i nstr ucte d t hat if a d ose is i na d verte ntl y misse d t he n it s h o ul d be ta ke n as s o o n as 
re me m bere d, b ut n ot wit hi n 1 2 h o urs of t he ne xt sc he d ule d d ose. T he s u bject s h o ul d e nter a 
dail y  rec or d i n t heir e Diar y e ver y ti me t he y ta ke a d ose of i n vesti gatio nal pr o d uct.


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T he f oll o wi n g c o m plia nce cases will be c o nsi dere d me dic ati o n err ors a n d will be disc usse d 
wit h t he s p o ns or f or p ossi ble wit h dra wal fr o m t he st u d y :

S u bjects i nterr u pti n g i n vesti gati o nal pr o d uct f or m ore t ha n 4 c o nsec uti ve da y s or f or a 
t otal o f m ore t ha n 7 d a y s bet wee n visits;

S u bjects a d mi ni steri n g > 8 ta blets i n o ne da y or a d mi nisteri n g 4 ta blets/ da y f or 
4 c o nsec uti ve da ys;

S u bjects w h o ha ve a n o verall c o m plia nce of < 8 0 % or > 1 2 0 % bet wee n visi ts 
A n y  de viati o n fr o m pr ot oc ol s pecifie d d osi n g s ho ul d be rec or de d as a pr ot oc ol de viati o n a n d 
t he in vesti gat or or desi g nee is t o c o u nsel t he s u bject , le gall y acce pta ble 
re prese ntati ve/pare nt(s) or le gal g uar dia n (if a p plica ble) a n d e ns ure ste ps are ta ke n t o 
i m pr o ve c o m pliance.  I n a d diti o n, if t he c o m plia nce de viati o n reac hes t he t hres h ol ds defi ne d 
a b o ve it s h o ul d als o be rec or de d as a me dicati o n err or (see Secti o n 8. 4. 4 ).
N ote: te m p orar y  i nterr u pti o n t o d osi n g per i n vesti gat or j u d ge me nt, as d escri be d i n 
A p pe n di x 4 , will n ot be c o nsi dere d a pr ot oc ol de viati o n or me dicati o n err or.
5. 5. I n vesti g ati o n al Pr o d uct S u p plies
5. 5. 1. D os a ge F or m(s) a n d P ac k a gi n g
P F -0 4 9 6 5 8 4 2 will be pr o vi de d as 1 0 0 m g ta blets f or oral a d mi nistrati o n d uri n g t he 
o pe n -la bel r u n i n a d mi nistrati o n of 2 0 0 m g P F -0 4 9 6 5 8 4 2 Q D. 
Bli n de d P F -0 4 9 6 5 8 4 2 a n d place b o will be pr o vi de d as 1 0 0 m g ta blets f or oral a d mi nistrati o n.  
T he 1 0 0 m g ta blets a n d t heir place b os will be s u p plie d i n se parate b ottles a n d la bele d 
acc or di n g t o l ocal re g ulat or y re quire me nts.
W he n recei ve d b y t he p har mac y , P F-0 4 9 6 5 8 4 2 a n d place b o will be i n c o ntai ners t hat will 
s ufficie ntl y bli n d all site staff t o c o nte nt wit hi n t he b ottles (ie, acti ve vers us place b o).
5. 5. 2. Pre p ar ati o n a n d Dis pe nsi n g
T he i n vesti gat io nal pr o d uct s h o ul d be dis pe nse d usi n g a dr u g ma na ge me nt s y ste m at eac h 
dis pe nsi n g visit.  A q ualifie d staff me m ber will dis pe nse t he i n vesti gati o nal pr o d uct via 
u ni q ue c o ntai ner n u m bers i n b ottles pr o vi de d, i n q ua ntities a p pr o priate f or t he st u d y  visit 
sche d ule.  T he s u bject/ca re gi ver s h o ul d be i nstr ucte d t o mai ntai n t he pr o d uct i n t he b ottles 
pr o vi de d t hr o u g h o ut t he c o urse of d osi n g a n d ret ur n t he b ottles t o t he site at t he ne xt st u d y  
visit. 
5. 6. A d mi nistr ati o n
D uri n g t he o pe n -la bel i n d ucti o n treat me nt a n d resc ue treat me nt peri o ds, s u bjects will recei ve 
2 0 0 m g P F -0 4 9 6 5 8 4 2 dail y .  T w o ( 2) b ottles of i n vesti gati o nal pr o d uct will be dis pe nse d t o 
t he s u bject at eac h dis pe nsi n g visit a n d t he s u bject gi ve n clear d osi n g i nstr ucti o ns t o ta ke o ne 
ta blet fr o m eac h b ottle, o nce dail y, prefera b l y i n t he m or ni n g at a p pr o xi matel y t he sa me ti me 


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of da y .  S u bjects s h o ul d ta ke t he i n vesti gati o nal pr o d uct orall y o nce a da y f or u p t o 1 2 wee ks, 
h o we ver, f or st u d y visit da ys, s u bjec ts are t o be i nstr ucte d t o refrai n fr o m d osi n g at h o me, 
a n d are t o ta ke t he d ose i n t he cli nic o n site visit da ys. 
D uri n g bli n de d treat me nt, s u bjects will be dis pe nse d t w o ( 2) b ottles at eac h dis pe nsi n g visit 
a n d gi ve n clear d osi n g i nstr ucti o ns t o ta ke o n e ta blet fr o m eac h b ottle, o nce dail y , prefera bly 
in t he m or ni n g, at a p pr o xi matel y  t he sa me ti me of da y.  S u bjects s h o ul d ta ke t he 
i n vesti gati o nal pr o d uct orall y o nce a da y f or u p t o 4 0 wee ks, h o we ver, f or st u d y  visit da ys, 
s u bjects are t o be i nstr ucte d t o refrai n fr o m d osi ng at h o me, a n d are t o ta ke t he d ose i n t he 
cli nic o n si te visit da ys.
Refer t o Ta ble 2 f or treat me nt a d mi nistrati o n a n d dis pe nsi n g of i n vesti gati o nal pr o d uct.
T a ble 2.
I n vesti g ati o n al Pr od uct A d mi nistr ati o n
Tre at m e nt Assi g n me nt
D uri n g O p e n-l a bel R u n-I n a n d 
Resc ue Tre at me nt - Q D D osi n g
D uri n g Bli n de d Tre at me nt
Q D D osi n g *
1 0 0 m g Q D
N ot a p plica ble
B ottle A 1 0 0 m g - 1 ta blet
B ottle B Place b o - 1 ta blet
2 0 0 m g Q D
B ottle A 1 0 0 m g - 1 ta blet
B ottle B 1 0 0 m g - 1 ta blet
B ottle A 1 0 0 m g - 1 ta bl et
B ottle B 1 0 0 m g - 1 ta blet
Place b o
N ot a p plica ble
B ottle A Place b o - 1 ta blet
B ottle B Place b o - 1 ta blet
* B ottle A a n d B desi g nati o ns are use d f or e xa m ple p ur p oses o nl y.
S u bjects will s wall o w t he i n v esti gati o nal pr o d uct w h ole, a n d will n ot ma ni p ulate or c he w t he 
me dicati o n pri or t o s wall o wi n g.  I n vesti gati o nal pr o d uct ma y  be ta ke n wit h or wit h o ut f o o d, 
ot her t ha n o n st u d y  visit da ys w here fasti n g is re q uire d. 
A n i n vesti gat or ca n te m p oraril y i nterr u pt d osi n g f or u p t o a ma xi m u m of 2 8 c o nsec uti ve da ys
f or a s u bject, f or safety reas o ns or w hile m o nit ori n g a b n or mal la b orat or y  tests if t he 
i n vesti gat or j u d ges t hat t his is necessar y (A p pe n di x 4 ).  T he i n vesti gat or s h o ul d use t heir 
j u d ge me nt wit h re gar d t o u nsc he d ule d visits/la b o rat or y/cli nical assess me nts re q uire d t o 
m o nit or t he s u bject d uri n g t his ti me- fra me. If wit hi n t his ti mefra me t he i n vesti gat or j u d ges 
t hat it is safe t o restart d osi n g, t he n t he s u bject ma y restart i n vestigati o nal pr o d uct. If t he 
i n vesti gat or j u d ges t hat it is n ot safe t o restart d osi n g wit hi n t his ti mefra me t he n t he s u bject 
m ust be per ma ne ntl y disc o nti n ue d f r o m treat me nt, ha ve a n E n d of Treat me nt visit a n d e nter 
t he 4-wee k f oll o w -u p peri o d.  D oses n ot ta k e n f or t he reas o ns me nti o ne d a b o ve d o n ot 
c o nstit u te pr ot oc ol de viati o ns or me dicati o n err ors a n d s h o ul d n ot be c o nsi dere d d osi n g 
err ors, b ut s h o ul d be n ote d i n t he d osi n g l o g wit h t he reas o n f or re d uce d dr u g c o ns u m pti o n 
clearl y descri be d. 
A g ui da nce d oc u me nt wit h detaile d d osi n g i nstr ucti o ns a n d i n vesti g ati ve pr o d uct (IP) st ora ge 
i nstr ucti o n will als o be pr o vi de d t o s u bjects t o s u p p ort at-h o me d osi n g.


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5. 7. I n vesti g ati o n al Pr o d uct St or a ge 
T he i n vesti gat or or a n a p pr o ve d re prese ntati ve, e g, p har macist, will e ns ure t hat all 
i n vesti gati o nal pr o d ucts are st ore d in a sec ure d area wit h c o ntr olle d access u n der re q uire d 
st ora ge c o n diti o ns a n d i n acc or da nce wit h a p plica ble re g ulat or y re q uire me nts. 
I n vesti gati o nal pr o d uct s h o ul d be st ore d i n t heir ori gi nal c o ntai ner a n d i n acc or da nce wit h t he 
la bels.  See t he I n vesti gati o nal Pr o d uct Ma n ual (I P Ma n ual) f or st ora ge c o n diti o ns of t he 
pr o d uct.
A n y  st ora ge c o n diti o ns state d i n the S R S D will be s u perse de d b y t he st ora ge c o n diti o ns 
state d o n t he pr o d uct la bel.
Site s y ste ms m ust be ca pa ble of meas uri n g a n d d oc u me nti n g (f or e xa m p le, via a l o g), at a 
mi ni m u m, dail y  mi ni m u m a n d ma xi m u m te m perat ures f or all site st ora ge l ocati o ns (as 
a pplica ble, i ncl u di n g fr oze n, refri gerate d, a n d/ or r o o m- te m perat ure pr o d ucts).  T his s h o ul d 
be ca pt ur e d fr o m t he ti me of i n vesti gati o nal pr o d uct recei p t t hr o u g h o ut t he st u d y.  E ve n f or 
c o nti n u o us-m o nit ori n g s y ste ms, a l o g or site pr oce d ure t hat e ns ures acti ve e val uati o n f or 
e xc ursi o ns s h o ul d be a vaila ble.  T he i nte nt is t o e ns ure t hat t he mi ni m u m a n d ma xi m u m 
te m perat ure is c hec ke d eac h b usi ness da y  t o c onfir m t hat n o e xc ursi o n occ urre d si nce t he last 
e val uati o n a n d t o pr o vi de t he site wit h t he ca pa bilit y  t o st ore or vie w t he mi ni m u m/ ma xi m u m 
te m perat ure f or all n o n-w or ki n g da y s u p o n ret ur n t o n or mal o peratio ns.  T he o perati o n of t he 
te m perat ure m o nit ori n g d e vice a n d st ora ge u nit (f or e xa m ple, refri gerat or), as a p plica ble, 
s h o ul d be re g ularly i ns pecte d t o e ns ure t h e y are mai ntai ne d i n w or ki n g or der. 
A n y  e xc ursi o ns fr o m t he pr o d uct la bel st ora ge c o n diti o ns s ho ul d be re p orte d t o Pfizer u p o n 
disc o ver y .  T he site s h o ul d acti vel y p urs ue o pti o ns f or ret ur ni n g t he pr o d uct t o t he st ora ge 
c o n diti o ns descri be d i n t he la beli n g, as s o o n as p ossi ble.  De viati o ns f r o m t he st ora ge 
re q uire me nts, i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d re p orte d t o Pfizer. 
O nce a n e xc ursi o n is i de ntifie d, t he i n vesti gati o nal pr o d uct m ust be q uara nti ne d a n d n ot use d 
u ntil Pfizer pr o vi des d oc u me ntati o n of per missi o n t o use t h e i n vesti gati o nal pr o d uct.  It will 
n ot be c o nsi dere d a pr o t oc ol de viati o n if Pfizer a p pr o ves t he use of t he in vesti gati o nal 
pr o d uct after t he te m perat ure e xc ursi o n.  Use of t he i n vesti gati o nal pr o d uct pri or t o Pfizer 
a p pr o val will be c o nsi dere d a pr ot oc ol de viati o n.   S pecific details re gar di n g i nf or mati o n t he 
site s h o ul d re p ort f or eac h e xc ursi o n will be pr o vi de d t o t he site i n t he IP Ma n ual. 
Recei pt of materials, d o or o pe ni n g a n d cl osi n g, a n d ot her r o uti ne ha n dli n g o perati o ns w here 
t he pr o d ucts are briefl y o ut of t he te m perat ure ra n ge descri be d i n t he la beli n g are n ot 
c o nsi dere d exc ursi o ns.
Site staff will i nst r uct s u bjects o n t he pr o per st ora ge re q uire me nts f or ta ke h o me 
i n vesti gati o nal pr o d ucts. 


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5. 8. I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y 
T he i n vesti gat or site m ust mai ntai n a de q uate rec or ds d oc u me nti n g t he recei pt, use, l oss, or 
ot h er dis p ositi o n of t he i n vesti gati o nal pr o d uct s u p plies.  All i n vesti gati o nal pr o d ucts will be 
acc o u nte d f or usi n g a dr u g acc o u nta bilit y f or m/rec or d.  T o e ns ure a de q uate rec or ds, all dr u g 
s u p plies will be acc o u nte d f or i n t he dr u g acc o u nta bilit y i n ve nt or y for ms as i nstr ucte d b y  
Pfizer a n d will be m o nit ore d b y  t he acc o u nti n g of u n use d i n vesti gati o nal pr o d uct ret ur ne d by 
t he s u bjects.  At t he e n d of t he cli nical trial, all dr u g s u p plies u nall ocate d or u n use d b y t he 
s u bjects m ust be ret ur ne d t o Pfizer or its a pp oi nte d a ge nt, or destr o ye d i n a n a p pr o ve d 
ma n ner u nless ot her wise a ut h orize d b y  Pfizer.  I n eit her case, t he f or ms m ust i de ntif y t he 
i n vesti gati o nal pr o d uct, i ncl u di n g batc h or c o de n u m bers, a n d acc o u nt f or its dis p ositi o n o n a 
s u bject-b y -s u bject basis, incl u di n g s pecific dates a n d q ua n tities. 
All b ottles of i n vesti gati o nal pr o d uct m ust be br o u g ht bac k t o t he site at e ver y visit f or 
i ns pecti o n b y t he site staff a n d all b ottles/ un use d i n vesti gati o nal pr o d uct m ust be ret ur ne d t o 
t he i n vesti gat or by t he s u bj ect at t he rele va nt visit(s).
5. 8. 1. Destr ucti o n of I n vesti g ati o n al Pr o d uct S u p plies 
T he s p o ns or or desi g nee will pr o vi de g ui da nce o n t he destr ucti o n of u n use d i n vesti gati o nal 
pr o d uct (e g, at t he site).  If destr ucti o n is a ut h orize d t o ta ke place at t he i n vesti g at or site, t he 
i n vesti gat or m ust e ns ure t hat t he materials are destr o y e d i n c o m plia nce wit h a p plica ble 
e n vir o n me ntal re g ulati o ns, i nstit uti o nal p olic y , a n d a n y s pecial i nstr ucti ons pr o vi de d b y  
Pfizer, a n d all destr ucti o n m ust be a de q uate l y d oc u me nte d.
F or all b ottles ret ur ne d t o t he i n v esti gat or by t he s u bject, t he i n vesti gat or will mai ntai n t he 
ret ur ne d s u p ply u ntil destr ucti o n is a ut h orize d.  Pfizer will pr o vi de i nstr ucti o ns as t o t he 
dis p ositi o n of a n y  u n use d i n vesti gati o nal pr o d uct.
5. 9. C o nc o mit a nt Tre at me n t(s)
S u bjects m ust c o nti n ue t o av oi d use of me dicati o ns t hat ha ve bee n was he d - o ut pri or t o 
e nr oll me nt a n d will a bstai n fr o m all c o nc o mita nt me dicati o ns as descri be d i n Secti o n 4. 2 a n d 
A p pe n di x 3 o f t he pr ot oc ol.  Me dicati o ns t hat are ta ke n i n t he Scree ni n g/ Was h o ut peri o d 
(after i nf or me d c o nse nt is o btai ne d a n d bef ore t he first d ose of i n vesti gati o nal pr o d uct o n 
D a y 1) will be d oc u me nte d as pri or me dicati o ns.  Me dicat i o ns ta ke n after t he first d ose of 
i n vesti gati o nal pr o d uct o n Da y 1 has bee n a d mi nistere d will be d oc u me nte d as c o nc o mita nt 
me dicati o ns.  All c o nc o mita nt me dicati o ns ta ke n d uri n g t he st u d y m ust be rec or de d i n st u d y 
rec or ds wit h i n dicati on (if At o pic Der mat itis), refere nce t o a ny ass ocia te d a d verse e ve nt, 
d ose, a n d start a n d st o p dates of a d mi nistrati o n.  S u bjects will be q uerie d a b o ut c o nc o mita nt 
me dicati o n (i ncl u di n g t o pical me dicati o ns a n d treat me nts, o ver -t he-c o u nter a n d prescri pti o n 
m e dicati o ns a n d treat me nts, a n d vacci nati o ns) at each st u d y  visit.  A n y ne w c o nc o mita nt 
me dicati o ns or d ose c ha n ges t o c urre nt c o nc o mi ta nt me dicati o ns s h o ul d be e val uate d f or 
p ote ntial ne w or w orse ni n g a d verse e ve nts. 
Me dicate d t o pical t hera pies ie, a t o pical pr o d uct t hat c ontai ns a n acti ve p har mace utical
i n gre die nt i n dicate d f or t he treat me nt of A D (irres pecti ve of w het her it is a n o ver-t he-c o u nter 
[ O T C] or prescri pti o n o nl y pr o d uct), are o nl y per mitte d i n t his trial d uri n g t he resc ue peri o d. 


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5. 9. 1. Per mitte d C o nc o mit a nt Me dic ati o ns
T he f oll o wi n g c o nc o mita nt A D t hera pies are per mitte d d uri n g t he st u d y:

Oral a nti hista mi nes; 

T o pical n o n -me dica te d e m ollie nt. 
T he f oll o wi n g c o nc o mita nt me dicati o ns are per mitte d d uri n g t he st u d y:

C ortic oster oi d i n halers a n d i ntra nasa l s pra ys are all o wed f or sta ble ast h ma a n d/ or 
allergic r hi nitis patie nts;

O p ht hal mic c ortic oster oi ds are all o we d f or patie nts recei vi n g a sta ble d ose t o treat 
r hi n oc o nj u nti vitis;

L o w d ose acet yl  salic ylic aci d (1 0 0 m g  Q D) is per mitte d, f or t he p ur p ose of 
car di o vasc ular pr o p h y la xis, at t he discreti o n of th e in vesti gat or ;

Aceta mi n o p he n/ paraceta m ol ma y  be use d i nter mitte ntl y ( n ot t o e xcee d 1 g/ da y ); 

Vita mi n a n d mi neral s u p ple me nts of sta n dar d p ote nc y are all o we d i n a m o u nts n ot 
k n o w n t o be ass ociate d wit h a d v erse effects (s uc h as h yper -vita mi n osis).
F or t he p ur p oses of t his pr ot oc ol, dietar y  s u p ple me nts are defi ne d as vita mi ns, mi nerals, an d 
p urifie d f o o d s u bsta nces.  Vita mi ns, mi nerals a n d p urifie d f o o d s u bsta nces are all o we d i n 
a m o u nts n ot k n o w n t o be ass oci ate d wit h a d verse e ffects (s uc h as hy p er-vita mi n os is).
U nless a pr o hi bite d me dicati o n or treat me nt, s u bjects ma y  be a d mi nistere d a n y ot her 
me dicati o ns necessar y  f or t he treat me nt of c o nc o mita nt me dical dis or ders as dee me d 
necessar y  b y t he treati n g p h ysician.  F oll o wi n g Da y 1 , a d diti o n of c o nc o mita nt me dicati o ns 
or a n y c ha n ge i n t he d osa ge s h o ul d be li mite d t o t h ose c o nsi dere d me dicall y esse ntial.
A s u bject w h o is recei vi n g a per mitte d c o nc o mita nt me dicati o n f or a n y reas o n m ust be o n a 
l ocall y- a p pr o ve d me dicati o n a n d d ose, a n d t his m ust be d oc u me nte d i n t he C R F.  S u bjects 
are n ot all o we d a n y ot her i n vesti gati o nal dr u gs or treat me nts d uri n g t he st u d y . 
S u bjects s h o ul d re p ort a n y  c ha n ges t o per mitte d me dicati o ns d uri n g t he st u d y t o t he 
i n vesti gat or as s o o n as the y  occ ur.  Me dicati o n c ha n ges m ust be d oc u me nte d in t he s u bject’s 
rec or d a n d C R F.
5. 9. 2. Pr o hi bite d Me dic ati o ns a n d Tre at me nts
S u bjects are re q uire d t o disc o nti n ue a n d a v oi d usi n g certai n me dicati o ns a n d treat me nts (see 
Secti o n 4. 2 , I ncl usi o n Criteria a n d E xcl usi o n Cr iteria, a n d A p pe n di x 3 ).  S u bjects s h o ul d be 
i nstr ucte d at eac h visit t o c o ntact t he st u dy site i n vesti ga t or pr o m ptl y if t here are a ny 
i nte n de d c ha n ges or ad diti o ns t o c o nc o mita nt me dicati o ns. 


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All me dicati o ns a n d treat me nts t hat c o ul d affect at o pic der matitis m ust be disc o nti n ue d 
e xce pt oral a nti hista mi nes.  D ue t o t he p ote ntial t o affect at o pic der matitis w it h ultra vi olet 
li ght e x p os ure, s u bjects m ust als o a v oi d pr ol o n ge d e x p os ure t o t he s u n a n d n ot t o use ta n ni n g 
b o ot hs, s u n la m ps or ot her ultra vi olet li g ht s o urces d uri n g t he st u d y. 
S u bjects w h o recei ve d pri or treat me nt wit h J A K i n hi bit ors are t o be e xcl u d e d fr o m t he st u d y. 
Her bal me dicati o ns wit h u n k n o w n pr o perties or k n o w n be neficial effects f or A D m ust be 
disc o nti n ue d at lea st 4 wee ks bef ore t he first d ose of i n vesti gati o nal pr o d uct. 
Restricti o ns o n certai n vacci nati o ns are descri be d i n S ecti o n 4. 4. 2 .
T he Pfizer st u d y tea m is t o be n otifie d of a n y  pr o hi bite d me dicati o ns ta ke n d uri n g t he st u d y.  
After c o ns ulti n g wit h t he Me dical M o nit or, t he i n vesti gat or will ma ke a j u d ge me nt o n t he 
o n g oi n g e li gi bilit y of a ny s u bject wit h pr o hi bite d me dicati o n use d uri n g t he st u d y. 
6. S T U D Y P R O C E D U R E S 
Refer t o t he Sc he d ule of Acti vities f or a detaile d list of st u d y pr oce d ures as t he y s h o ul d be 
c o n d ucte d at eac h res pecti ve visit. 
D ue t o p ossi ble ne e d f or P P D testi n g a n d c hest ra d i o gra p h, scree ni n g pr oce d ures ma y be 
perf or me d o ver m ore t ha n 1 visit i n t he 2 8 da y s pri or t o t he Da y 1 visit. 
Visit wi n d o ws are base d o n t he Da y 1 Baseli ne visit ( Visit 2).  T o ass ure c o nsiste nc y  a n d 
re duce varia bilit y , all st u d y visits s h o ul d occ ur i n the m or ni n g w h e ne ver p ossi ble.  O n da y s 
of st u d y  visits, s u bjects will recei ve t heir d ose at t he cli nic d uri n g t he visit. 
S u bjects are re q uire d t o fast f or at least 8 h o urs pri or t o all visits t hat i ncl u de li pi d pr ofile 
pa ne l testi n g ( Da y 1, Wee k 4, Wee k 1 2, Wee k 5 2, E O S a n d Resc ue Da y 1, Resc ue Wee k 4, 
Resc ue Wee k 1 2).  D uri n g t he fasti n g peri o d, s u bjects s h o ul d refrai n fr o m all f o o d a n d 
li q ui ds ( water a n d per mitte d n o n-st u d y me dicati o ns are all o we d). 
Uri ne pre g na nc y  test must be perf or me d at e ver y  visit, be gi n ni n g wi t h Da y 1 t hr o u g h E O S 
pri or t o d osi n g wit h t he i n vesti gati o nal pr o d uct f or fe male s u bjects of c hil d beari n g p ote ntial 
i ncl u di n g a d olesce nts a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d 
me nar c he. 
Pri or t o atte n di n g a st u d y visit, s u bje cts are all o we d t o s h o wer a n d bat he b ut s h o ul d n ot 
m oist urize or a p pl y  e m ollie nt. 
E C Gs will be i nter prete d b y  a ce ntral rea der.
I n t he e ve nt of a s us pecte d o p p ort u nistic i nfecti o n, eff ort s h oul d be ma de t o i de n tif y t he 
pat h o ge n utilizi n g la b o rat or y or ot her met h o ds a p pr o priate t o t he cli nical sit uati o n. 


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I n case of a s us pecte d viral s ki n i nfecti o n (e g, her pes z oster a n d her pes si m ple x) or ecze ma 
her petic u m, a s peci me n f or viral D N A s h o ul d be o btai ne d f or c o nfir m ati o n.  Details f or s uc h 
c ollecti o n will be pr o vi de d i n t he la b orat or y ma n ual. 
F or s u bjects wit h a past hist or y  of oral or ge nital H S V a n d a prese ntati o n c o nsiste nt t o pri or 
i nfecti o ns, a sa m ple ma y be o btai ne d at t he discreti o n of t he i n vesti gat or. 
Refe r t o A p pe n di x 4 f or g ui deli nes o n s u bject safet y m o nit ori n g a n d disc o nti n uati o n. 
6. 1. Visit 1, Scree ni n g
S u bjects will be scree ne d ( Visit 1) wit hi n 2 8 da y s pri or t o a d mi nistrati o n of t he 
i n vesti gati o nal pr o d uct t o co nfir m t hat t he y  meet t he s u bject selecti o n criteria f or t he st u d y.  
T he i n vesti gat or ( or a n a p pr o priate dele gate at t he i n vesti gat or site) will o btai n i nf or me d 
c o nse nt fr o m eac h s u bject, le gally acce pta ble re prese ntati ve /pare nt(s) or l eg al g uar dia n (a n d 
asse nt fr o m t he s u bject, as a p pro priate), i n acc or da nce wit h t he pr oce d ures descri be d i n t he 
S u bj ect Inf or mati o n a n d C o nse nt i n Secti o n 1 2. 3 . 
S u bjects n ot meeti n g e nr oll me nt criteria (scree n fail ures) f or a n y reas o n s h o ul d be c o ntacte d 
q uic kl y  t o res u me/i nitiate A D treat me nts. 
If t he Ma nt o u x P P D t u berc uli n s ki n test is gi ve n, t he s u bject m ust ret ur n bet wee n 
4 8 - 7 2 h o urs p ost -i njecti o n f or i n d urati o n e valuati o n.
Scree ni n g la b orat or y  tests wit h a b n or mal res ults ma y be re peate d o nce t o c o nfir m a b n or mal 
res ults; t he last val ue will be use d t o deter mi ne eli gi bilit y.  If res ults ret ur n t o n or mal wit hi n 
t he 4-wee k scree ni n g peri o d, t he s u bject ma y  e nter t he st u dy. 
T he f oll o wi n g pr oce d ures wi ll be c o m plete d: 

O btai n writte n i nf or me d c o nse nt; f or s u bjects u n der t he le gal a ge of maj orit y  (le gal 
a d ult h o o d) i n t he s u bject’s c o u ntr y , o btai n writte n i nf or me d c o nse nt fr o m le gall y 
acce pta ble re prese nta ti ve/pare n t(s) or le gal g uar dia n a n d i nf or me d asse n t fr o m t he 
patie nt (if a ge a p pr o priate acc or di n g t o l ocal re g ulati o ns);

Re gister s u bject usi n g t he I R T s ys te m;

C ollect de m o gra p h y;

A d mi nister a n d sc ore t he C -S S R S, S B Q -R a n d P H Q -8.  S u bjects meeti n g a n y  of t he 
criteria s peci fie d i n E xcl usi o n Criteri o n 2 will be i neli gi ble f or partici pati o n; i t is 
rec o m me n de d t he s u bject’s pri mar y care p hys icia n ( P C P) s h o ul d be i nf or me d, a n d t he 
s u bject referre d t o a me ntal healt h pr ofessi o nal , eit her by t he P C P or t he i n vesti gat or 
acc or di n g to t heir us ual practice ;


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
C o m plete me dical hist or y, i ncl u di n g hist or y  of alc o h ol a n d t o bacc o use.  S m o ki n g 
stat us a n d a vera ge wee kl y alc o h ol c o ns u m pti o n ( u nits/ wee k) will als o be c ollecte d, 
w here a u nit c o nt ai ns 1 2 g of p ure a lc o h ol, a n a m o u nt e q ui vale nt t o t hat c o ntai ne d i n 
5 oz/ 1 5 0 ml (a glass) of wi ne, 1 2 oz/ 3 6 0 ml of beer, or 1. 5 oz/ 4 5 ml of 9 0 pr o of 
( 4 5 % alc o h ol b y v ol u me) of s pirits;

C o m plete A D disease hist or y  i ncl u des c ollecti o n of details of A D: A D dia g n osis a n d 
d urati o n, t he use of t o pical treat me n ts, sys te mic treat me nts a n d ot her treat me nts f or 
A D;

O btai n c o m plete me dicati o n hist or y  of all prescri pti o n or n o n prescri pti o n dr u gs, a n d 
dietar y  a n d her bal s u p ple me nts ta ke n wit hin 2 8 da ys pri or t o t he pla n ne d first d ose, 
e x ce pt as n ote d bel o w: 
T he f oll o wi n g ti mefra me pri or t o t he pla n ne d first d ose m ust be use d f or c ollecti o n of 
t he f oll o wi n g C urre nt/ Pri or Me dicati o ns:

1 ye ar: Pre vi o us t o pical treat me nts use d f or A D;

A n y  pre vi o us hist or y of s yste mic treat me nt f or A D;

A n y  pre vi o us hist or y of i nt olera nce/aller g y t o a ny dr u g, re gar dless of i n dicati o n;

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y  rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

O btai n wei g ht a n d hei g ht of all s u b jects;

Perf or m a si n gle 1 2 -lea d electr ocar di o gra m ( E C G).  Cli nicall y  si g nifica nt or 
e xcl usi o nar y E C G fi n di n gs re q uire scree n fail ure;

C o n d uct c o m plete p h y sical e xa mi nati o n;

Dis pe nse electr o nic patie nt re p orte d o utc o me (e P R O) ha n d hel d de v ice a n d i nstr uct 
s ubject i n h o w t o use t he de vice. I nstr uct t he s u bject t o be gi n daily c o m pleti o n of t he 
P S A A D (i n selecte d c o u ntries) a n d pr urit us N R S q uesti o n naire; 

Pr urit us N R S will be c ollecte d dail y i n a s u bject e Diar y  d urin g t he scree ni n g peri o d 
a nd fr o m Da y 1 t o 1 5 a n d t he n o n st u d y visit da ys; 

P S A A D will be c ollecte d dail y  i n a s u bject e Diar y d uri n g t he scree ni n g peri o d a n d 
fr o m Da y 1 t hr o u g h t he E n d of St u d y  visit, i n selecte d c o u ntries; 


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
C hest X -ra y or ot her a p pr o priate dia g n ostic i ma ge (ie, c o m p uterize d t o m o gra p h y  
[ C T] or ma g netic res o na nce im a gi n g [ M RI]) ma y be perf or me d u p t o 1 2 wee ks pri or 
t o St u d y D a y 1.   C hest X -ra ys ( p osteri or-a nteri or a n d lateral vie ws) are re q uire d f or 
a d ults a n d rec o m me n de d f or a d olesce nts as per l ocal g ui deli nes a n d s ta n dar d of care.  
Official rea di n g m ust be l ocate d a n d a vaila ble i n t he s o urce d oc u me ntati o n;

O btai n sa m ples f or la b orat or y testi n g: ser u m c he mistr y , he mat ol o g y (i ncl u di n g 
c oa g ulati o n pa nel, re d bl o o d cell ( R B C) a n d w hite bl o o d ce ll ( W B C) i n dices, a n d 
l ym p h oc y te s u bsets a n d mar kers), uri nal ys is, ser u m F S H ( p ost-me n o pa usal w o me n) 
or ser u m pre g na nc y  test ( w o me n of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts a ge d 
1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he), HI V, 
he patitis B s urfac e a nti ge n ( H Bs A g), he patitis B c ore a nti b o d y  ( H Bc Ab ), he patitis B 
s urface a nti b o dy ( H Bs A b), he patitis C viral a nti b o d y  ( H C V A b), he patitis C viral 
ri b o n ucleic aci d ( H C V R N A) (see Secti o n 7. 6. 2. 1 ), V Z V I g G a nti b o dy testi n g f or 
a d olesce nt s u bject s w h o ha ve n ot recei ve d at least o ne d ose of a varicella vacci ne, 
a nd baseli ne viral scree n sa m ple . F or C hi na a n d Tai wa n o nl y : S u bjects w h o are 
H Bs A g ne gati ve , H Bc A b p ositi ve , a n d H Bs A b p ositi ve will ha ve refle x testi n g f or
H B V D N A.

Q ua nti F E R O N – T B G ol d test ( u nless perf or me d wit hi n 1 2 wee ks of Da y 1).  If 
Ma nt o u x P P D t u berc uli n s ki n test is perf or me d, t he s u bject m ust ret ur n bet wee n 
4 8 - 7 2 h o urs p ost -i njecti o n f or e val uati o n of i n d urati o n (see Secti o n 7. 3. 4 f or f urt her 
details o n T B testi n g);

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble life styl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w I ncl usi o n a n d E xcl usi o n criteria f or s u bject eli gi b ilit y;

Assess f or o cc urre nce of A d verse E ve nts: T h e a d verse e ve nt a n d S A E re p orti n g 
peri o d starts wit h t he si g ni n g of t he i nf or me d c o nse nt d oc u me nt;

If s u bject is eli gi ble f or c o nti n ue d partici pati o n, pr o vi de s u bject wit h patie nt 
e mer ge nc y c o ntact car d.
6. 2. R u n-I n I n d ucti o n Tre a t me nt Peri o d
6. 2. 1. Visit 2, D a y 1/ Wee k 0 ( B aseli ne)
A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  S u bjects meeti n g a n y of t he criteria 
s pecifie d i n Secti o n 7. 5. 1 will be i neli gi ble f or partici p ati o n; a ris k assess me nt b y a qualifie d 
me ntal hea lt h pr ofessi o nal (M H P ) s h o ul d be d o ne t o deter mi ne w het her it is safe f or t he 
s u bject t o c o nti n ue t o partici pate i n t he trial.


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
A d mi nister patie nt -re p orte d o utc o me ( P R O)s i ncl u di n g: Pt G A, D L QI ( or C D L QI), 
P O E M, H A D S, E Q - 5 D-5 L  ( or E Q-5 D -Y i n select c o u ntries), S F-3 6 v 2, Ac ute a n d 
F A CI T -F ( or Pe ds -F A CI T -F).  S F -3 6 v 2 will be c o m plete d b y  a d ult s u bjects o nl y; 

A d olesce nts 1 2 -1 7 y ears of a ge will n ot c o m plete t he S F -3 6 v 2.  A d olesce nts 1 2- 1 7 
ye ars of a ge will c o m ple te t he C D L QI i nstead of t he D L Q I, t he E Q-5 D- Y i n s elect 
c o u ntries i nstea d of t he E Q - 5 D-5 L  a n d Pe ds-F A CI T -F i nstea d of t he F A CI T -F;

Re vie w P S A A D dail y  c o m pleti o n (i n selecte d c o u ntries) a n d pr urit us N R S dail y 
c o m pleti o n i n t he e Diar y.  Re vie w e Diar y pr oce d ures wit h s u bject as necessar y ;

Re vie w a n y c ha n ges i n t he s u bject’s pri or a n d c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;

A d mi nister Ast h ma C o ntr ol Q uesti o n naire ( A C Q) test f or all s u bjects wit h a pri or 
dia g n osis of ast h ma;

O btai n pre -d ose vital si g n s i ncl u di n g p ulse rate, bl o o d p ress ure, res pirat ory rate a n d 
oral or t y m pa nic te m perat ure (after at least 5 mi n utes of rest);

O btai n wei g ht ( hei g ht n ot re q uire d);

Perf or m a si n gle 1 2 -lea d E C G pri or t o d osi n g wit h i n vesti gati o nal pr o d uct.  Cli nicall y 
si g nifica nt or e xcl usi o nar y E C G fi n di n g s re q uire scree n fail ure;

C o n d uct c o m plete p h y sical e xa mi nati o n; 

C o n d uct cli nical e val uati o ns i ncl u di n g Fitz patric k S ki n T y pe Assess me nt, I G A, 
S C O R A D, E A SI  a n d B S A (calc ulate d i n t he E A SI);

O btai n fasti n g sa m ples f or la b or at or y testi n g: ser um c he mistr y , he mat ol o g y 
(i ncl u di n g c oa g ulati o n, R B C/ W B C In dices, a n d l y m p h oc yte s u bsets a n d mar kers), 
li pi d pr ofile, a n d uri nalys is; 
 

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p otential i ncl u d i ng a d olesce nts 
a ged 1 2 y ears a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

C ollect sa m ple f or viral s ur v eilla nce: Her pes sim ple x vir us ( HS V) H S V- 1, H S V - 2 
a n d V ZV; 

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bilit y t o c o m pl y wit h lifestyl e re q uire m e nts 
g oi n g f or war d i n t he st u d y;
C CI


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
Re vie w of I ncl usi o n/ E xcl usi o n Criteria;

If s u bject c o nti n ues t o meet all I ncl usi o n/ E xcl usi o n criteria, officially e nr oll s u bject 
i nt o t he st u d y;

Dis pe nse i n vesti gati o nal pr o d uct t o t he s u bject ;

A d mi nister first d ose of i n ve sti gati o nal pr o d uct t o s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit. 
6. 2. 2. Visit 3, D a y 8/ Wee k 1 ( 1 d a y)

Call s u bject a n d c o nfir m c o m plia nce wit h dail y c o m pleti o n of pr urit us N R S a n d 
P S A A D (i n selecte d c o u nt ries); 

Ver ball y c o nfir m s u bjec t has bee n c o m plia n t wit h st u d y d osi n g a n d e ntr y i n t he 
e Diar y.  Re vie w e Diar y pr oce d ures wit h s u bject as necessar y;

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;

Assess nee d f or c o ntr ace pti o n a n d a d here nce t o a p pli cable lifest yl e re quire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bilit y t o c o m pl y wit h lifestyl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit.
6. 2. 3. Visit 4, D a y 1 5/ Wee k 2 ( 1 d a y)

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q 5 D-Y i n selec t c o u ntries);

A d olesce nts 1 2 -1 7 y ears of a ge will c o m plete t he C D L QI  i nstea d of t he D L QI a n d t he 
E Q - 5 D- Y i n select c o u ntries i nstea d of t he E Q - 5 D-5 L ;

Re vie w dail y P S A A D c o m pleti o n (i n selecte d c o u ntries) a n d dail y pr urit us N R S 
c o m pleti o n i n t he e Diar y.  In str uct s u bject t hat pr urit us N R S will n o w be c o m plete d 
o nl y  at site visits, b ut t he P S A A D will still be c o m p lete d dail y i n t he e Diar y.  Re vie w 
e Diar y pr oce d ures wit h s u bject as necessar y;

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y  rate a n d oral or 
t ym pa nic te m per ature (after at lea st 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d E C G;


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
C o n d uct a tar gete d p h ys ical e xa m;

C o n d uct cl i nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI a n d B S A (calc ulate d i n 
t he E A SI);

O btai n sa m ples f or la b orat or y t esti n g: ser u m c he mistr y, he matol o g y  (i ncl u di n g 
c oa g ulati o n, R B C/ W B C i n dices, l ym p h oc y te s u bsets a n d mar kers) a n d uri nal ysis;

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve u ri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct;

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Sect i o n 4. 4 ).  Esta blis h willi n g ness a n d a bilit y t o c o m pl y wit h lifestyl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w e Diar y  t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts s i nce t he last visit.
6. 2. 4. Visi t 5, D a y 2 9/ Wee k 4 (2 d a ys)

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q-5 D -Y i n select c o u ntries);

A d olesce nts 1 2 -1 7 y ears of a ge will c o m plete t he C D LQI  i nstea d of t he D L QI a nd t he 
E Q - 5 D- Y i n select c o u ntries i nstea d of t he E Q - 5 D-5 L ;

Re vie w P S A A D dail y  c o m pleti o n (i n selecte d c o u ntries) a n d pr uritis N R S c o m pleti o n 
f or t his visit i n t he e Diar y;

Perf or m a si n gle 1 2 -lea d E C G;

Re vie w a n y c ha n ges i n t he s u bject’s c o nc omita nt me dic ati o ns a n d treat me nts 
i nf or mati o n;

O btai n vi tal si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

C o n d uct tar gete d p h ys ical e xa mi nati o n;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6

C o n d uct cli nical e val uati o n s i ncl u di n g I GA, S C O R A D, E A SI  an d B S A (calc ulate d i n 
t he E A SI);

O btai n fasti n g sa m ples f or la b orat or y  testi n g: ser u m c he mistr y, he mat ol o g y 
(i ncl u di n g c oa g ulati o n pa nel, R B C/ W B C i n dices, l ym p h y c yte s u bsets a n d mar kers), 
li pi d pr ofile a n d uri nal ys is; 

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntia l i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

Assess n eed f or c o ntrace pti o n a n d a d here nce t o a p pli ca ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vi e w e Diar y t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Dis pe nse i n vesti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last v isit.
6. 2. 5. Visit 6, D a y 4 3/ Wee k 6 ( 3 d a ys)

Call s u bjec t a n d c o nfir m c o m plia nce wit h daily c o m pleti o n of P S A A D (i n selecte d 
c o u ntries);

Ver ball y c o nfir m s u bject has bee n c o m plia nt wit h st u d y  d osi n g a n d e ntr y i n t he 
e Diar y.  Re vie w e Diar y pr oce d ures wit h s u bject as necessar y;  

Re vie w a n y c ha n g es i n t he s u bject ’s c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bilit y t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 7
6. 2. 6. Visit 7, D a y 5 7/ Wee k 8 ( 3 d a ys)

A d mi nister a n d sc ore t he Si nce Last Visi t C-S S R S.  F or s u bj ects meeti n g an y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s h o ul d be 
d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o nti n ue t o partici pate i n t h e 
trial;

A d m i nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q-5 D -Y i n select c o u ntries);

A d olesce nts 1 2 -1 7 y ears of a ge will c o m plete t he C D L QI  i nstea d of t he D L QI a n d t he 
E Q - 5 D- Y i n select c o u ntries i nstea d of t he E Q- 5 D-5 L ;

Re v ie w P S A A D dail y c o mpleti o n (i n selecte d c o u ntries) a n d pr uritis N R S c o m pleti o n 
f or t his visit i n t he e Diar y; 

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nts 
i nf or mati o n;

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, r es pirat or y rate a n d oral or 
t ym pa nic te m perat ure ( after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d E C G;

C o n d uct tar gete d p h ys ical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

O btai n sa m p les f or la b orator y  testi n g: ser u m c he mistr y, he matol o g y  (i ncl u di n g 
c oa g ulati o n pa nel, R B C/ W B C I n dices, l y m p h oc y te s u bsets a n d mar kers) a n d 
uri nal y sis; 

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar d less of w het her t he y ha ve e x perie nce d me narc he) .  A 
ne gati ve uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w e Diar y  t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister i n v esti gati o nal pr o d uct t o t he s u bject;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 8

Dis pe nse i n ve sti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit.
6. 3. D o u ble - Bli n d M ai nte n a nce Tre at me nt Peri o d
6. 3. 1. Visit 8, D a y 8 5/ Wee k 1 2 ( 3 d a ys) R a n d o miz ati o n i nt o M a i nte n a nce Tre at me nt

A d mi ni ster a nd sc ore t he Si nce Last Visit C -S S R S.  F or s u bjects meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s h o ul d be 
d o ne t o deter mi ne w het her it is safe f o r t he s u bject t o c onti n ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S, E Q -5 D- 5 L  
( or E Q- 5 D-Y i n select c o u ntries), S F -3 6 v 2, Ac ute a n d F A CI T -F ( or Pe ds -F A CI T- F).  
S F -3 6 v 2 will be c o m plete d b y  a d ult s u bjects onl y ;

A d olesce nts 1 2 - 1 7 ye ars of a ge will n ot c o m plete t he S F-3 6 v 2.  A d olesce nts
1 2- 1 7 ye ars of a ge will c o m plete t he C D L QI i nstea d of t he D L QI, t he E Q - 5 D- Y i n 
select c o u ntries i nstea d of t he E Q - 5 D-5 L  a n d Pe ds-F A CI T -F i nstea d of t he F A CI T -F;

Re vie w P S A A D d ail y c o m pleti o n (i n sel ecte d c o u ntries) a n d pr urit us N R S 
c o m pleti o n f or t his visit i n t he e Diar y; 

O btai n wei g ht f or all s u bjects a n d hei g ht f or a d olesce nts o nl y  ( 1 2 t o < 1 8 ye ars ol d);

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y rate an d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d electr ocar di o gra m ( E C G);

C o n d uct c o m plete p h y sical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

O bta i n fasti n g sa m ples f or la b orat or y testi n g: ser u m c he mistr y, he mat ol o g y 
(i ncl u di n g c oa g ulati o n pa nel, R B C/ W B C I ndices, l ym p h oc y te s u bsets a n d mar kers), 
li pi d pr ofile, a n d uri nalys is; 
 

F or C hi na a n d Tai wa n o nl y : F or s u bjects w h o ha d H B V D N A testi n g at Scree ni n g, 
c ollect bl o o d sa m ple f or r e peat H B V D N A testi n g;
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 9

Uri ne pre g na nc y test (fe male s u bjects of c h il d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

Deter mi ne if t he s u bject meets al l of t he res p o n der criteri a f or r a n d o miz ati o n :
a.
I GA of cl ear ( 0) or al m ost clear ( 1);
b.
A re d ucti o n i n I G A fr o m b aseli ne ( Da y 1) of 2 p oi nts or m ore, a n d 
c.
Reac hi n g a n E A SI- 7 5 res p o nse c o m pare d t o baseli ne ;

Re vie w of I ncl usi o n/ E xcl usi o n Cri teria;

Ra n d o mize s u bject if all res p o n der a n d i ncl usi o n criteria are met , an d n o ne of t he 
e xcl usi o n criteria are met; 

S u bjects n ot meeti n g t he res p o n der criteria re q uire d f or ra n d o mizati o n 
(ie, n o n -res p o n ders) are t o be disc o nti n ue d a n d e nter t he 4 - wee k foll o w - u p safety 
per i o d; or e nr oll i nt o t he P F-0 4 9 6 5 8 4 2 L o n g Ter m E xte nsi o n ( L TE) st u d y B 7 4 5 1 0 1 5 
pr o vi di n g t he y  re mai n eli gi ble;

A ssess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifestyl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w a n y c ha n ges i n t he s u bj ect’s c o nc o mita nt me dicati o ns a n d treat me nts 
i nf or mati o n;

Re vie w e Diar y  t o assess c o m pleti o n;

Perf or m dr u g acc o u n ta bilit y pr oce d ures;

A d mi nister last d ose of o pe n-la bel r u n-i n peri o d st u d y dr u g ( 2 0 0 m g) ;

O btai n a bl o o d sa m p le f or P K a nalys is at 2. 0 h o urs (3 0 mi n) p ost d ose of o pe n -la bel 
st u d y dr u g ( 2 0 0 m g ).  For Earl y Ter mi nati o n ( E T) visits, if t he s u bject disc o nti n ues 
bef ore Wee k 4, d o n ot c ollect a P K sa m ple.  If t h e ET visit occ urs at or after Wee k 4 
a n d bef ore Wee k
1 2, c ollect a P K sa m ple o nl y if t he s u bject ta kes t he i n vesti gati o nal 
pr o d uct at t he site vi sit;

Dis pe nse bli n d e d i n vesti gati o nal pr o d uct t o t he s u bject t o i nitiate ra n d o mize d 
treat me nt me dicati o n t he day after t he Wee k 1 2 visit; 

Assess a n d rec or d a n y  A d verse E ve nts si nce t he last visit;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 0

A d mi nister A C Q test f or all s u bjects wit h a pri or dia g n osi s of ast h ma. 
6. 3. 2. Visit 9, D a y 1 1 3/ Wee k 1 6 ( 3 d a ys) 

A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  F or s u bjec ts meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s h o uld be 
d o ne t o deter m i ne w het her it is safe f or t he s u bject t o c o ntin ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q-5 D -Y i n select c o u ntries); 

A d olesce nts 1 2 - 1 7 ye ars of a ge will c o m plete t he C D L QI  i nstea d of the D L QI a n d t he 
E Q - 5 D- Y i n select c o u ntries i nstea d of t he E Q- 5 D-5 L ;

Re vi e w P S A A D dail y c o m pleti o n (i n selecte d c o u ntries) a n d pr urit us N R S 
c o m pleti on f or t his visit i n t he e Diar y ; 

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure , res pirat or y rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2-lea d E C G;

C o n d uct tar gete d p h ys ical e xa mi nati o n;

O btai n sa m p les f or la b orat or y testi n g: ser u m c he mistr y, he mat ol o g y (i ncl u di n g 
c oa g ulati o n pa nel, R B C/ W B C I n dices, l y m p h o c y te s u bsets a n d mar kers) a n d 
uri nal y sis; 

Uri ne pre g na nc y  test (fe male s ubjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o btaine d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

Det er mi ne if t he s u bject e x perie nce d a flare, defi ne d as a l oss of at least 5 0 % of t he 
E A SI res p o nse at Wee k 1 2 a n d a n I G A of 2 or hi g her.  If flare, t he s u bject will e nter 
t he resc ue pe ri o d (see Secti o n 6. 5 );

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifestyl e re q uir e me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bilit y t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or w ar d i n t he st u d y;

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nts 
i nf or mati o n;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 1

R e vie w e Diar y t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Dis pe nse i n vesti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit.
6. 3. 3. Vis it 1 0, D a y 1 9 7/ Wee k 2 8 ( 7 d a ys) 

A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  F or s u b jects meeti n g a n y of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s h o ul d be 
d o ne t o det er mi ne w het her it i s safe f or t he s u bject t o c o ntin ue t o partici pate i n t he 
trial;

A d mi nist er P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q-5 D - Y i n select c o u ntries); 

A d olesce nts 1 2 - 1 7 ye ars of a ge will c o m plete t he C D L QI  i nstea d of t he D L QI a n d t he 
E Q - 5 D- Y i n select c o u ntries i nstea d of t he E Q- 5 D-5 L ;

R e vie w P S A A D dail y c o m pleti o n (i n selecte d c o u ntries) a n d pr urit us N R S 
c o m pleti o n f or t his visit i n t he e Diar y; 

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y  rate a n d oral or 
t ym p a nic te m perat ure (after at least 5 mi n utes of rest);

P erfor m a si n gle 1 2 -lea d E C G;

C o n d uct tar gete d p h ys ical e xa mi nati o n;

O btai n sa m ples f or la b orat o r y testi n g: ser u m c he mistr y, he mat ol o g y (i ncl u di n g 
c oa g ulati o n pa nel, R B C/ W B C i n dices, l y m p h oc y te s u bsets a n d mar kers) a n d 
uri nal y sis; 

F or C hi na a n d Tai wa n o nl y : For s u bjects w h o ha d H B V D N A testi n g at Scree ni n g, 
c ollect bl o o d sa m ple f or re peat H B V D N A testi n g; 

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calculate d i n 
t he E A SI);


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 2

Deter mi ne if t he s u bject e x perie nce d a flare, defi ne d as a l oss of at least 5 0 % of t he 
E A SI  res p o nse at Wee k 1 2 a n d a n I G A of 2 or hi g her.  If flar e, t he s u bject will e nter 
t he resc ue peri o d (see Secti o n 6. 5 );

Assess nee d f or c o ntrace pti o n a n d a d he re nce t o a p plica ble lifestyl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w a n y c ha n ges i n t he s u bje ct’s c o nc o mita nt me dicati o ns a n d treat me nts 
i nf or mati o n;

Re vie w e Diar y  t o assess c o m pleti o n;

Pe rf or m dr u g acc o u nta bilit y pr oce d ures;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Dis pe nse i n vesti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d ve rse E ve nts si nce t he last visit.
6. 3. 4. Visit 1 1, D a y 2 8 1/ Wee k 4 0 ( 7 d a ys) 

A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  F or s u bjects meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s h o ul d be 
d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o nti n ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q-5 D -Y i n select c o u ntries); 

A d oles ce nts 1 2-1 7 y ears of a ge will c o m plete t he C D LQI  i nstea d of t he D L QI a n d t he 
E Q - 5 D-Y i n select c o u ntries i nstea d o f t he E Q- 5 D-5 L ;

Re vie w P S A A D dail y c o m pleti o n (i n selecte d c o u ntries) a n d pr urit us N R S 
co m pleti o n f or t his visit i n t he e Diar y ; 

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d E C G;

C o n d uct tar gete d p h ys ical e xa mi nati o n;

O bt ai n sa m ples f or la b orat or y  testi n g: ser u m c he mistr y, he matol o g y  (i ncl u di n g 
c oa g ulati o n pa nel, R B C/ W B C In dices, l y m p h oc y te s u bsets a n d mar kers) a n d 
uri nal y sis; 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 3

F or C hi n a a n d Tai wa n o nl y : F or s u bjects w h o ha d H B V D N A testi n g at Scree ni n g, 
c ollect bl o o d sa m p le f or re peat H B V D N A testi n g;

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

C o n d uct cli n ical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

Deter mi ne if t he s u bject e x perie nce d a flare, defi ne d as a l oss of at least 5 0 % of t he 
E A SI  res p o nse at Wee k 1 2 a n d a n I G A of 2 or hi g her.  If flare, t he su bject will e nter 
t he rescue peri o d (see Secti o n 6. 5 );

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bilit y t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w a n y  c han ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nts 
i nf or mati o n;

Re vie w e Diar y  t o assess c o m pleti on;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Dis pe nse i n vesti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit.
6. 3. 5. Visit 1 2, D a y 3 6 5/ Wee k 5 2 ( 3 d a ys) E n d of Tre at me nt ( E O T) or E arl y 
Ter mi n ati o n ( E T)

A d mi nist er a n d sc ore t he Si nce Last Visit C- S S R S.  F or s u bjects meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s h o uld be 
d o ne t o deter m i ne w het her it is safe f or t he s u bject t o c o nti n ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S, E Q - 5 D- 5L 
( or E Q- 5 D-Y i n select c o u ntries), S F - 3 6 v 2, Ac ute a n d F A CI T-F ( or Pe ds -F A CI T- F).  
S F - 3 6v 2 will be c o m plete d b y  a d ult s u bjects onl y ; 

A d olesce nts 1 2 - 1 7 ye ars of a ge will n ot c o m plete t he S F -3 6 v 2.  A d olesce nts
1 2 - 1 7 ye ars of a ge will c o m plete t he C D L QI i nst ea d of t he D L QI, t he E Q - 5 D- Y i n 
select c o u ntries i nstea d of t he E Q- 5 D-5 L  a n d Pe ds-F A CI T - F i nstea d of t he F ACI T- F;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 4

Re vie w P S A A D d ail y c o m pleti o n (i n selecte d c o u ntries) a n d pr urit us N R S 
c o m pleti o n f or t his visit i n t he e Diar y; 

O btai n wei g ht f or all s u bject s a n d hei g ht f or a d olesce nts o nl y ( 1 2 t o < 1 8 ye ars ol d);

O btai n vital si g ns i ncl u di n g p u lse rate, bl o o d press ure, res pirat or y rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d E C G; 

C o n d uct a c o m plete p h ys ical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

Deter mi ne if t he su bject e x perie nce d a flare, defi ne d as a l oss of at least 5 0 % of t he 
E A SI  res p o nse at Wee k 1 2 a n d a n I G A of 2 or hi g her.  If flare, t he s u bject will e nter 
t he resc ue peri o d (Secti o n 6. 5 );

O bt ai n fasti n g sa m ples f or la b orat or y  testi n g: ser u m c he mistr y, he mat ol o g y 
(i ncl u di n g c oa g ulati o n pa nel, R B C/ W B C i n dices, l y m p h oc y te s u bsets a n d mar kers), 
lipi d pr ofile, a n d uri nal ys is; 
 

F o r C hi na a n d Tai w a n o n l y: F or s u bjects w h o ha d H B V D N A testi n g at Scree ni n g, 
c ollect bl o o d sa m ple f or re peat H B V D N A testi n g;

F oll o wi n g o ne year of t otal e x p os ure t o st u d y dr u g si nce t he last T B test, all s u bjects 
i n re gi o ns w hic h are a bo ve a l o w ris k f or T u berc ul osis (ie , > 1 0/ 1 0 0, 0 0 0 pre vale nce) 
will u n der g o t u berc ul osis ( T B) testi n g.  If s o, e ns ure testi n g is perf or me d as per 
Secti o n 7. 3. 4 .  A n e gati ve test res ult f or t u berc ul osis is re q uire d f or o n g oi n g 
eli gi bilit y f or st u d y partici pati o n;

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g n a nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct; 

S u bjects w h o c o m plete d t he 4 0 w ee ks of bli n de d treat me nt wit h o ut e x perie nci n g flare 
will b e assesse d f or eli gi bilit y t o e nter L T E st u d y B 7 4 5 1 0 1 5.  S u bjects w h o are n ot 
eli gi ble or are n ot i nterested are t o c o nti n u e i n t he 4-wee k, u ntreate d safet y f oll o w- u p 
peri o d;

Assess nee d f or c o ntra ce pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a b ilit y t o c o m pl y wit h lifesty le re q uire me nts 
g oi n g f or war d i n t he st u d y;
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 5

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nts 
i nf or mati o n;

Re vie w e Diar y  t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister last d ose of i n vesti gati o nal p r o d uct as part of t he bli n de d mai nte na nce 
peri o d t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit;

A d mi nister A C Q test f or all s u bjects wit h a pri or dia g n osis of ast h ma. 
6. 4. F oll o w -u p Visit
6. 4. 1. Visi t 1 3, 4 Wee ks P ost E n d of Tre at me nt / E arly Ter mi n ati o n - E n d of St u d y
( ±3 d a ys)

A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  F or s u bjects meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k asses s me nt b y a q ualified M H P s h o ul d be 
d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o nti n ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S, E Q - 5 D-5 L  
( or E Q- 5 D-Y i n select c o u ntries), S F - 3 6 v 2, Ac ute a n d F A CI T-F ( or Pe ds -F A CI T- F ).  
S F -3 6 v 2 will be c o m plete d b y  a d ult s u bjects o nl y; 

A d olesce nts 1 2 -1 7 y ears of a ge will n ot c o m plete t he S F -3 6 v 2.  A d olesce nts
1 2 - 1 7 ye ars of a ge will c o m p lete t he C D L QI i nstea d of t he D L QI, t he E Q- 5 D- Y i n 
select c o u ntries i nstea d of t he E Q- 5 D-5 L  a n d Pe ds- F A CI T -F i nstea d of t he F A CI T -F; 

Re vie w P S A A D dail y  c o m pleti o n (i n selecte d c o u ntr ies) a n d pr urit us N R S 
c o m pleti o n f or t his visit i n t he e Diar y;

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y rate a n d oral or 
ty m pa nic te m perat ure (after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d E C G;

C o n d uct tar gete d p h ys ical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

O btai n fasti n g sa m ples f or la b orat or y  testi n g: ser u m c hemistr y, he mat ol o g y 
(i ncl u di n g c oa g ulati o n pa nel, R B C/ W B C In dices, l y m p h oc y te s u bsets a n d mar kers), 
li pi d pr ofile, a n d uri nalys is; 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 6

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of whet he r t he y ha ve e x perie nce d me narc he); 

Assess a d here nce t o c o ntrace pti o n a n d a p plica ble lifest y le re q uire me nts (Secti o n 4. 4 );

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt m e dicati o ns a n d t reat me nts 
i nf or mati o n;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit;

A d mi nister A C Q test f or all s u bjects wit h a pri or dia g n osis of ast h ma.
6. 5. Resc ue Tre at me nt Peri o d 
S u bjects will be i nstr ucte d t o c o ntact t he site if t he y e x per ie nce a si g nifica nt w orse ni n g of 
t heir at o pic der matitis, s uc h as a rec urre nce of pr urit us, d uri n g t he d o u ble-bli n d treat me nt 
peri o d.   Site staff will deter mi ne if t he s u bject s h o ul d ret ur n t o t he site f or a n u nsc he d ule d 
(see Secti o n 6. 5. 1 ) or re g ularl y sc he d ule d visit (see Secti o n 6. 3 ).  At t he visit (re g ular or 
u n pla n ne d) t he s u bject will be assesse d f or flare, defi ne d as a l oss of at least 5 0 % of t he 
E A SI  res p o nse at Wee k 1 2 a n d a n I G A sc ore of 2 or hi g her.  S u bjects w h o meet t he 
defi niti o n of flare are t o recei ve resc ue treat me nt a n d e nter a n o pe n -la bel resc ue peri o d 
d uri n g w hic h t he y  recei ve 1 2-wee ks of 2 0 0 m g  P F -0 4 9 6 5 8 4 2 Q D wit h c o nc o mita nt t o pical 
t hera py per S O C.  See Secti o n 5. 2. 1 f or g ui da nce o n t o pical t hera pies. 
After c o m ple ti n g t he resc ue peri o d, s u bjects are all o we d t o e nter t he L T E st u d y  B 7 4 5 1 0 1 5, if 
eli gi ble.  If a s u bject di sco nti n ues pre mat urel y or is n ot eli gi ble or willi n g t o partici pate i n 
B 7 4 5 1 0 1 5, t he n t he s u bject e nters t he 4 - wee k, u ntreate d f oll o w- u p safety peri o d.  Ref er t o 
Sc he d ule of Acti vities f or Resc ue Treat me nt . 
S u bjects n ot me eti n g t he defi niti o n of flare will c o nti n ue o n t heir bli n de d treat me nt.  
P h y sicia ns ma y c o nti n ue t o cli nicall y e val uate f or flare usi n g t he E A SI a nd I G A as sess me nts 
at t heir discreti o n. 
6. 5. 1. Resc ue Tre at me nt - Fl are Occ urri n g at a n U n pl a n n e d Visit ( Resc ue Vi sit 1, 
D a y 1/ Wee k 0 ( 3 d a ys) )

A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  F or s u bjects meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s ho ul d b e 
d o ne t o deter m i ne w het her it is safe f or t he s u bject t o c o ntin ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S, E Q - 5 D- 5L 
( or E Q- 5 D-Y i n select c o u ntries), S F - 3 6 v 2, Ac ute a n d F A CI T-F ( or Pe ds -F A CI T- F).  
S F - 3 6 v 2 will be c o m plete d b y  a d ult s u bjects o nl y; 

A d olesce nts 1 2 - 1 7 ye ars of a ge will n ot c o m plete t he S F -3 6 v 2.  A d olesce nts
1 2 - 1 7 ye ars of a ge will c o m p lete t he C D L QI i nstea d of t he D L QI, t he E Q - 5 D- Y i n 
select c o u ntries i nstea d of t he E Q- 5 D-5 L  a n d Pe ds-F A C I T-F i nstea d of t he F A CI T- F;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 7

Re vie w P S A A D dail y  c o m pleti o n (i n selecte d c o u ntr ies) a n d pr urit us N R S 
c o m pleti o n f or t his visit i n t he e Diar y.  I nstr uct the s u bject t hat t he pr uritis N R S 
c o m pleti o n will be c ollecte d dail y  i n t he e Diar y fr o m D a ys 1-1 5 d uri n g resc ue
treat me nt a n d the n o nl y o n st u d y  visit da ys at t he i n vesti gat or site t hereafter.  P S A A D 
will be c o m plete d dail y  (i n selecte d c o u ntries) i n t he e Diar y fr o m D a y 1 t hr o u g h t he 
E O S visit d uri n g resc ue treat me nt.  Re vie w e Diar y pr oce d ures wit h s u bject as
ne cess ar y;

O btai n wei g ht f or all s u bjects a n d hei g ht f or a d olesce nts o nl y  ( 1 2 t o < 1 8 ye ars ol d);

C o n d uct tar gete d p h ys ical e xa mi nati o n; 

O btai n vital s i g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y  rate a n d oral or 
t ym pa nic te m perat ure (after at l east 5 mi n utes of rest );

Perf or m a si n gle 1 2 -lea d E C G;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI); 

O btai n fasti n g sa m ples f or la b orat or y  testi n g: ser u m c he mistr y, he mat ol o g y 
(i ncl u di n g c oa g ulati o n, R B C/ W B C In dic es, l ym p h oc y te s u bsets a n d mar kers), li pi d 
pr ofile, a n d uri nal ys is;
 

F oll o wi n g o ne year of t otal e x p os ure t o st u d y  dr u g si nce t he last T B test, all s u bjects 
i n re gi o ns w hic h are a b o ve a l o w ris k f or Tu be rc ul osis (ie, > 1 0/ 10 0, 0 0 0 pre vale nce) 
will u n der g o t u berc ul osis ( T B) testi n g.  If s o, e ns ure testi n g is perf or me d as per 
Secti o n 7. 3. 4 .  A ne gati ve test res ult f or t u berc ul osis is re q uire d f or o n g oi n g 
eli gi bilit y f or st u d y partici pati o n;

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o b taine d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct;

Re vie w a n y c ha n ges i n t he s u bject’s pri or a n d c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n; 

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w e Diar y t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 8

A d mi nister i n vesti gat i o nal pr o d uct t o t he s u bject;

Dis pe nse i n vesti gati o nal pr o d uct t o t he s u b ject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit;

A d mi nister A C Q test f or all s u bje cts wit h a pri or dia g n osis of ast h ma. 
6. 5. 2. Resc ue Tre at me nt – Visit 2, D a y 8/ Wee k 1 ( 1 d a y)

Ca ll s u bject a n d co nfir m c o m plia nce wit h dail y c o m pleti o n of pr urit us N R S a n d 
P S A A D (i n selecte d c o u ntries); 

Ver ball y c o nfir m s u bject has bee n c o m plia nt wit h st u d y  d osi n g a n d e ntr y i n t he 
e Diar y.  Re vie w e Diar y pr oce d ures wit h s u bject as necessar y;

Re vie w a n y  c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h w illi n gness a n d a bilit y t o c o m pl y wit h lifestyl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit .
6. 5. 3. Resc ue Tre at me nt – Visi t 3, D a y 1 5/ Wee k 2 (1 d a y)

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a nd 
E Q - 5 D-5 L  ( or EQ- 5 D -Y i n select c o u ntries);

A d olesce nts 1 2 -1 7 y ears of a ge will c o m plete t he C D L QI  i nstea d of t he D L QI a n d t he 
E Q - 5 D-Y i n select c o u ntries i nstea d o f t he E Q- 5 D-5 L ;

Re vie w dail y P S A A D c o m pleti o n (i n selecte d c o u ntries) a n d dail y pr ur it us N R S 
c o m pleti o n i n t he e Diar y; Instr uct s u bject t hat pr urit us N R S will n o w be c o m plete d 
o nl y  at site visits, b ut t he P S A A D will still be c o m plete d dail y i n t he e Diar y. Re vie w 
e Diar y pr oce d ures wit h s u bject as necessar y;

Re vie w a n y c ha n ges i n t he s u bje ct’s c onc o mita nt me dica ti o ns a n d treat me nt 
i nf or mati o n;

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y  rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d E C G;

C o n d uct a tar gete d p h ys ical e xam; 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 9

C o n d uct cli nica l e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI a n d B S A (calc ulate d i n 
t he E A SI);

O btai n sa m ples f or la b orat or y testi n g: ser u m c he mistr y , he mat ol o g y (i ncl udi n g 
c oa g ulati o n, R B C/ W B C i n dices, l ym p h oc y te s u bsets a n d mar kers) a n d uri nal ysis;

F o ll owi n g o ne year of t o tal e x p os ure t o st u d y dr u g si nce t he last T B test, all s u bjects 
i n re gi o ns w hic h are a b o ve a l o w ris k f or T u berc ul osis (ie, > 1 0/ 1 0 0, 0 0 0 pre vale nce) 
will u n der g o t u berc ul osis ( T B) testi n g.  If s o, e ns ure testi n g is perf or me d as per 
Secti o n 7. 3. 4 .  A ne g ati ve test res ult f or t u berc ul osis is re q uire d f or o n g oi n g 
eli gi bilit y f or st u d y partici pati o n;

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olescents
a ge d 1 2 ye ars an d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne gati ve uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct;

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e req ui re me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bilit y t o c o m pl y wit h lifestyl e re q uire me nts 
g oi n g f or war d i n t he st u d y ;

Re vie w e Diar y  t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  proce d ur es;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit.
6. 5. 4. Resc ue Tre at me nt – Visit 4, D a y 2 9/ Wee k 4 ( 2 d a ys)

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q-5 D -Y i n s elect c o u ntries) ; 

A d olesce nts 1 2 -1 7 y ears of a ge will c o m plete t he C D L QI  i nstea d of t he D L QI a n d t he 
E Q - 5 D- Y i n select c o u ntries i nstea d of t he E Q- 5 D-5 L ;

Re vie w P S A A D dail y c o m pleti o n (i n selecte d c o u ntr ies) a n d pr urit us N R S 
c o m pleti o n f or t his visi t in t he e Diar y .  Re vie w e Diar y pr oce d ures wit h s u bject as 
necessar y ;

Re vie w a n y c ha n ges i n t he s u bject’s pri or a n d c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;

O bta i n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y rate a n d oral or 
t ym pa n ic te m perat ure (after at least 5 mi n utes of rest);


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 0

Perf or m a si n gle 1 2 -lea d electr ocar di o gra m ( E C G);

C o n d uct tar gete d p hys ical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI a n d B S A (calc ulate d i n 
t he E A SI);

O btai n fasti n g sa m ples f or la b orat or y testi ng: ser u m c he mistr y , he mat ol o g y 
(i ncl u di n g c oa g ulati o n pa ne, R B C/ W B C i n dices, l y m p h oc yte s ubsets a n d mar kers), 
li pi d pr ofile a n d uri nalys is;

F oll o wi n g o ne y ear of t otal e x p os ure t o st u d y dr u g si nce t he last T B test, all s u bjects 
i n re gi o ns whic h are a b o ve a l o w ris k f or T u berc ul osis (ie, > 1 0/ 1 0 0, 0 0 0 pre vale nce) 
will u n der g o t u berc ul osis ( T B) testi n g.  If s o, e ns ure testi n g is perf or me d as per 
Secti o n 7. 3. 4 .  A ne gati ve test result f or t u berc ul osis is re q uire d f or o n g oi n g 
eli gi bilit y f or st u d y partici pati o n;

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y  ha ve e x perie nce d me narc he).  A 
ne g ative uri ne pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vesti gati o nal pr o d uct;

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire ments 
(Secti o n 4. 4 ).  Esta blish willi n g ness a n d a bilit y t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w e Diar y  t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Dis pe nse i n vesti gati o nal pr o d uct to t he s u bject;

Asse ss a n d rec or d a ny A d verse E ve nts si nce t he last visit.
6. 5. 5. Resc ue Tre at me nt – Visit 5, D a y 4 3/ Wee k 6 ( 3 d a ys)

Call s u bject a n d c o nfir m c o m plia nce wit h d ail y c o m pleti o n of P S A A D (i n selecte d 
c o u ntries);

Ver ball y c o nf ir m s u bject has bee n co m p liant wit h st u d y  d osi n g a n d e ntr y i n t he 
e Diar y.  Re vie w e Diar y pr oce d ures wit h s u bject as necessar y;  

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 1

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble life sty le re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifestyl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Assess a n d rec or d a n y A d verse E ve nts si nce t he l ast visit.
6. 5. 6. Resc u e Tre at me nt – Visit 6, D a y 5 7/ Wee k 8 ( 3 d a ys)

A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  F or s u bjects meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a ris k assess me nt b y a q ualifie d M H P s h o ul d be 
d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o nti n ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S a n d 
E Q - 5 D-5 L  ( or E Q-5 D -Y i n select c o u ntries); 

A d olesce nt s 1 2- 1 7 ye ars of a ge w ill c o m plete t he C DL Q I i nstea d of t he D L QI a n d t he 
E Q - 5 D- Y i n select c o u ntries i nstea d of t he E Q- 5 D-5 L ;

Re vie w P S A A D dail y c o m pleti o n (i n selecte d c o u ntr ies) a n d pr u ritus N R S 
c o m pleti o n f or t his visit i n t he e Diar y.  Re vie w e Diar y pr oce d ures wit h s u bject a s 
necessar y ;

Re vie w a n y c ha n ges i n t he s u bject’s pri or a n d c o nc o mita nt me dicati o ns a n d treat me nt 
i nf or mati o n;

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure , res pirat or y rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n ute s of rest);

Per f or m a si n gle 1 2-lea d E C G;

C o n d uct tar gete d p h ys ical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

O btai n s a m ples f or la b orat or y testi n g: ser u m c he mistr y, he mat ol o g y (i ncl u di n g
c oa g ul ati o n pa nel, R B C/ W B C i n dices, l y m p h oc y te s u bsets a n d mar kers) a n d 
uri nal y sis; 

F oll o wi n g o ne year of t otal e x p os ure t o st u d y dr u g si nce t he last T B test, all s u bjects 
i n re gi o ns w hic h are a b o ve a l o w ris k f or T u berc ul osis (ie, > 1 0/ 1 0 0, 0 0 0 pre vale nce ) 
will u n der g o t u berc u l osis ( T B) testi n g.  If s o, e ns ure testi n g is perf or me d as per 
Secti o n 7. 3. 4 .  A ne gati ve test res ult f or t u berc ul osis is re q uire d f or o n g oi n g 
eli gi bilit y f or st u d y partici pati o n;


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 2

Uri ne pre g na n c y test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y ha ve e x perie nce d me narc he).  A 
ne gati ve uri n e pre g na nc y test m ust be o btai ne d pri or t o d osi n g wit h t he 
i n vestigati o na l pr o d uct;

Asse ss nee d f or c o ntrace pti o n a n d a d here nce t o a p plica ble lifest yl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y;

Re vie w e Diar y  t o assess c o m pleti o n;

Perf or m dr u g acc o u nta bilit y  pr oce d ures;

A d mi nister i n vesti gati o nal pr o d uct t o t he s u bject;

Dis pe nse i n vesti gati o nal pr o d uct t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit.
6. 5. 7. Resc ue Tre at me nt - Vi sit 7, D a y 8 5/ Wee k 1 2 ( 3 d a ys) E n d of Tre at me nt 
( E O T)/ E arl y Ter mi n ati o n ( E T)

A d mi nister a n d sc ore t he Si nce Last Visit C -S S R S.  F or s u bjects meeti n g a n y  of t he 
criteri a s pecifie d i n Secti o n 7. 5. 1 a ris k assess m e nt b y a q ualifie d M H P s h o ul d be 
d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o nti n ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S, E Q - 5 D-5 L  
( or E Q- 5 D-Y i n se lect c o untries), S F - 3 6 v 2, Ac ute a n d F A CI T-F ( or Pe ds -F A CI T- F ).  
S F -3 6 v 2 will be c o m plete d b y  a d ult s u bjects o nl y; 

A d olesce nts 1 2 -1 7 y ears of a ge will n ot c o m plete t he S F -3 6 v 2.  A d olesce nts
1 2 - 1 7 ye ars of a ge will c o m p lete t he C D L QI i nstea d of t he D L QI, t he E Q - 5 D- Y i n 
select c o u ntries i nstea d of t he E Q- 5 D-5 L  a n d Pe ds-F A CI T -F i nstea d of t he F A CI T -F;

Re vie w P S A A D dail y  c o m pleti o n (i n selecte d c o u ntries) a n d pr urit us N R S 
c o m pleti o n f or t his visit i n t he e Diar y.  Re vie w e Diar y pr oce d ures wit h s u bject as 
necessa r y;

Re v ie w a ny c ha n ges i n t he s u bject’s c o nc o mita nt me dicat i o ns a n d treat me nts 
i nf or mati o n;

O btai n wei g ht f or all s u bjects a n d hei g ht f or a d olesce nts o nl y  ( 1 2 t o < 1 8 years ol d);

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y rate a n d oral or
t ym pa nic te m perat ure (after at l east 5 mi n utes of r est);


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 3

Perf or m a si n gle 1 2 -lea d E C G;

C o n d uct a c o m plete p h ys ical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d B S A (calc ulate d i n 
t he E A SI);

O btai n fasti n g sa m ples f or l a b orat or y testi n g: ser u m c he mistr y, he mat ol o g y  
(i ncl u di n g c oa g ulati o n pa nel, R B C/ W B C i n dices, l ym p h oc y te s u bsets a n d mar kers), 
li pi d pr ofile, a n d uri nalys is; 

F or C hi na a n d Tai wa n o nl y : F or s u bjects w h o ha d H BV D N A testi n g at Scree ni n g, 
c ollect bl o o d sa m pl e f or repeat H B V D N A testi n g;

F oll o wi n g o ne y ear of t otal ex p os ure t o st u d y  dr u g si nce t he last T B test, all s u bjects 
i n re gi o ns w hic h are a b o ve a l o w ris k f or T u berc ul osis (ie, > 1 0/ 1 0 0, 0 0 0 pre vale nce) 
will u n der g o t u berc ul osis ( T B) testi n g.  If s o, e ns ure testi n g is perf or me d as per 
Secti o n 7. 3. 4 .  A ne gat i ve test res ult f or t u berc ul osis is re q uire d f or o n g oi n g 
eli gi bilit y f or st u d y partici pati o n;
 

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of w het her t he y ha ve e x perie nce d me narc he);

Assess nee d f or c o ntrace pti o n a n d a d here nce t o a p pl ica ble lifestyl e re q uire me nts 
(Secti o n 4. 4 ).  Esta blis h willi n g ness a n d a bility t o c o m pl y wit h lifest yl e re q uire me nts 
g oi n g f or war d i n t he st u d y ;

If t he s u bject c o m plete d t he 1 2 wee ks of resc ue treat me nt t he y  will be assesse d f or 
eligi bilit y  t o e nter L T E st u d y B 7 4 5 10 1 5.  S u bjects w h o are n ot eli gi ble or u n willi n g 
t o partici pate are t o c o nti n ue i n t he 4- wee k, u ntreate d safety f oll o w - up peri o d;

Re vie w e Diar y  t o assess c o m pleti o n;

Pe rf or m dr u g acc o u nta bilit y pr oce d ures;

A d mi niste r last dose of i n vesti gati o nal pr o d uct as part of t he resc ue treat me nt peri o d 
t o t he s u bject;

Assess a n d rec or d a n y A d verse E ve nts si nce t he last visit;

A d mi nister A C Q test f or all s u bjects wit h a pri or dia g n o sis of ast h ma. 
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 4
6. 5. 8. Resc ue Tre at me nt - Visit 8, F ol l o w-u p V isit a n d E n d of St u d y ( ±3 d a ys)

A d mi nister a n d sc or e t he Si nce Last Visit C -S S R S.  F or s u bjects meeti n g a n y  of t he 
criteria s pecifie d i n Secti o n 7. 5. 1 a risk assess me nt b y  a q ualifie d M H P s h o ul d be 
d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o ntin ue t o partici pate i n t he 
trial;

A d mi nister P R Os i ncl u di n g: Pt G A, D L QI ( or C D L QI), P O E M, H A D S, E Q - 5 D-5 L  
( or E Q- 5 D-Y i n select c o u ntries), S F -3 6 v 2, Ac ute a n d F A CI T -F ( or Pe ds -F A CI T- F ).  
S F - 3 6v 2 will be c o m plete d b y  a d ult s u bjects o nl y; 

A d ol esce nts 1 2 -1 7 y ears of a ge will n ot c o m plete t he S F -3 6 v 2.  A d olesce nts
1 2 - 1 7 ye ars of a ge will c o m plete t he C D L QI i nstea d of t he D L QI, t he E Q- 5 D- Y i n 
select c o u ntries i nstea d of t he E Q- 5 D-5 L  a n d Pe ds-F A CI T -F i nstea d of t he F A CI T -F; 

Re vie w P S A A D dail y  c o m pleti o n (i n selecte d c o u ntries) a n d pr urit us N R S 
co m pleti o n f or t his visit i n t he e Diar y ;

Re vie w a n y c ha n ges i n t he s u bject’s c o nc o mita nt me dicati o ns a n d treat me nts 
i nf ormati o n;

O btai n vital si g ns i ncl u di n g p ulse rate, bl o o d press ure, res pirat or y  rate a n d oral or 
t ym pa nic te m perat ure (after at least 5 mi n utes of rest);

Perf or m a si n gle 1 2 -lea d E C G;

C o n d uct a tar gete d p h ys ical e xa mi nati o n;

C o n d uct cli nical e val uati o ns i ncl u di n g I G A, S C O R A D, E A SI  a n d BS A (calc u late d i n 
t he E A SI);

O btai n fasti n g sa m ples f or la b orat or y  testi n g: ser u m c he mistr y, he mat ol o g y
(i ncl u di n g c oa g ulati o n pa nel, R B C/ W B C i n dices, l y m p h oc yte s u bsets a n d mar kers), 
li pi d pr ofile, a n d uri nalys is; 

F oll o wi n g o n e year of t otal e x p os ure t o st u d y dr ug si nce t he last T B test, all s u bjects 
i n re gi o ns w hic h are a b o ve a l o w ris k f or T u berc ul osis (ie, > 1 0/ 1 0 0, 0 0 0 pre vale nce) 
will u n der g o t u berc ul osis ( T B) testi n g.  If s o, e ns ure testi n g is perf or me d as per 
Secti o n 7. 3. 4 .  A ne gati ve test res u lt f or t u berc ul osis is re q uire d f or o n g oi n g 
eli gi bilit y f or st u d y partici pati o n;

Uri ne pre g na nc y  test (fe male s u bjects of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts 
a ge d 1 2 ye ars a n d ol der re gar dless of whet her t he y  ha ve e x perie nce d me narc he); 

Assess a d here nce t o c o ntrace pti o n a n d a p plica ble lifest y le re q uire me nts (Secti o n 4. 4 );  

Re vie w e Diar y  t o assess c om pleti o n;


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
As sess a n d rec or d a n y A d ver se E ve nts si nce t he last visit;

A d mi nister A C Q test f or all s u bjects wit h a pri or dia g n osis of ast h ma .
6. 6. S u bject Wit h dr a w al
O n g oi n g s afet y c o ncer n at t he ti me of s u bject wit h dr a w al fr o m t he st u d y :
If a s u bject has a cli nicall y si g nifica nt, treat me nt-e mer ge nt, a b n or malit y at t he ti me of 
wit h dra wal fr o m t he st u d y, t he Pfizer Me dical M o nit or ( or desi g nee) s h o ul d be n otifie d a n d 
e ver y eff ort s h o ul d be ma de t o arra n ge f oll o w-u p e val uati o ns at a p pr o priate i nter vals t o 
d oc u me nt t he c o urse of t he a b n or mality.  All a b n or mal la b orat or y  e ve nts of cli nical 
si g nifica nce s h o ul d be f oll o we d u ntil t he la borat or y val ues ha ve ret ur ne d t o n or mal or 
baseli ne le vels or are dee me d cli nicall y  sta ble.  F oll o w-u p f or a b n or mal la b orat or y  fi n di n gs 
a nd a d verse e v e nts b y t he i n vestigat or is re q uire d u ntil t he e ve nt or its se q uelae res ol ve or 
sta bilize at a le vel acce pta ble t o t he i n vesti gat or, a n d Pfizer c o nc urs wit h t hat assess me nt.  
Refer t o A p pe n di x 4 f or G ui deli nes f or Mo nit ori n g a n d Disc o nti n uati o n. 
Wit h d r a w al of c o nse nt :
S u bjects ( le gall y acce pta ble re prese ntati ve/pare nt(s) or le gal g uar dia n, as a p plica ble) w h o 
re q uest t o disc o nti n ue recei pt of st u d y treat me nt will re mai n i n t he st u d y.  If t his re q uest 
occ urs at a sc he d ule d visit, a n e n d of treat me n t visit s h o ul d be perf orme d a n d t he s u bject 
s h o ul d e nter i nt o t he f oll o w-u p peri o d, wit h a n e n d of st u d y  visit sc he d ule d f or 4 wee ks after 
t he e n d of treat me nt visit.  If t he re q uest occ urs o utsi de of a sc he d ule d visit (e g, via tele p h o ne
c o ntact) t he s u bje ct s h oul d be sc he d ule d t o ret ur n t o site f or a n e n d of treat me nt visit wit hi n 
o ne wee k after t heir last d ose, a n d t he s u bject s h o ul d e nter i nt o t he f oll o w -u p peri o d, wit h a n 
e n d of st u d y visit sc he d ule d f or 4 wee ks after t he e n d of treatme nt visit. 
T he o n l y e xce pti o n t o t his is w he n a s u bject ( le gall y acce pta ble re prese ntati ve/pare nt(s) or 
le gal g uar dia n, as a p plica ble) s pecificall y wit h dra ws c o nse nt f or a n y f urt her c o ntact wit h hi m 
or her or pers o ns pre vi o usl y  a ut h orize d b y t he s u bject t o pr o vi de t his i nfor mati o n.  S u bjects 
(le gall y acce pta ble re prese ntati ve/pare nt(s) or le gal g uar dia n, as a p plica ble) s h o ul d n otif y t he 
i n vesti gat or i n writi n g of t he decisi o n t o wit h dra w c o nse nt fr o m f ut ure f oll o w-u p, w he ne ver 
p ossi ble.  T he w it h dra wal of c o nse nt s h o ul d be e x plaine d i n detail i n t he me dical rec or ds b y 
t he i n vesti gat or, as t o w het her t he wit h dra wal is o nl y fr o m f urt her recei pt of i n vesti gati o nal 
pr o d uct or als o fr o m st u d y pr oce d ures a n d/ or p osttreat me nt st u d y  f oll o w-u p, a n d e nte re d o n 
t he ap pr o priate C R F p a ge.  I n t he e ve nt t hat vital stat us ( w het her t he s u bject is ali ve or dea d) 
is bei n g meas ure d, p u blicl y a vaila ble i nf or mati o n s h o ul d be use d t o deter mi ne vital stat us 
o nl y  as a p pr o priately directe d i n acc or da nce wit h l ocal la w.
L ost t o f oll o w -u p: 
All reas o na ble ef f orts m ust be ma de t o l ocate s u bjects t o deter mi ne a n d re p ort t heir o n g oi n g 
stat us.  T his i ncl u des f oll o w-u p wit h pers o ns a ut h orize d b y  t he s u bject as n ote d a b o ve.  L ost 
t o f oll o w-u p is defi ne d b y  t he i na bility t o reac h t he s u bject after a mi ni m u m of 2 d oc u me nte d 
p h o ne c alls, fa xes, or e - mails as well as lac k of res p o nse by t he s u bject t o 1 re gistere d mail 


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letter.  All atte m pts s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds.  If it is 
deter mi ne d t hat t he s u bject h as die d, t he site will use loca ll y per missi ble met h ods t o o btai n 
t he date a n d ca use of deat h.  If t he i n vesti gat or’s use of a t hir d-part y re prese ntati ve t o assist 
i n t he f oll o w-u p p orti o n of t he st u d y  has bee n i ncl u de d i n t he s u bject’s (le gall y acce pta ble 
re prese ntative/ pare nt(s) or le gal g uar dia n, as a p plica ble) i nf or me d c o nse nt, t he n t he 
i n vesti gat or ma y use a s p o ns or-retai ne d t hir d-part y  re prese ntati ve t o assist site staff wit h 
o btai ni n g t he s u bject’s c o ntact i nf or mati o n or ot her p u blic vital stat us data necessar y  t o 
c o m plete t he f oll o w- u p p orti o n of t he st u d y.  T he site staff a n d re prese ntati ve will c o ns ult 
p u blicl y  a vaila ble s o urces, s uc h as p u blic healt h re gistries a n d data bases, i n or der t o o btai n 
u p date d c o ntact i nf or mati o n.  If, after all atte m pts, t he s u bject re mai ns l ost t o f oll o w- u p, t he n 
t he last-k n o w n -ali ve date as deter mi ne d b y t he i n vesti gat or s h o ul d be re p orte d a n d 
d oc u me nte d i n t he s u bject’s me dical rec or ds.
S u bjects ma y wit h dra w fr o m t he st u d y  at a n y ti me at t heir o w n re q uest, or t he y m a y be 
wit h dra w n at a n y ti me at t he discre ti o n of t he i n vesti gat or or s p o ns or f or safet y  (see als o t he 
Wit h dra wal Fr o m t he St u d y  D ue t o A d verse E ve nts secti o n) or be ha vi oral reas o ns, or t he 
i na bilit y of t he s u bject t o c om pl y  wit h t he pr ot oc ol -re q uire d sc he dule of st u d y  visits or 
pr oce d ures at a gi ve n st u d y site.  S u bjects t hat disc o nti n ue st u d y  treat me nt will re mai n i n t he 
st u d y a n d m ust ha ve t heir e n d of treat me nt visit wit hi n 1 wee k after t heir last d ose, a n d will 
t he n e nter t he 4 wee k f oll o w u p p erio d wit h a n E n d of St u d y visit 4 wee ks after E n d of 
Treat me nt visit.  See A p pe n di x 4 f or G ui deli nes f or M o nit ori n g a n d Disc o nti n uati o n. 
If a s u bject d oes n ot ret ur n f or a sc he d ule d visit, e ver y eff ort s h o ul d be ma de t o c o ntact t he 
s ubject.  All atte m pts t o c o ntact t he s u bject a n d i nf or mati o n recei ve d d uri n g c o ntact atte m pts 
m ust be d oc u me nte d i n t he s u bject’s me dical rec or d.  I n a n y circ u msta nce, e ver y  eff ort 
s h o ul d be ma de t o d oc u me nt su bject o utc o me, if p oss i ble.  T he i n vesti gat or sh o ul d i n q uire 
a b o ut t he reas o n f or wit h dra wal, re q uest t hat t he s u bject ret ur n all u n use d i n vesti gati o nal 
pr o d uct(s), re q uest t hat t he s u bject ret ur n f or a fi nal visit, if a p plica ble, a n d f oll o w u p wit h 
t he su bject re ga r di n g a ny u n res ol ve d A Es.
If t he s u bj ect wit h dra ws fr o m t he st u d y , a n d als o wit h dra ws c o nse nt f or discl os ure of f ut ure 
i nf or mati o n, n o f urt her e val uati o ns s h o ul d be perf or me d, a n d n o a d diti o nal data s h o ul d be 
c ollecte d.  T he s p o ns or ma y  retai n an d c o nti n ue t o use a ny data c ollecte d b ef ore s uch 
wit h dra wal of c o nse nt.
7. A S S E S S M E N T S
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat t he pr ot oc ol-re q uire d tests a n d pr oce d ures are 
c o m plete d as descri be d.  H o we ver, it is a ntici pate d t hat fr o m ti me t o ti me t here m a y  be 
circu msta nces o u tsi de of t he c o ntr ol of the i n vesti gat or t hat ma y  ma ke it u nfeasi ble t o 
perf or m t he test.  I n t hese cases t he i n vesti gat or will ta ke all ste ps necessar y t o e ns ure t he 
safety a n d well -bei n g of t he s u bject.  W he n a pr ot oc ol -re q uire d test ca n n ot be perf or me d, t he 
i n vesti gat or will d oc u me nt t he reas o n f or t his a n d a n y  c orrecti ve a n d pre ve nti ve acti o ns t hat 
he or s he has ta ke n t o e ns ure t hat n or mal pr ocesses are a d here d t o as s o o n as p ossi ble.  T he 
st u d y tea m will be i nf or me d of t hese i ncide nts i n a ti mel y ma n ner.


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F or sa m ples b ei n g c oll ecte d a n d s hi p pe d, detaile d c ollecti o n, pr ocessi n g, st ora ge, a n d 
s hi p me nt i nstr ucti o ns a n d c o ntact i nf or mati o n will be pr o vi de d t o t he i n vesti gat or site pri or 
t o i nitiati o n of t he st u d y. 
7. 1. Pre g n a nc y Testi n g
F o r fe male s ubjects of c h il d beari n g p ote ntial i nclu di n g a d olesce nts a ge d 1 2 ye ars a n d ol der 
re gar dless of w het her t he y ha ve e x perie nce d me narc he, a ser u m pre g na nc y test wit h a 
se nsiti vit y of at least 2 5 mI U/ m L, will be perf or me d at scree ni n g.  A uri ne pre g na n c y  test 
wi t h a se nsitivit y  of at least 2 5 mI U/ m L, will be perf or me d at e ver y  site visit i ncl u di n g t he 
E n d of Treat me nt ( E O T) a n d f oll o w - u p visit t o c o nfir m t he s u bject has n ot bec o me pre g na nt 
d uri n g t he st u d y, a n d at t he f oll o w -u p visit. 
A ne gati ve pre g n a nc y test res ult is re quire d bef ore t he s ubject m a y  recei ve t he i n vesti gati o nal 
pr o d uct.  Pre g na nc y  tests will als o be d o ne w he ne ver 1 me nstr ual c y cle is misse d d uri n g t he 
acti ve treat me nt peri o d ( or w he n p ote ntial pre g na nc y  is ot her wise s us pecte d).  Pre g na nc y 
tests ma y  als o be re peate d if re q ueste d b y i nstit uti o nal re vie w b oar ds (IR Bs)/et hics 
c o m mittees ( E Cs) or if re q uire d b y l ocal re g ulati o ns. 
Uri ne pre g na nc y  tests m ust be se nsiti ve t o at least 2 5 mI U/ m L a n d will be c o n d ucte d wit h t he 
test kit pr o vi de d b y  t he ce ntral la b orat or y i n acc or da nce wi t h i nstr ucti o ns pr o vi de d i n its 
pac ka ge i nsert.  S u bjects w h o ha ve misse d a me nstr ual peri o d or w h o s h o w a n i n deter mi nate 
or p ositi ve res ult o n t he uri ne test ma y  n ot f urt her pr o gress i n t he st u dy u ntil pre g na nc y i s 
r ule d o ut usi n g f urt h er dia g n ostic testin g (e g , a ne gati ve q ua ntitati ve ser u m pre g na nc y  test 
c o n d ucte d at a certifie d la b orat or y).
I n t he case of a p ositi ve c o nfir me d pre g na nc y, t he s u bject will be wit h dra w n fr o m 
a d mi nistrati o n of i n vesti gati o nal pr o d uct b ut ma y re mai n i n t he st u d y u ntil c o m pleti o n of t he 
4 wee k u ntreate d f oll o w -u p peri o d.
 
 
 
 
 
 
  
 
 
C CI


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C CI


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B 7 4 5 1 0 1 4
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7. 3. S afet y Assess me nts
Safet y  will be assesse d b y t he s p o nta ne o us re p ortin g of A Es, p h ys ical e xa mi nati o ns, vital 
si g ns a n d cli nical la b orat or y res ults i n all s u bjects w h o recei ve at least o ne d ose of t he 
i n vesti gati o nal pr o d uct.  U nsc he d ule d safety assess me nts ma y be perf or me d at a n y ti me 
d uri n g t he st u d y t o assess a n y percei ved safe t y c o ncer ns.  I n vesti gat ors a n d Pfizer Cli nicia ns 
( or desi g nees) will re vie w i n di vi d ual s u bject data t hr o u g h o ut t he c o n d uct of t he st u d y t o 
e ns ure s u bjects’ well -bei n g.
7. 3. 1. Vit als Si g ns
Vital si g ns (sitti n g bl o o d press ure, p ulse rate, res pirat or y rates an d te m perat ure) will be 
meas ure d after 5 mi n utes of rest as i n dicate d i n t he Sc he d ule of Acti vities . 
B o d y te m perat ure will be c ollecte d usi n g t he t y m pa nic or oral met h o ds a n d t he sa me met h o d 
s h o ul d be used c o nsiste ntl y  thr o u g h o ut t he st u d y. 
Bl o o d press ure ( B P) will be meas ure d usi n g a sta n dar d cali brate d bl o o d press ure meas uri n g 
de vice.  A B P de vice t hat uses m ulti ple c uff sizes base d o n t he ar m circ u mfere nce is t he 
re q uire d ty pe of de vice.  T he a p pr o pria te c uff size f or t he s u bj ect m ust be use d t o e ns ure 
acc urate meas ure me nt.  T he ar m circ u mfere nce at t he mi d p oi nt of t he le n gt h of t he u p per ar m 
s h o ul d be meas ure d t o deter mi ne t he a p pr o priate c uff size i n acc or da nce wit h t he 
s pecificati o ns of the B P meas ur i n g de vice.  T he s ame pr o perl y  size d a n d cali brate d bl o o d 
press ure c uff will be use d t o meas ure bl o o d press ure eac h ti me. 
S u bjects s h o ul d be seate d i n a c hair, bac k s u p p orte d, a n d ar ms bare d (free of restricti o ns s uc h 
as r olle d - u p slee ves, etc.) a n d s u p p orte d at heart level .  Meas ure me nts s h o ul d be ta ke n o n t he 
sa me ar m at eac h visit ( prefera bly n o n - d o mi na nt).  S u bjects s h o ul d refrai n fr o m s m o ki n g or 
i n gesti n g caffei ne d uri n g t he 3 0 mi n utes prece di n g t he meas ure me nts.  Meas ure me nts s h o ul d 
be gi n after at least 5 mi n utes of rest. 
H eart rate s h o ul d be meas ure d at a p pr o xi matel y  t he sa me ti me as B P f or a mi ni m u m of 
3 0 sec o n ds.  W he n t he ti mi n g of B P a n d p ulse ( heart) rate meas ure me nts c oi nci des wit h a 
bl o o d c ollecti o n or ot her st u d y  pr oce d ure, B P a nd p ulse ( hea rt) rate s h o ul d be o btai n e d first.
7. 3. 2. Me dic al H ist or y, P h ysic al E x a mi n ati o n, Hei g ht, a n d Wei g ht
C o m plete A D disease hist or y  i ncl u des c ollecti o n of details of A D at Scree ni n g: A D 
dia g n osis, t he use of t o pical treat me nts, s ys te mic treat me nts a n d ot her treat me nt s f or A D.  
Me dic al hist or y i n a d diti o n t o A D hist or y  i ncl u di n g disease d urati o n will be c ollecte d at 
scree ni n g.  Me dical hist or y als o i ncl u des hist or y of dr u g, alc o h ol a n d t o bacc o use.  S m o ki n g 
stat us a n d a vera ge wee kl y alc o h ol c o ns u m pti o n ( u nits/ wee k) will be c ollecte d, w he re a unit 
c o ntai ns 1 2 g o f p ure alc o h ol, a n a m o u nt e q ui vale nt t o t hat c o ntai ne d i n 5 oz/ 1 5 0 m L  (a 
glass) of wi ne, 1 2 oz/ 3 6 0 m L  of beer, or 1. 5 oz/ 4 5 m L  of 9 0 pr o of of s pirits.  Hei g ht a n d 
wei g ht will be meas ure d wit h o ut t he s u bject weari n g s h oes.  Hei g h t (i nc hes or ce nti meters) 
a nd wei g ht (l bs. or k g) will be meas ure d a n d rec or de d i n t he s o urce d oc u me nt at t he 
scree ni n g visit a n d at vari o us ti me p oi nts, see Sc he d ule of Acti vities .


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C o m plete p h y sical e xa mi nati o ns m ust be perf orme d b y t he i n vesti gat or, su b- i n vesti gat or or a 
q ualifie d healt h pr ofessi o nal per l ocal g ui deli nes.  C o m plete p h y sical e xa mi nati o ns c o nsist of 
assess me nts of ge neral a p peara nce; s ki n; hea d, e yes, ears, n ose a n d t hr oat ( H E E N T); m o ut h, 
hear t; l u n gs; breast ( opti o na l); a b d o me n; e xter nal ge nitalia ( o pti o nal); e xtre mities; ne ur ol o gic 
f u ncti o n; a n d l ym p h n o des.
Tar gete d p h ys ical e xa mi nati o ns m ust be perf or me d b y t he i n vesti gat or, s u b-i n vesti gat or or a 
q ualifie d healt h pr ofessi o nal pe r l ocal g ui deli nes a n d s h o ul d i ncl u de s ki n, heart, l u n gs, a n d 
a b d o me n a n d e xa mi nati o n of b o d y sys te ms w here t here are sy m pt o m c o m plai nts b y  t he 
s u bject. 
C o m plete a n d Tar gete d p h y sical e xa mi nati o ns are perf or me d at vari o us ti me p oi nts, see 
Sc he d ule of A ctivities .
7. 3. 3. C hest X -R a y
C hest ra di o gra p h ( p osteri or-a nteri or a n d lateral vie ws) are re q uire d f or a d ults a n d 
rec o m me n de d f or a d olesce nts (as per l ocal g ui deli nes a n d sta n dar d of care) or ot her 
a p pr o priate dia g n ostic i ma ge (ie, c o m p ute d t o m o g ra p hy [ C T] or mag ne tic res o na nce i ma gi n g
[ M RI]) wit h n o e vi de nce of c urre nt, acti ve T B or pre vi o us i nacti ve T B, ta ke n at scree ni n g or 
wit hi n 1 2 wee ks pri or t o St u d y  D a y 1 a n d rea d b y  a q ualifie d ra di ol o gist.  D oc u me ntati o n of 
t he official rea din g m ust be l ocate d a n d a vail a ble i n the s o urce d oc u me ntati o n.
7. 3. 4. T u berc ul osis Testi n g
At t he ti me of scree ni n g, all s u bjects will u n der g o t u berc ul osis ( T B) testi n g u nless perf or me d 
wit hi n 1 2 wee ks of Da y  1.  Q ua nti F E R O N-T B G ol d I n- T u be Test is t he preferre d testi n g 
met h o d.  If t he Q ua n ti FE R O N -T B G ol d I n -T u be test ca n n ot be perf or me d, or if t he res ults 
ca n n ot be deter mi ne d b y t he refere nce la b orat or y t o be eit her p ositi ve or ne gati ve, t he n 
s u bjects ma y be scree ne d usi n g t he P urifie d Pr otei n Deri vati ve ( P P D) Tu berc uli n S k i n Test 
( Ma nt o u x me t h o d) wit h a p pr o val of t he Pfizer Me dical M o nit or. 
I n a d diti o n t o T B testi n g as s pecifie d i n t his cli nical pr ot oc ol, a c hest X-r a y will be 
perf or me d t o ai d i n T B stat us deter mi nati o n f or all a d ults, a n d rec o m me n de d f or a d ole sce nts 
acc ordi n g t o l ocal g u i deli nes a n d sta n dar d of care a n d/ or i n c o u ntries wit h a hi g h i nci de nce 
rate of T B.  F oll o wi n g o ne year of t otal e x p os ure t o st u d y dr u g si nce t he last T B test, all 
s u bjects i n re gi o ns w hic h are a b o ve a l o w-ris k f or T u berc ul osis (ie, > 1 0/ 1 0 0, 0 0 0 i ncide nce ) 
will u n de r g o t u berc ul osis testi n g. 
Q ua nti F E R O N -T B G ol d I n- T u be is a n i n vitr o dia g n ostic test usi n g a pe pti de c oc ktail 
si m ulati n g E S A T-6, C F P - 1 0 a n d T B 7. 7 pr otei ns t o sti m ulate cells i n he pari nize d w h ole 
bl o o d.  Detecti o n of i nterfer o n-ga m ma b y  E nz y me - Li n ke d I m mu n os or be nt Assa y  ( E LI S A) is 
use d t o i de ntif y  i n vitr o res p o nses t o t hese pe pti de a nti ge ns t hat are ass ociate d wit h 
Myc o b acteri u m t u berc ul osis
i nfecti o n.  Q ua nti F E R O N-T B G ol d I n - T u be is a n i n direct test 
f or M. t u bercul o sis i nfecti o n (incl u di n g dis ease) a n d is i nte n de d f or use i n c o nj u ncti o n wit h 
ris k assess me nt, ra di o gra p h y a n d ot her me dical a n d dia g n ostic e val uati o ns.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 1
A bl o o d sa m ple (a p pr o xi matel y  3 m L ) will be c ollecte d at scree ni n g f or Q ua nti F E R O N-T B 
G ol d I n- T u be testi n g.  F oll o wi n g sa mple pr oc essi n g, the sa m ple will be s hi p pe d t o t he 
s p o ns or’s desi g nate d refere nce la b orat or y f or testi n g.  T he pr oce d ure f or pr ocessi n g a n d 
pre pari n g t he sa m ple f or s hi p me nt is descri be d f ull y  i n t he la b orat or y ma n ual, w hic h will be 
p r o vi de d t o i n vesti gat ors.
A ne g ati ve P P D test ca n be s u bstit ute d f or t he Q ua nti F E R O N-T B G ol d I n -T u be test o nl y  if 
t he ce ntral la b orat or y is u na ble t o perf or m t he Q ua nti F E R O N-T B G ol d I n-T u be test or 
ca n n ot deter mi ne t he res ults t o be p ositi ve or ne gati ve a n d t he Pfizer Me dical M o nit or 
a p pr o ves it, o n a case-b y -case basis.
P urifie d Pr otei n Deri v ati ve ( P P D) Test
If t he Q ua nti F E R O N-T B G ol d I n - T u be test ca n n ot be perf or me d, or if t he res ults ca n n ot be 
deter mi ne d t o be p ositi ve or ne gati ve, t he n s u bjects ma y  be s cree ne d usi n g t h e P urifie d 
P r otei n Deri vati ve ( P P D) T u berc uli n Test ( Ma nt o u x met h o d), wit h t he a p pr o val of t he Pfizer 
Me dical M o nit or. 
S u bjects m ust ha ve t he P P D test a d mi nistere d a n d e val uate d b y a healt h care pr ofessi o nal 
4 8 t o 7 2 h o urs later i n or de r to be eli gi ble f o r t he st u d y, u nless perf or me d a n d d oc u me nte d 
wit hi n t he last 3 m o nt hs.  T he test s h o ul d be perf or me d acc or di n g t o l ocal sta n dar ds wit h 
i n d urati o n of < 5 m m re q uire d f or i ncl usi o n.
7. 3. 5. Electr oc ar di o gr a m
Si n gle 1 2 -lea d E C Gs s h o ul d be c ollecte d at ti mes s pecifie d i n the Sc he d ule of Acti vities
usi n g a mac hi ne pr o vi de d b y  t he ce ntral rea der.  E C G rea di n gs will be perf or me d b y a ce ntral 
rea der.
All sc he d ule d E C Gs s h o ul d be perf or me d after t he s u bject has reste d q uietl y f or at least 
1 0 m i n utes i n a s u pi ne p ositi o n a n d pri or t o a n y bl o o d c ollecti o n. 
T he scree ni n g E C G val ues will ser ve as eac h s u bject’s baseli ne val ues.  S u bjects wit h 
cli nicall y si g nifica nt E C G a b n or malities at scree ni n g are t o be e xcl u de d fr o m t he st u d y. 
7. 3. 6. S peci al S afet y A ssessme nt
I n t he e ve nt of a s us pecte d o p p ort u nistic i nfecti o n, eff ort s h o ul d be ma de t o i de ntif y t he 
pat h o ge n utilizi n g la b orat or y  or ot her met h o ds a p pr o priate t o t he cli nical sit uati o n. 
I n case of a s us pecte d viral s ki n i nfecti o n (e g, her pes z oster or he r pes si m ple x), or ecze ma 
her petic u m, a s peci me n f or viral D N A ma y  be a nal yze d l ocall y f or c o nfir mati o n a n d res ults 
pr o vi de d t o t he a dj u dicati o n c o m mittee t o s u p p ort e val uati o n. 
F or s u bjects wit h a past hist or y  of oral or ge nital her pes si mple x vir us ( H S V) a n d a 
prese ntati o n c o nsiste nt t o pri or i nfecti o ns, f urt her la b orat or y  a nalys is ma y be perf or me d at 
t he discreti o n of t he i n vesti gat or. 


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B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 2
7. 4. S ki n T y pe Assess me nt
As part of baseli ne c haracteristics, a s ki n t y pe assess me nt will be d o ne at t he Da y 1 visit 
usi n g t he Fitz patric k S ki n T y pe assess me nt ( Refer t o A p pe n di x 5 ).  T his is use d t o classif y a 
pers o n’s s ki n t y pe b y  t heir res p o nse t o s u n e x p os ure (ie, b ur ni n g or ta n ni n g).
7. 5. Assess me nt of S uici d al I de ati o n a n d Be h a v i or
S u bjects meeti n g e xcl usi o na r y res ults o n t he C-S S R S, S B Q -R a n d P H Q -8 s h o ul d be 
e xcl u de d fr o m partici pati o n; it is rec o m me n de d t he s u bject’s pri mar y  care p h ysicia n ( P C P) 
s h o ul d be i nf or me d, a n d t he s u bject referre d t o a me ntal healt h pr ofessi o nal, eit her by t he 
P C P or t he i n vesti gat or acc or din g t o t heir us ual practice.  S uc h s u bjects ma y  be rescree ne d, 
at a later date, if t he y were e val uate d a n d treate d as a p pr o priate, a n d t he re peat sc ores per mit 
i ncl usi o n.
7. 5. 1. C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S )
T he C ol u m bia S uic i de Se verity Rati n g S cale is a vali date d t o ol f or i n vesti gati ve staff t o use 
t o e val uate s uici dal i deati o n a n d be ha vi or (A p pe n di x 1 5 ).1 8  At t he scree ni n g visit, i f there 
are “ yes” ans wers o n it e ms 4 or 5 i n t he past y ear or o n a n y q uesti o n in t he s uici dal be ha vi or 
secti o n of t he C-S S R S i n t he past 5 ye ars, t he s u bject will n ot be i ncl u de d i n t he st u d y .  
Trai ne d site staff will a d mi nister t he C -S S R S t o all s u bjects at scree ni n g a n d score 
i m me diatel y t o assess t he s u bject’s eli gi bilit y base d o n t he a ns wers.
At p ost -baseli ne visits, if t here are “ y es” a ns wers o n ite ms 4, 5 or o n a n y  be ha vi oral q uesti o n 
of t he Si nce Last Visit C -S S R S ( A p pe n di x 1 6 ), a ris k asses s me nt b y a qualifie d M H P s h o ul d 
be d o ne t o deter mi ne w het her it is safe f or t he s u bject t o c o nti n ue t o partici pate i n t he trial.
S u bjects w h o ha ve rec urre nt s uici dal i deati o n a n d beh a vi or (SI B) d uri n g a cli nical trial 
s h o ul d be disc o nti nue d fr o m t he st u d y a n d treate d a p pr o priately.  If a st u dy s u bject e n d orses 
a 4 or 5 o n t he i deati o n s u bscale or a n y  be ha vi oral ite m of t he C-S S R S o n m ore t ha n 
2 occasi o ns a n d is c o nfir me d t o ha ve acti ve SI B o n b ot h occasi o ns b y a ris k assess me nt 
c o n d ucte d b y  a q ualifie d M H P,
t he n t he s ubject s h oul d be disc o nti n ue d fr o m t he st u d y  a n d 
treate d a p pr o priately.  T hese s u bjects s h o ul d be disc usse d wit h t he Pfizer Me dical M o nit or.
7. 5. 2. S uici d al Be h a vi ors Q uesti o n n aire - Re vise d ( S B Q-R)
T he S uici dal Be ha vi ors Q uesti o n naire- Re vise d ( A p pe n di x 1 7 ) is a patie nt-re p orte d 
q uesti o n naire c o nsisti n g of 4 ite ms t o assess s uici dal i deati o n, s uici de atte m pts, t hreat of 
s uici dal be ha vi or, a n d li keli h o o d of s uici dal be havi or.  At t he Scree ni n g Vi sit, if S B Q-R t ot al 
sc ore 8, t he s u bject wil l n ot be i ncl u de d i n t he st u d y.4 0  Site staff will a d mi nister t he S B Q -R 
t o all s u bjects at scree ni n g a n d sc ore i m me diatel y.
7. 5. 3. P atie nt He alt h Q uesti o n n aire – 8 ite ms ( P H Q - 8)
T he Patie nt Healt h Q uesti o n naire – 8 ite ms ( A p pe n di x 1 8 ) is a patie nt-re p orte d q uesti o n naire 
c o nsisti n g of 8 ite ms t o assess t he s u bject’s de pressi o n le vel.  At Scree nin g Visit, if P H Q - 8 
t otal sc ore 1 5, t he s u bject will n ot be i ncl u de d i n t he st u dy. 4 1  Site staff will a d mi nister t he 
P H Q -8 t o all s u bjects at scree ni n g a n d sc ore i m me diatel y .


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B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 3
7. 6. Cli nic al L a b or at o r y Tests
7. 6. 1. Bl o o d V ol u me
T otal bl o o d sa m pli n g v ol u me esti mate d f or t his st u d y de pe n ds u p o n s u bject res p o nse:

T otal bl o o d v ol u me f o r n o n-resp o n ders c o m pleti n g 1 2 wee ks is a p pr o xi matel y  
1 1 3 mls;

T otal bl o o d v ol u me f or res p o n ders c o m pleti n g 5 2 wee ks is a p pr o xi ma tel y 1 6 6 mls;

Ma xi m u m t otal bl o o d v ol u me esti mate d f or a res p o n der t hat flares o n t he last da y  of 
the mai nte na nce peri o d a n d c o m pleti n g 6 4 wee ks is a p pr o xi matel y  1 9 8 mls. 
A n a d diti o nal 5 mls is a d de d t o t hese v ol u mes f or a d olesce nts re q uiri n g V Z V testi n g.
F urt her details r e gar di n g t he c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p pi n g of t he bl o o d 
sa m ples will be pr o vi de d i n t he la b ma n ual.
7. 6. 2. L a b or at or y Tests
T he f oll o wi n g la b orat or y tests will be perf or me d at ti me p oi nts i de ntifie d i n t he Sc he d ule o f 
Acti vit ies.  U nsc he d ule d cli nical la bs ma y be o btai ne d at a ny ti me d uri n g t he st u d y t o assess 
a n y percei ve d safet y c o ncer ns at t he i n vesti gat or’s discreti o n.
Sa m ple c ollecti o n, la beli n g, st ora ge, a n d s hi p pi n g i nf or mati o n ca n be f o u n d i n t he la b orat or y 
m a n ual.  Al l la b orat or y tests wit h cli nicall y i m p orta nt c ha n ges fr o m baseli ne i dentifie d after 
a d mi nistrati o n of i n ves ti gati o nal pr o d uct will be f oll o we d u ntil t he val ue sta bilizes.
S u bjects m ust a bstai n fr o m all f o o d a n d dri n k (e xce pt wa ter a n d n o n-st u d y me dicati o ns ) f or 
a n 8-h o ur o ver ni g ht fast pri or t o la bs t hat i ncl u de t he li pi d pr ofile pa nel o n Da y 1, Wee k 4 , 
Wee k
1 2 , Wee k 5 2, a n d E O S f or s u bjects w h o c o m plete d o u ble - bli n d treat me nt.  F or 
s u bjects t hat e nter t he resc ue peri o d, fasti n g la bs are re q uire d at Resc ue Da y 1, Wee k 4, 
Wee k
1 2, a n d E O S.  All ot her la bs d o n ot re q uire fasti n g.


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B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 4
L a b or at or y Tests
H e m at ol o g y
Ser u m C he mistr y
Uri n al ysis
Ot her
H e m o gl o bi n
H e m at ocrit
R B C i n dices
M C H
M C H C
M C V
R B C M or p h ol o g y
R B C c o u nt
Retic ul oc yte c o u nt
Platelet c o u nt
W B C c o u nt wit h differe ntial
T otal ne utr o p hils ( %, 
A bs)
E osi n o p hils ( %, A bs)
M o n oc yte s ( %, A bs)
Bas o p hils ( %, A bs )
L y m p h oc ytes ( %, A bs)
C oa g ulati o n Pa nel
Acti vate d Partial 
T hr o m b o plasti n Ti me 
Pr ot hr o m bi n 
Ti m e/I nter nati o nal 
N or malize d Rati o 
(P T/I N R)
B U N a n d Creati ni ne
Creati ne P h os p h o ki nase
Gl uc ose
Na +, K +, Cl - , Ca + +
T otal C O 2 ( Bicar b o nate )
A S T,  A L T
G G T
T otal, I n dir ect & Dir ect Bilir u bi n
Al kali n e p h os p hatase
Lactate de h y dr o ge nase 
Uric aci d
Al b u mi n
T otal pr otei n
Li pi d Pr ofile Pa nel f
T otal c h olester ol
L D L 
H D L
Tri gl yceri des
p H
Gl uc ose ( q ual)
Pr otei n ( q ual)
Bl o o d ( q ual)
Ket o nes
Nitrites
Le u k oc yte esterase
Micr osc o p y a n d/ or 
c ult ured
HI V a
H Bs A g a
H Bc A b a
H Bs A b b
H C V A b a
H C V R N A b
V Z V I g G A b g
Ser u m F S H 
( p ost-me n o pa usal w o me n) 
or Pre g na nc y Test a, c
Uri ne pre g na nc y test c
Q F T -G or P P D (if 
a p plica ble) e
H S V -1, H S V -2, V Z V 
L y m p h oc yte S u bsets 
( L y m p h oc yte Mar kers)
T otal T cells ( C D 3 +)
C D 4 + T cells ( C D 3 + C D 4 +)
C D 8 + T cells ( C D 3 + C D 8 +)
N K cells 
( C D 3-C D 1 6 + C D 5 6 +)
B cells ( C D 3-C D 1 9 +)
H B V D N A h
a
At Scree ni n g o nl y.
HI V testi n g will b e perf or me d f or all s u bjects.
b
H Bs A b refle x testi n g o nl y if H Bs A g ne gati ve b ut H Bc A b p ositi ve.  H C V R N A is refle x testi n g o nl y if 
H C V A b is p ositi ve.
c
Pre g na nc y testi n g f or w o me n of c hil d beari n g p ote ntial i ncl u di n g a d olesce nts a ge d 1 2 years a n d ol der 
re gar dless of w het her t he y ha ve e x perie nce d me narc he; ser u m F S H f or w o m e n w h o ha ve bee n a me n orr heic 
f or at least 1 2 c o nsec uti ve m o nt hs.
d
Micr osc o p y wit h c ult ure perf or me d as a p pr o priate. 
e
P P D res ults s h o ul d be rea d w it hi n 4 8 t o 7 2 h o urs . 
f
Li pi d Pr ofile Pa nel re q uires at least a n 8 h o ur fast.  Li pi d pr ofile pa nel will be c o m plete d a t Da y 1, Wee k 4, 
Wee k
1 2, We e k 5 2, a n d E O S, a n d will i ncl u de t otal c h olester ol, L D L, H D L, a n d tri gl yceri des.  F or s u bjects 
recei vi n g resc ue t hera p y, a li pi d pr ofile w ill be c o mplete d at resc ue Da y 1, Wee ks 4, 1 2 a n d E O S. 
g
O nl y f or a d olesce nts w h o d o n ot ha ve d oc u me ntati o n of at lea st o ne d ose of varicella vacci ne.
h
F or C hi na a n d Tai wa n o nl y : S u bjects w h o are H Bs A g ne gati ve, H Bc A b p ositi ve, a n d H Bs A b p ositi v e at 
Scree ni n g will ha ve refle x testi n g f or H B V D N A. S u bjects w h o ha ve H B V D N A a b o ve t he l o w er li mit of 
q ua ntificati o n ( L L Q) w ill be e xcl u de d.  S u bjects w h o are H B V D N A ne gati ve or bel o w  L L Q ma y e nr oll 
b ut will ha ve H B V D N A testi n g re peate d at Wee ks 1 2, 2 8, 4 0, 5 2, Resc ue W ee k 1 2, a n d earl y ter mi nati o n
fr o m st u d y d uri n g a n y treat me nt peri o d. 
Cli nical l y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as A Es.  A b n or mal test res ults 
deter mi ne d t o be ca use d fr o m la b orat or y  err or s h o ul d n ot be re p orte d as A Es.  Cli nicall y 
si g nifica nt la b orat or y fi n di n gs at t he fi nal assess me nt s h o ul d be f oll o we d to res ol u ti o n or 
u ntil deter mi ne d b y  t he i n vesti gat or t o be sta bilize d.  Re peat tests ma y be i n dicate d t o 
esta blis h t his.  S u bjects w h o are p ositi ve f or HI V will be s cree n -faile d.  Refer t o A p pe n di x 4
f or G ui deli nes o n M o nit ori n g a n d Disc o nti n uati o n.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
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P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 5
7. 6. 2. 1. He p atitis Tes ti n g 
He p atitis B testi n g: H B s urface a nti ge n ( H Bs A g), H B c ore a nti b o d y ( H Bc A b), H B s urface 
a nti b o d y ( H Bs A b).
I nter pret ati o n of He p atitis B Testi n g Res ults:

H Bs A g ne gati ve a n d H Bc A b ne gati ve: S u bject is eli gi ble f or t he st u d y ;

H Bs A g p ositi ve a n d H Bc A b ne g ati ve: S u bject is e xcl u de d fr o m st u d y  partici pati o n;

H Bs A g ne gati ve a n d H Bc A b p ositi ve a n d H Bs A b p ositi ve: S u bject is eli gi ble f o r 
st u d y;

H Bs A g ne ga ti ve a n d H Bc A b p ositi ve a n d H Bs A b ne gati ve: S u bject is e xcl u de d fr o m 
st u d y partici pati o n.
F or C hi n a a n d T ai w a n o nl y : S u bjects w h o are H Bs A g ne gati ve, H Bc A b p ositi ve, 
a n d H Bs A b p ositi ve at Scree ni n g will ha ve refle x testi n g f or H B V D N A. S u bjects 
w h o ha ve H B V D N A a b o ve t he L L Q will be e xcl u de d.  S u bjects w h o are H B V D N A 
ne gati ve or bel o w L L Q ma y  e nr oll b ut will ha ve H B V D N A testi n g re peate d at 
Wee ks 1 2, 2 8, 4 0, 5 2, Resc ue Wee k
1 2, a n d earl y ter mi nati o n fr o m st u d y d uri n g a ny 
treat me nt peri od. 
A si n gle p o sitive H B V D N A test res ult a b o ve t he L L Q f or a s u bject re q uires 
i m me diate a n d per ma ne nt disc o nti n uati o n fr o m tre at me nt, an d t he Me dical M o nit or 
( or desi g nee) m ust be n otifie d. T he s u bject m ust be sc he d ule d f or a n E n d of 
Treat me nt visit/ Earl y Ter mi nati o n v isit, e nters t he e n d of treat me nt f oll o w u p peri o d, 
a n d m ust be sc he d ule d f or a n E n d of St u d y  visit. N o f urt her sc he d uled H B V D N A 
tests will be re q uire d f or a s u bject o nce a res ult a b o ve t he L L Q is esta blis he d f or t hat 
s u bject d uri n g a ny st u d y  i n t he pr o gra m.  F oll o w u p b y  t he i n vesti gat or is re q uire d as 
detaile d i n Secti o n 8. 1. 4. 1 . 
He p atitis C testi n g: He patitis C A nti b o d y  ( H C V A b), He patitis C Viral R N A ( H C V R N A 
f or c o nfir matio n of p ositi ve H C V A b res ult). 
I nter pret ati o n of He p atitis C Testi n g Res ults:

H C V A b p ositi ve a n d H C V R N A p ositi ve: S u bject i s e xcl u ded fr o m st u d y 
partici pati o n. 
7. 6. 2. 2. V aricell a Z ost er Vir us ( V Z V) I g G A nti b o d y ( A b) Testi n g
A d olesce nt s u bjects wit h o ut d oc u me nt e d e vi de nce of ha vi n g recei ve d at least a si n gle d ose of 
t he varicella vacci ne i n c o u ntries w here the varicella vacci ne is a p pr o ve d a n d sta n dar d of 
care will be teste d f or varicel la z oster vir us I g G A b as descri be d i n t he la b ma n ual.  S u bjects 
t hat lac k e vi de nce of pri or e x pos ure t o varicella z oster vir us base d o n ser ol o gical V Z V I g G 
A b testi n g are e xcl u de d.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 6
7. 6. 2. 3. B aseli ne Vir al Scree n 
A ser u m sa m ple will be c ollecte d at baseli ne b ut a nal yze d o nl y if t he s u bject has s us pecte d 
varicella or her pes z oster.  I n t hat e ve nt, t he sa m ple w o ul d be a nal y ze d f or H S V 1, H S V 2 a n d 
V Z V.  A d diti o nal sa m ple c ollecti o n i nstr uct i o ns will be pr o vi de d i n t he la b ma n ual (Sc he d ule
of Acti vities ).  T he retai ne d sa m ples will be destr o ye d u p o n s u bject c o m ple ti o n of t his st u d y 
or t he l o n g -ter m e xte nsi o n st u d y. 
7. 7. Effic ac y Assess me nts
7. 7. 1. R ater Q u alific ati o ns
Cli nical e val uati o ns of at o pic der matiti s will be perf or me d b y a n e x perie nce d a n d q ualifie d
der mat ol o gist ( b oar d certifie d or e q ui vale nt). A n e x perie nce d a n d q ualifie d 
n o n -der mat ol o gist p h y sicia n or e x perie nce d me dical pr ofessi o nal wit h e x perie nce i n t he
c o nd uct of der mat ol o g y cli nical trials ma y be per mitte d t o perf or m t he cli nical e val uati o ns of 
at o pic der matitis w he n desi g nate d b y t he pri mar y site I n vesti ga t or.  T he e val uat or m ust 
recei ve a n d d oc u me nt pr ot oc ol s pecific a n d a p plica ble efficac y assess me nt scales trai ni n g 
pri or t o perf o r mi n g t hese e val uati o ns.  T o ass ure c o nsiste nc y a n d re d uce v ari a bilit y, t he 
s a me e v al u at or m ust assess all der m at ol o gic al cli ni c al e v al u ati o ns f or a n y i n di vi d u al 
s u bject t hr o u g h o ut t he st u d y w he ne ver p ossi ble; a bac k-u p e x perie n ce d a n d q ualifie d, 
pr ot oc ol -trai ne d eval uat or will o nl y be all o we d a n d d oc u me nte d i n case of e mer ge n c y or
s pecial sit uati o ns w he n t he desi g nate d e val uat or is u na ble t o perf orm t he e val uati o n.
7. 7. 2. I n vesti g at or’s Gl o b al Assess me nt (I G A)
T he I G A of at o pic der mati tis is sc ore d o n a 5-p oi nt s cale ( 0- 4), reflecti n g a gl o bal 
c o nsi derati o n of er yt he ma, i n d urati o n an d scali n g.  T he cli nical e val uat or of at o pic der matitis
will perf or m a n as sess me nt of t he o verall se verity of at o pic der matitis a n d assi g n a n I G A 
sc ore a n d cate g or y as descri be d i n Ta ble 3 .  T he assess me nt will be a static e val uati o n 
wit h o ut re gar d t o t he sc ore at a pre vi o us visit.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 7
T a ble 3.
I n vesti g at or’s Gl o b al Assess me nt (I G A) Sc ore
Sc ore
C ate g or y
Descri pti o n 
0
Clear
At o pic der matiti s is cleare d, e xce pt f or a n y resi d ual disc ol orati o n 
( p ost-i nfla m mat or y h y per pi g me ntati o n a n d/ or h y p o pi g me ntati o n).
1
Al m ost 
Cl ear
O verall, t he at o pic der matitis is n ot e ntirel y cleare d a n d re mai ni n g lesi o ns 
are li g ht pi n k ( n ot i ncl u di n g p ost i nfla m mat or y h y per pi g m e ntati o n) a n d/ or; 
ha ve barel y pal pa ble har d t hic ke ne d s ki n a n d/ or pa p ules a n d/ or; ha ve barel y 
perce pti ble lic he nificat i o n; e xc oriati o n a nd o ozi n g/cr usti n g are a bse nt.
2
Mil d
O verall, t he at o pic der matitis c o nsists of l esi o ns t hat are li g ht re d; wit h 
sli g ht, b ut defi nite har d t hic ke ne d s ki n a n d/ or pa p ules; wit h sli g ht, b ut 
defi nite li near or pic ke d scratc h mar ks or pe netr ati n g s urface i nj ur y; wit h 
sli g ht, b ut defi nite t hic ke ne d s ki n, fi ne s ki n mar ki n gs, a n d lic he n oi d scale; 
o ozi n g/cr us ti n g is a bse nt.
3
M o d erate
O verall, t he at o pic der matitis c o nsists of lesi o ns t hat are re d; wit h easil y 
pal pa ble m o derate har d t hic ke ne d s k i n a n d/ or pa p ules; wit h m o derate li near 
or pic ke d scratc h mar ks or pe netrati n g s urface i nj ur y; wit h m o derate 
t hic ke ne d s ki n, c oarse s ki n mar ki n gs, a n d c oarse lic he n oi d scale; wit h sli g ht 
o ozi n g/cr usti n g.
4
Se vere
O verall, t he at o pic der matitis c o nsists of lesi o ns t hat are d ee p, dar k re d; wit h 
se vere har d t hic ke ne d s ki n a n d/ or pa p ules; wit h se vere li near or pic ke d 
scratc h mar ks or pe netrati n g s urface i nj ur y; wit h se vere t hic ke ne d s ki n wit h 
ver y c oarse s ki n mar ki n gs a n d lic he n oi d scale; wit h m o derate t o se ve re 
o ozi n g/cr usti n g.
T he I G A will e xcl u de scal p, pal ms, a n d s oles fr o m t he assess me nt/sc ori n g.
7. 7. 3. Ecz e m a Are a a n d Se verit y I n de x ( E A SI)
T h e E A SI q ua ntifies t he se verit y of a s u bject’s at o pic der matitis base d o n b ot h se verit y of 
lesi o n cli nical si g ns a n d t he perce nt of B S A af fecte d.  E A SI is a c o m p osite sc ori n g by t he 
at o pic der matitis cli nical e val uat or o f t he de gree of er yt he ma, i nd urati o n/ pa p ulati o n, 
e xc oriati o n, a n d lic he nificati o n (eac h sc ore d se paratel y ) f or eac h of f o ur b o d y re gi o ns, wit h 
a dj ust me nt for t he perce nt of B S A i n v ol ve d f or eac h b o d y  re gi o n a n d f or t he pr o p orti o n of 
t he b o d y re gi o n t o t he w h ol e b o d y.
Lesi o n Se verit y b y Cli nic al Si g ns: T he basic c haracteristics of at o pic der matitis 
lesi o ns-er yt he ma, i n d urati o n/ pa p ulati o n, e xc oriati o n, a n d lic he nificati o n -pr o vi d e a mea ns f or 
assessi n g t he se verit y of lesi o ns.  Assess me nt of t hese f o ur mai n cl i nical si g ns is perf or me d 
separatel y  f or f o ur b o dy re gi o ns: hea d a n d nec k, u p per li m bs, tr u n k (i ncl u di n g a xillae a n d 
gr oi n) a n d l o wer li m bs (i ncl u di n g b utt oc ks).  A vera ge er y t he ma, i n d urati o n/ pa p ulati o n, 
e xc oriati o n, a n d lic he nificati o n are sc ore d f or eac h b o d y re gi o n acc or di n g t o a 4 p oi nt s cale: 
0 = a bse nt; 1 = mil d; 2 = m o derate; 3 = se vere.  M or p h ol o gic descri pt ors f or eac h cli nical 
si g n se verit y sc ore are s h o w n i n Ta ble 4 .


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 8
T a ble 4.  
Cli nic al Si g n Se verit y Sc ori n g Criteri a f or t he E cze m a Area a n d Se verit y 
I n de x ( E A SI)
Sc ore
Descri pti o n *
Er y t he ma ( E)
0
A bse nt
N o ne; ma y  ha ve resi d ual disc ol orati o n ( p ost-i nfla m mat or y 
h y per pi g m e ntati o n a n d/ or h yp o pi g me ntati o n).
1
Mil d
Li g ht pi n k t o li g ht re d
2
M o derate
Re d
3
Se vere
Dee p, dar k re d
In d urati o n / Pa p ulati o n (I)
0
A bse nt
N o ne
1
Mil d
Barel y pal pa ble t o sli g ht, b ut defi nite har d t hic ke ne d s ki n a n d/ or 
pa p ules
2
M o derate
Easil y  pal pa ble m o derate har d t hic ke ne d s ki n a n d/ or pa p ules
3
Se vere
Se vere har d t hic ke ne d s ki n a n d/ or pa p ules
E xc oriat i o n ( E x)
0
A bse nt
N o ne
1
Mil d
Sli g ht, b ut defi nite li near or pic ke d scratc h mar ks or pe netrati n g 
s urface i nj ur y
2
M o derate
M o derate li near or p ic ke d scratc h mar ks or pe netrati n g s urface 
i nj ur y
3
Se vere
Se vere li near or pic ke d scratc h mar ks or pe netrati n g s urfac e 
i nj ur y
Lic he nificati o n ( L)
0
A bse nt
N o ne
1
Mil d
Barel y perce pti ble t o sli g ht, b ut defi nite t hic ke ne d s ki n, fi ne ski n 
mar ki n gs, a n d l ic he n oi d scale
2
M o derate
M o derate t hic ke ne d s ki n, c oarse s ki n mar ki n gs, a n d c oar se 
lic he n oi d scale
3
Se vere
Se vere t hic ke ne d s ki n wit h ver y  c oarse s ki n mar ki n gs a n d 
lic he n oi d scale
T he E A SI will e xcl u de scal p, pal ms, a n d s oles fr o m t he assess me nt/sc ori n g.
Perce nt B S A wit h At o pic Der m atitis: T he n u m ber of ha n d pri nts of s ki n affli cte d wit h 
at o pic der matitis i n a b o d y re gi o n ca n be use d t o deter mi ne t he e xte nt ( %) t o w hic h a b o d y 
re gi o n is i n v ol ve d wit h at o pic der matitis (Ta ble 5 ).  W he n meas uri n g, t he ha n d pri nt u nit 
refers t o t he size of eac h i n di vi d ual s u bject’s ha n d wit h fi n gers i n a cl ose d p ositi o n.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 9
T a ble 5.  
H a n d pri nt Deter mi n ati o n of B o d y S urf ace Are a ( B S A)
B o d y Re gi o n
T ot al N u m ber o f 
H a n d pri nts i n B o d y 
Re gi o n *
S urf ace Are a of B o d y 
Re gi o n E q ui v ale nt of O ne 
H a n d pri nt *
Hea d a n d Nec k
1 0
1 0 %
U p per Li m b s
2 0
5 %
Tr u n k (i ncl u di n g a xillae a n d 
gr oi n/ ge nitals)
3 0
3. 3 3 %
L o wer Li m bs (i ncl u di n g 
b utt oc ks)
4 0
2. 5 %
Ha n d pri nt re fers t o t he ha n d size of eac h i n di vi d ual s u bject.
* T he n u m ber of ha n d pri nts will be f or t he e ntire b o d y  re gi o n; t hese val ues will n ot be a dj uste d f or e xcl usi o n 
of scal p, pal ms, a n d s oles fr o m t he B S A assess me nt.
T he e xte nt ( %) t o w hic h eac h o f t he f o ur bo d y  re gi o ns is i n v ol ve d wit h at o pic der matitis is 
cate g orize d t o a n u merical Area Sc ore usi n g a n o n-l i near scali n g met h o d acc or din g t o t he
f oll o wi n g B S A sc ori n g criteria (Ta ble 6 ).
T a ble 6.
Ecze m a Are a a n d Se v erit y I n de x ( E A SI) Are a Sc ore Criteri a
Perce nt B S A wit h At o pic Der m atitis i n a B o d y Re gi o n
Are a Sc ore
0 %
0
> 0 - < 1 0 %
1
1 0 - < 3 0 %
2
3 0 - < 5 0 %
3
5 0 - < 7 0 %
4
7 0 - < 9 0 %
5
9 0 - 1 0 0 %
6
B o d y Re gi o n Wei g hti n g: Eac h b o d y re gi o n is wei g hte d acc or di n g t o its a p pr o xi mate 
perce nta ge of t he w h ole b o d y  (Ta ble 7 ).
T a ble 7. 
Ecze m a Are a a n d Se verit y I n de x ( E A SI) B o d y Re gi o n Wei g hti n g
B o d y Re gi o n
B o d y Re gi o n Wei g hti n g
Hea d a n d Nec k
0 . 1
U p per Li m bs
0. 2
Tr u n k (i ncl u di n g a xillae a n d 
gr oi n/ ge nitals)
0. 3
L o wer Li m bs (i ncl u di n g b utt oc k s)
0. 4
* N o a dj ust me nt f or b o d y re gi o ns e xcl u de d f or assess me nt
I n eac h b o dy re gi o n, t he s u m of t he Cli nical Si g ns Se verit y Sc ores f or er yt he ma, 
i n d urati o n/ pa p ulati o n, e xc oriati o n, a n d lic he nificati o n is m ulti plie d b y t he Area Sc ore a n d b y 
t he B o dy Re gi o n Wei g hti n g t o pr o vi de a b o d y re gi o n val ue, w hic h is t he n s u m me d acr oss all 
f o ur b o dy re gi o ns res ulti n g i n a n E A SI  sc ore as descri be d i n E q uati o n 3 .


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 0
E q u ati o n 3:
E A SI = 0. 1 A h( E h +I h + E x h + L h) + 0. 2 A u( E u +I u + E x U + L u) + 
0. 3 At( Et +It + E xt + L t) + 0. 4 Al( El +Il + E xl + Ll)
A = Area Sc ore; E = er y t hema; I = i n d urati o n/ pa p ulati o n; E x = e xc oriati o n; 
L = lic he nificati o n; h = hea d a n d nec k; u = u p per li m bs; t = tr u n k; l = l o wer li m bs
T he E A SI sc or e ca n var y i n i ncre me nts of 0. 1 a n d ra n ge fr o m 0. 0 t o 7 2. 0, wit h hi g her sc ores 
re prese nti n g greater se verit y of at o pic der matitis.
7. 7. 3. 1. B o d y S urf ace Are a – Effic ac y ( B S A Effic ac y)
B S A Efficac y  will be deri ve d fr o m t he s u m of t he B S A i n ha n d pri nts acr oss 4 b o d y  re gi o ns 
assesse d as part of t he E A SI  assess me nt (Ta ble 5 ).  Ha n d pri nt refers t o t hat of eac h 
i n di vi d ual s u bject f or t heir o w n meas ure me nt.  T he B S A Efficac y ra n ges fr o m 0 t o 
1 0 0 %, wit h hi g her val ues re prese nti n g gr eater se verit y of at o pic der matitis.  Si nce t he scal p, 
pal ms, a n d s oles will be e x cl u de d fr o m t he B S A ( Efficac y) assess me nt, t he ma xi m u m 
p ossi ble val ue will be less t ha n 1 0 0 %.
7. 7. 4. Sc ori n g At o pic Der m atitis ( S C O R A D)
S C O R A D is a vali date d sc or i n g i n de x f or at o pic der matitis, w hic h c o m bi nes e xte nt ( 0 -1 0 0), 
se verity ( 0 -1 8), a n d s u bjecti ve s y m pt o ms ( 0 - 2 0) base d o n pr urit us a n d slee p l oss, eac h sc ore d 
usi n g a vis ual a nal o g scale ( 0 -1 0). 
E xte nt ( A, m a xi m u m sc ore of 1 0 0 %)
T o deter mi ne e xte nt of A D, r ule of 9 is use d to calc ulate b o d y s urface area affecte d b y A D as 
a perce nta ge of t he w h ole b o d y  s urface area.  B o d y s urface area as perce nta ge of t otal b o d y 
s urface area f or eac h b o d y re gi o n is as f oll o ws:

Hea d a n d nec k 9 %; 

U p per li m bs 9 % eac h; 

L o wer l i m bs 1 8 % eac h; 

A nt eri or tr u n k 1 8 %; 

Bac k 1 8 %; 

1 % f or ge nitals. 
T he sc ore f or eac h b o d y re gi o n is ad de d u p t o deter mi ne t he B S A affecte d b y  A D ( A), w hic h 
has a p os si ble ma xi m u m sc ore of 1 0 0 %. 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 1
Se verit y ( B, m a xi m u m sc ore of 1 8)
A re prese ntati ve area of A D is selecte d.  I n this area, t he se verit y of eac h of t he f oll o wi n g 
si g ns is assesse d as n o ne ( 0), mild ( 1), m o derate ( 2) or se ver e ( 3). 

E r yt he ma (re d de ni n g);

E de ma (s welli n g)/ pa p ulati o n;

O ozi n g/cr usti n g; 

E xc oriati o n (scratc h mar ks);

S ki n t hic ke ni n g (lic h e nificati o n); 

Xer o sis ( dr yness) (t his is assesse d i n a n area w here t here is n o i nfla m mati o n).
T he se verit y sc ores are a d de d t o ge t her t o gi ve ' B' ( ma xi m u m sc ore of 18).
S u bjecti ve S y m pt o ms ( C, m a xi m u m sc ore of 2 0)
S u bjecti ve s y m pt o ms, ie , itc h a n d slee p l oss, are eac h sc ored b y  t he s u bject or care gi ver 
usi n g a vis ual a nal o g scale ( V A S) w here “ 0” is n o itc h ( or n o slee p l oss) a n d “ 1 0” is t he 
w orst i ma gi na ble itc h ( or slee p l oss).  T he val ue f or eac h s h o ul d reflect t he a vera ge o n a 
1 0 p oi nt scale f or t he last 3 da y s/ ni g hts.  These sc ores are a d de d t o gi ve ' C' ( ma xi m u m sc ore 
of 2 0). 
S C O R A D T ot al Sc ore
T he S C O R A D f or a n i n di vi d ual is ca lc ulate d b y  t he f or m ula: A/ 5 + 7 B/ 2 + C (ca n ra n ge 
fr o m 0 t o 1 0 3). 
7. 8. P atie nt - Re p orte d O utc o mes ( P R Os)
S u bjects will c o m plete P R O s a n d A D cli nical assess me nts at t he cli nic i n t he or der t he y  are 
prese nte d i n t he electr o nic ta blet (e P R O de vice).  All P R Os a n d A D cli ni cal assess me nts 
s h o ul d be c o m plete d pri or t o ot her cli nical acti vities a n d i n vesti gat or pr o d uct a d mi nistrati o n.  
Res ul ts of cli nical assess me nt of A D s h o ul d n ot be s hare d wit h t he s u bject u ntil t he y  ha ve 
c o m plete d t heir P R Os. T he P R Os s h o ul d be c hec ke d f o r c o m plete ness b y t he st u d y site staff 
bef ore pr ocee di n g wit h ot her ste ps of t he cli nical visit pr oce d ures.  C o m plia nc e wit h 
sc he d ule d PR Os acti vities will be m o nit ore d.  Dele gate d site staff will o versee t he 
a d mi nistrati o n of P R Os at site visits t o e ns ure pr ot oc ol c o m plia nce.  S u bjects are gi ve n a 
ha n d hel d de vice t o c o m plete t he pr urit us N R S a n d P S A A D o n a dail y  basis.  Dele gate d site 
staff will re vie w c o m plia nce at eac h visit a n d c o u nsel as a p pr o priate.  If a s u bject has 
re peate d n on -c o m plia nce, t he s u bject s h o ul d be re -trai ne d o n t he de vice.  If a s u bject is 
u na ble t o c o m plete t he P R Os o n t he ha n d hel d de vice d ue t o d oc u me nte d diffic ult y  usi n g t he 
tec h n ol o gical de vices or ot her li mitati o n, t he s u bject will be per mitte d t o e nter or re mai n i n 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 2
t he stu d y .  I n t he e ve nt of electr o nic malf u ncti o n, a re place me nt de vice will be s hi p pe d t o t he 
site. 
S o me e xa m ples of t he vali date d pa per versi o ns of Patie nt Re p orte d O utc o mes i nstr u me nts 
are i ncl u de d i n t he A p pe n dices of t his pr ot o c ol.  I n i nsta nces w here a n electr o n de vice is use d 
to c ollect t he P R O data, t he electr o nic versi o n ma y differ sli g htl y i n f or mat or w or di n g 
c o m pare d wit h t he pa per versi o n t o facilitate electr o nic i m ple me ntati o n. 
7. 8. 1. Pr urit us N u meric al R ati n g Sc ale ( N R S) 
Se verit y of Pr urit us
T he se ve rity of i tc h ( pr urit us) due t o at o pic der matitis will be assesse d usi n g t he pr urit us 
N u merical Rati n g Scale, a vali date d h oriz o ntal N R S ( A p pe n di x 6 ).4 4  S u bjects will be as ke d
t o assess t heir “ w orst itc hi n g d ue t o at o pic der matitis o ver t he past 2 4 h o urs” o n a n N R S 
a nc h ore d b y t he ter ms “ n o i tc h” ( 0) a n d “ w orst itc h i magi na ble” ( 1 0).  T his ite m will be 
a d mi nistere d t o all s u bjects.  S u bjects will e nter pr urit us N R S ass ess me nt int o a n e Diar y .  
Se verit y  of pr urit us sc ore as it is assesse d o n t he da y of t he baseli ne visit will be i ncl u de d i n 
t he e val uati o n of I ncl usi o n Crit eria 3 .
Fre q ue nc y of Pr urit us 
T he fre q ue nc y of itc h ( pr urit us) d ue t o a t o pic dermatitis will be assesse d usi n g a h oriz o ntal 
N R S ( A p pe n di x 6 ).  S u bjects will be as ke d t o assess fre q ue nc y of itc hi n g d ue t o at o pic 
der matitis o ver t he past 2 4 h o urs o n a n N R S a nc h ore d b y t he ter ms “ ne ve r/ n o itc hi n g” 
( 0) a n d “al wa ys/c o nsta nt itc hi n g” ( 1 0).  T his ite m will be a d mi nistere d t o all s u bjects.  
S u bjects will e nter pr u rit us N R S assess ment i nt o a n e Diar y .  Fre q ue nc y of pr urit us will n ot 
be i ncl u de d i n t he e val uati o n of I ncl usi o n Criteria 3 .
T he pr urit us N R S s h o ul d be c o m plete d as per Sc he d ule of Acti vities . 
7. 8. 2. P a tie nt Gl o b al Assess me nt ( Pt G A)
T he Pt G A as ks t he s u bject t o e val uate t he o verall c uta ne o us disease at t hat p oi nt i n ti me o n a 
si ngle -ite m, 5 -p oi nt scale ( A p pe n di x 7 ).  T he sa me cate g or y la bels use d i n t he I n vesti gat or’s 
Gl o bal Assess me nt will b e use d f or t he Patie nt Gl o bal Assess me nt, ie, “se vere ( 4)”, 
“ m o derate ( 3)”, “ mil d ( 2)”, “al m ost clear ( 1)”, a n d “clear ( 0)”.  T he Pt G A s h o ul d be 
c o m plete d as per Sc he d ule of Acti vities .  T his si n gle-ite m scale will be a d mi nistere d t o all 
s u bjects.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 3
7. 8. 3. E ur o Q ol Q u alit y of Life 5- Di me nsi o n 5 -Le vel Sc ale ( E Q - 5 D-5 L) a n d E ur o Q ol 
Q u alit y of Life 5 -Di me ns i o n Y o ut h Sc ale ( E Q-5 D -Y i n select c o u ntries)
T he E Q -5 D is a vali date d, sta n dar dize d, ge neric i nstr u me nt t hat is t he m ost wi del y  use d 
pr efere nce-base d healt h -relate d q ualit y of life q uesti o n naire i n c ost-effecti ve ness an d healt h 
tec h n ol o gies assess me nt ( H TA) ( A p pe n di x 8 ).1 9 -2 2  Rece ntl y , a versi o n was de vel o pe d calle d 
E Q - 5 D-5 L  wit h 5 resp o nse le vels o n e ac h di me nsi o n c o m pare d t o t h e 3 res p o nse le vels i n t he 
E Q - 5 D-3 L .1 9 ,2 1 ,2 3 ,2 4 ,2 5 A versi o n of t he i nstr u me nt s pecific all y de vel o pe d a n d vali date d f or 
use b y  yo ut hs a ge 1 2 t hr o u g h 1 7 ye ars is calle d t he E Q- 5 D-Y a n d is o nl y a vaila ble i n select 
c o u ntries. 2 6 ,2 7 ,2 8
Meas ure me nt pr o perties of t he E Q- 5 D- 5 L  de m o nstrate d t o be a vali d versi o n of t he 3-le vel 
q uesti o n naire t hat i m pr o ve d meas ure ments b y  a d di n g discri mi nat or y p o wer, re d uci n g t he 
ceili n g, a n d esta blis hi n g c o n ver gent a n d k n o w n -gr o u ps vali dit y .2 1 ,2 0 ,2 3 ,2 5  B ot h t he E ur o Q ol 
E Q - 5 D-3 L  a n d E Q- 5D- 5 L  versi o ns are well-esta b lis he d i nstr u me nts use d t o meas ure healt h 
states a n d utilities i n vari o us diseases areas a n d assess m o bilit y, self-care, us ual acti vities, 
pai n/ d isc o mf ort, a n xiet y/ de pressi o n a n d healt h stat us usi n g a vis ual a nal o g ue scale 
( V A S).2 2 ,2 8  T he E Q - 5 D-3 L  was use d pre vi o usl y i n A D st u dies, i ncl u din g t he d u pil u ma b 
trials, t o meas ure utilities.2 9 -3 2
7. 8. 4. Der m at ol o g y Life Q u alit y I n de x ( D L QI) a n d C hil dre n’s Der m at ol o g y Life 
Q u alit y I n de x ( C D L QI)
T he D L QI is a vali da te d ge neral der mat o l o g y q uesti o n naire t hat c o nsists of 1 0 ite ms t o assess 
s u bject-re p orte d healt h-relate d q ualit y of life ( dail y acti vities, pers o nal relati o ns hi ps, 
s ym pt o ms a n d feeli n gs, leis ure, w or k a n d sc h o ol, a n d treat me nt) ( A p pe n di x 9 ).3 3  It has bee n 
e xte nsi vel y use d i n cli nical trials f o r A D.  T he D L QI is a ps yc h o metricall y vali d a n d relia ble 
i nstr u me nt t hat has bee n tra nslate d i nt o se veral la n g ua ges, a n d t he D LQI  t otal sc ores have 
bee n s h o w n t o be res p o nsi ve t o c ha n ge.  T he mi ni mall y  i m p orta nt differe nce f or t he D L QI 
has bee n esti mate d a s a 3 t o 5 p oi nt c ha n ge fr o m baseli ne.  A versi o n of t he i nstr u me nt 
s pecifically de vel o pe d a n d vali date d f or use b y a d olesce nts fr o m a ge 1 2 t o 1 7 is calle d t he 
C L D QI .3 4  T he D L QI  s h o ul d be c o m plete d as per Sc he d ule of Acti vities .
7. 8. 5. P atie nt - Orie nte d Ecze m a Me as ure ( P O E M)
T he P O E M is a vali date d 7 -ite m P R O meas ure use d t o assess t he i m pact of A D recalle d o ver 
t he past wee k ( A p pe n di x 1 0 ).  T his i nstr ume nt is a p pr o priate f or use b y s u bjects a ge d 1 2 a n d 
ol der. 3 5 ,3 6  T he P O E M s h o ul d be c o m plete d as per Sc he d ule of Acti vitie s.
7. 8. 6. H os pit al A n xiet y a n d De pressi o n Sc ale ( H A D S)
T he H A D S is a vali date d 1 4 -ite m P R O meas ure use d t o assess states of a n xiet y a n d 
d e pressi o n o ver t he past wee k ( A p pe n di x 1 1 ).  T he i nstr u me nt has bee n vali date d f or u se by 
a d olesce nts a ge d 1 2 a n d ol der.3 7  T he H A D S s h o ul d be c o m plete d as per S c he d ule of 
Acti vities .


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 4
7. 8. 7. Pr urit us a n d S y m pt o ms Assess me nt f or At o pic Der m atitis ( P S A A D)
T he P S A A D is a da il y patie nt re p orte d sy m pt o m diar y .  T he preli mi nar y versi o n 
(A p pe n di x 1 2 ) is a 1 5-ite m q uesti o n naire t hat i ncl u des 1 1 ite ms de vel o pe d t o meas ure 
s ym pt o ms of at o pic der matitis, ca pt uri n g t h ose i de ntifie d b y patie nts t o be m ost i m p orta nt, 
base d o n a 2 4 -h o ur recall. A nal y sis of t he P S A A D will be base d s olely o n t hese 1 1 ite ms.  
F o ur a d diti o nal ite ms were a d de d f or e x pl orat or y an d ps y c h o metric vali dati o n p ur p oses 
( Slee p & Us ual Acti vities Q uesti o ns a n d Patie nt Gl o bal I m pressi o n of Se verit y  [ P GIS] a n d 
Patie nt Gl o bal I m pressi o n of C ha n ge Q uesti o ns [ P GI C]).   T he P S A A D is a n electr o nic P R O 
t hat was de vel o pe d t hr o u g h c o nce pt elicitati o n a n d c o g niti ve de briefi n g i n A D patie nts 
a ges 1 2 t o 6 7; t he q uesti o n naire utilize d i n B 7 4 5 1 0 0 6 as a n e x pl orat or y  e n d p oi nt will be 
i m ple me nted i n t his st u d y wit h a n y refi ne me nts a n d c ha n ges assesse d as a res ult of t he 
preli mi nar y  ps yc h o metric vali dati o n. All tec h nical d oc u me nts descri bi n g meas ure me nt 
pr o perties of t he P S A A D will be s u b mitte d as re q uire d t o t he Re g ulat or y A ge ncies u p o n 
fi nalizati o n.  T he P S A A D s h o ul d be c o m plete d b y s u bjects ( o nl y i n selecte d c o u ntries) as per 
Sc he d ule of Acti vities o n a n e Diar y . 
7. 8. 8. S h ort F or m -3 6 He alt h S ur ve y, Versi o n 2, Ac ute ( S F -3 6 v 2, Ac ute) 
T he S F -3 6 v 2 is a vali date d ge neric healt h stat us meas ure (A p pe n di x 1 3 ). It meas ures 
8 ge neral healt h d o mai ns: p h y sical f uncti o ni n g, r ole li mitati o ns d ue t o p h y sical healt h, b o dil y
pai n, ge neral healt h per ce pti o ns, vitalit y , social f u ncti o ni n g, r ole li mitati o ns d ue t o e m oti o nal
pr o ble ms, a n d me ntal healt h.  T hese d o mai ns ca n als o be s u m marize d as p h y sical a nd me ntal
c o m p o ne nt s u m mar y sc ores.  T he use of t his scale is restricte d t o a d ult s u bjects a n d n ot f or
a d olesce nts t o c o m plete. 3 8  S F -3 6 v 2 will be c o m plete d b y a d ult s u bjects o nl y.  A d olesce nts 
1 2 - 1 7 ye ars of a ge will n ot c o m plete t his assess me nt.
7. 8. 9. F A CI T F ati g ue Sc ale ( F A CI T -F) a n d Pe di atric F A CI T -F ( Pe ds -F A CI T - F)
T he F u ncti o nal Asse ss me nt of C hr o nic Ill ness T hera p y Fati g ue Scale ( F A CI T – F) is a 
vali date d s u bject c o m plete d q uesti o n naire c o nsisti n g of 1 3 ite ms t hat assess fati g ue.  
I nstr u ment sc ori n g yi el ds a ra n ge fr o m 0 t o 5 2, wit h hi g her sc ores re prese nti n g bette r o verall 
healt h stat us (less fati g ue ) (A p pe n di x 1 4 ).3 9  T he F A C T -F s h o ul d be c o m pl ete d as per
Sc he d ule of Acti vities .  F A CIT- F will b e c o m plete d b y a d ult s u bjects o nly.  A d olesce nts 
1 2 - 1 7 ye ars of a ge will c o m plete t he Pe diatric F A CI T- F ( Pe ds -F A CI T -F) i nstea d of t he 
F A CI T -F. 4 2
7. 8. 1 0. Ast h m a C o ntr ol
Ast h ma c o ntr ol f or all s u bjects wit h ast h ma s h o ul d be assesse d at ti mes s pecifie d i n t he 
Sc he d ule of Acti vities usi n g t he Ast h ma C o ntr ol Q uesti o n naire ( A C Q; A p pe n di x 1 9 ).  T he 
A C Q meas ures t he a de q uac y  of ast h ma c o ntr ol a n d c ha n ge i n ast h ma c o ntr ol w hic h occ urs 
eit her s p o nta ne o usl y or as a res ult of treat me nt.  T he A C Q has 5 q uesti o ns (t he t o p sc ori n g 
5 s ym pt o ms).  S u bjects are as ke d t o recall h o w t heir ast h ma has bee n d uri n g t he pre vi o us 
wee k a n d t o res p o n d t o t he s y m pt o m q uesti o ns o n a 7 -p oi nt scale ( 0 = n o i m pair me nt, 
6 = ma xi m u m i m pair me nt).  T he q uesti o ns are e q uall y wei g hte d a n d t he A C Q sc ore is t he 
mea n of t he 5 q uesti o ns a n d t heref ore bet wee n 0 (t otall y  c o ntr olle d) an d 6 (se verel y 
u nc o ntr olle d). 1 6 ,1 7 ,4 5


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 5
7. 9. P h ar m ac o ki netics
7. 9. 1. Pl as m a f or A n al ysis of P F -0 4 9 6 5 8 4 2 a n d Met a b olites
D uri n g t he st u d y, bl o o d sa m ples ( 8 m L ) t o pr o vi de mi ni m u m 3. 2 m L  of plas ma f or P K 
a nal ys is will be c ollecte d i nt o a p pr o priately l a bele d t u bes c o ntai ni n g di p otassi u m
et h yle ne dia mi netetraacetic aci d ( K2E D T A) f or meas ure me nt of plas ma c o nce ntrati o n of 
P F - 0 4 9 6 5 84 2 a n d its meta b olites P F -0 6 4 7 1 6 5 8, P F -0 7 0 5 5 0 8 7, a n d P F -0 7 0 5 4 8 7 4 at ti mes 
s pecifie d i n t he Sc he d ule of Acti viti es. T h e actual 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.
A bl o o d sa m ple f or P K a nal y sis will be c ollecte d at 2. 0 h o urs ( 3 0 mi n) p ost d ose at 
Wee k
1 2. 
All eff orts will be ma de t o o btai n t he P K sa m ple at t he e xact n o mi nal ti me re lati ve t o d osi n g.  
T he e xact ti m e of t he sa m ple c ollecti o n is t o be n ote d o n t he s o urce d oc u me nt a n d data 
c ollecti o n t o ol (e g, C R F).  A sa m ple o btai ne d o utsi de t he wi n d o ws s pecifi e d i n t he Sc he d ule 
of Acti viti es will be c o ns i dere d a prot oc ol de viati o n.   F o r E T visits, if t he s u bject 
disc o nti n ues bef ore Wee k 4 d o n ot c ollect t he P K sa m ple.  If t he E T visit occ urs after 
Wee k
4, c ollect t he P K sa m ple o nl y if t he s u bject ta kes t he i n vesti gati o nal pr o d uct at t he si te 
visit.

T he pl as ma will be st ore d i n a p pr o priately la bele d scre w -ca p pe d p ol y pr o p yle ne t u be 
at a p pr o xi matel y - 2 0C wit hi n 1 h o ur of c ollecti o n.

F urt her details re gar di n g t he c ollecti o n, pr ocessi n g, st ora ge a n d s hi p pi n g of t he bl o o d 
sam ples will be pr o vi de d i n t he la b ma n ual.

Sa m ples will be a nal y ze d us i n g a vali date d a nalyt ical met h o d i n c o m plia nce wit h 
Pfizer sta n dar d o perati n g pr oce d ures. 

T he P K sa m ple m ust be pr ocesse d a n d s hi p pe d as i n dicate d t o mai ntai n sa m ple 
i nte grity.  A n y de v iati o ns fr o m t he P K pr ocessi n g ste ps, i ncl u di n g a ny acti o ns ta ke n, 
m u st be d oc u me nte d a n d re p orte d t o t he s p o ns or.  O n a case-b y -case basis, t he 
s p o ns or ma y ma ke a deter mi nati o n as t o w het her sa m ple i nte grit y has bee n
c o m pr o mise d.  A n y sa m ple dee me d o utsi d e of esta blis he d sta b ilit y, or of q uesti o na ble 
i nte grit y, will be c o n si dere d a pr ot oc ol de viati o n.

As part of u n dersta n di n g t he P Ks of t he i n vesti gati o nal pr o d uct, sa m ples ma y be use d 
f or meta b olite i de ntificati o n a n d/ or e val uati o n of t he bi oa nalyt ical meth o d.  T hese 
data will be use d f or i nt er nal e x pl ora t or y p ur p oses a n d will n ot be i ncl u de d i n t he 
cli nical re p ort.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 6
7. 9. 2. S hi p me nt of P h ar m ac o ki netic S a m ples
T he ce ntral la b orat or y  will pr o vi de c ollecti o n materials a n d directio ns f or pac ka gi n g a n d 
s hi p me nt of sa m ples a n d will f or war d sa m ples t o t he c o ntract a nal yt ical la b orat or y.  Refer t o 
t he ce ntral la b ve n d or ma n ual f or f urt her i nf or mati o n.
8. A D V E R S E E V E N T R E P O R T I N G
8. 1. Re q uire me nts
T he ta ble bel o w s u m marizes t he re q uire me nts f or rec or di n g safet y e ve nts o n t he C R F a n d f or 
re p orti n g safet y e ve nts o n t he Cl i nical Trial ( C T) Seri o us A d verse E ve nt ( S A E) Re p ort F or m 
t o Pfizer Safet y.  T hese re q uire me nts are deli neate d f or 3 t ypes of e ve nts: ( 1) S A Es; 
( 2) n o n -seri o us a d verse e ve nts ( A Es); a n d ( 3) e x p os ure t o t he i n vesti gati o nal pr o d uct u n der 
st u dy d uri n g pre g na n c y or breastfee di n g, a n d occ u pati o nal e x p os ure. 
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E 
Re p ort F or m t o Pfizer 
S afet y Wit hi n 2 4 H o urs of 
A w are ness
S A E
All
All
N o n -seri o us A E
All
N o ne
E x p os ure t o t he 
in vesti gati o nal pr o d uc t 
u n der st u d y  d uri n g 
pre g na nc y  or 
breastfee di n g , a n d 
occ u pati o nal e x p os ure
All (re gar dless of w het her 
ass ociate d wit h a n A E), 
e xce pt occ u pati o nal e x p os ure
E x p os ure d uri n g pre g na nc y , 
e x p os ure via breastfee di n g, 
occ u pati o nal e x p os ure 
(regar dless of w het her 
ass ociate d wit h an A E)
All o bser ve d or v ol u ntee re d e ve nts re gar dless of treat me nt gr o u p or s us pecte d ca usal 
relati o ns hi p t o t he i n vesti gati o nal pr o d uct(s) will be re p orte d as descri be d i n t he f oll o wi n g 
para gra p hs.
E ve nts liste d i n t he ta ble a b o ve t hat re q uire re p orti n g t o Pfizer Safet y o n t he C T S A E Re p ort 
F or m wit hi n 2 4 h o urs of a ware ness of t he e ve nt b y  t he i n vesti gat or are t o be re p orte d 
re g ar dless of w het her t he e ve nt is deter mi ne d b y t he i n ve sti g at or t o be rel ate d t o a n 
i n vesti g atio n al pr o d uct u n der st u d y .  In partic u lar, if t he S A E is fatal or life-t hreate ni n g, 
n oti ficati o n t o Pfizer Safet y m ust be ma de i m me diatel y, irres pecti ve of t he e xte nt of a vaila ble 
e ve nt i nf or mati o n.  T his ti me fra me als o a p plies t o a d diti o nal ne w (f oll o w -u p ) i nf or mati o n o n 
pre v i o usl y f or war de d re p orts.  In t he rare sit uati o n t hat t he i n vesti g at or d oes n ot bec o me 
i m me diatel y a ware of t he occ urre nce of a n e ve nt, t he i n vesti gat or m ust re p ort t he e ve nt 
wit hi n 2 4 h o urs afte r lear ni n g of it a n d d oc u me nt t he ti me of his/ her first a wareness of t he 
e ve nt.
F or eac h e ve nt, t he i n vesti g at or m ust p urs ue a n d o btai n a de q uate i nf or mati o n b ot h t o 
deter mi ne t he o utc o me a n d t o assess w het her it meets t he criteria f or classificati o n as a n S A E 
(see t he Seri o us A d verse E ve n ts secti o n bel o w).  I n a d diti o n, t he i n vesti gat or may be 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 7
re q ueste d by Pfizer Safet y t o o btai n s pecific f oll o w -u p i nf or mati o n i n a n e x pe dite d fas hi o n.  
T his i nf or mati o n is m ore detaile d t ha n t hat rec or de d o n t he C R F .  I n ge neral, t his will i ncl u de 
a descri pti o n of t he e ve nt i n s ufficie nt d etail t o all o w f or a c o m plete me dical assess me nt of 
t he case a n d i n de pe n de nt deter mi nati o n of p ossi ble ca usalit y.  A n y i nf or mati o n rele va nt t o 
t he e ve nt, s uc h as c o nc o mita nt me dicati o ns a nd ill nesses, m ust be pr o vi de d.  I n t h e case of a 
s u bject deat h, a s um mar y of a vaila ble a ut o ps y fi n di n gs m ust be s u b mitte d as s o o n as p ossi ble 
t o Pfizer Safet y.  A ny perti ne nt a d diti o nal i nf or mati o n m ust be re p orte d o n t he C T S A E 
Re p ort F or m; a d diti o nal s o u rce d oc u me nts (e g, medical rec or ds, C R F, la b orat or y  data) are t o 
be se nt t o Pfizer Safet y O N L Y u p o n re q uest.
A n y  cli nicall y si g nifica nt w orse ni n g of A D is c o nsi dere d a n A E re gar dless of meeti n g t he 
defi niti o n of flare. 
As part of o n g oi n g safet y re vie ws c o n d ucte d b y  t he s p o ns or, a ny n o n -seri ous A E t hat is 
deter mi ne d b y t he s p o ns or t o be serio us will be re p orte d b y  t he s p o ns or as a n S A E.  T o assist 
i n t he deter mi nati o n of case seri o us ness, f urt her i nf or mati o n ma y  be re q ueste d fr o m t he 
i n vesti gat or t o pr o vi de clarit y a n d u n dersta n di n g of t he e ve nt i n t he c o nte xt of t he cli nical 
st u d y.
8. 1. 1. A d diti o n a l Det ails o n Rec or di n g A d verse E ve nts o n t he C R F
All e ve nts detail e d i n t he ta ble a b o ve will be rec or de d o n t he A E pa ge(s) of t he C R F.  I t 
s h o ul d be n ote d t hat t he C T S AE Re p ort F or m f or re p orti n g of S A E i n f or mati o n is n ot t he 
sa me as t he A E pa ge of t he C R F.  W he n t he sa me data are c ollecte d, t he f or ms m ust be 
c o m plete d i n a c o nsiste nt ma n ner.  A Es s h o ul d be rec or de d usi n g c o ncise me dical 
ter mi n ol o g y a n d t he sa me A E ter m s h o ul d be use d o n b oth t he C R F a n d t he C T S A E Re p ort 
F or m f or re p ort i n g of S A E i nf or mati o n.
8. 1. 2. Eliciti n g A d verse E ve nt I nf or m ati o n
T he i n vesti gat or is t o re c or d o n t he C R F all directl y o bser ve d A Es a n d all A Es s p o nta ne o usl y 
re p orte d by t he st u d y s u bject , le gall y acce pta ble re prese ntati ve/ pare nt(s) or le gal g uar dia n, if 
a p plica ble.  I n a d diti o n, eac h st u d y s u bject, le gally acce pta ble re prese ntati ve/ pare nt(s) o r 
le gal g uar dia n, if a p plica ble, will be q uesti o ne d a b o ut t he occ urre nce of A Es i n a n o n-lea di n g 
ma n ner .
8. 1. 3. Wit h dr a w al fr o m t he
St u d y D ue t o A d verse E ve nts (see als o t he S u bject 
Wit h dr a w al
secti o n)
Wit h dra wal d ue t o A Es s h o ul d be disti n g uis he d fr o m wit h dra wal d ue t o ot her ca uses, 
acc or di n g t o t he defi niti o n of A E n ote d bel o w, a n d rec o r de d o n t he C R F. 
W he n a s u bject wit h dra ws fr o m t he st u d y  beca use of a n S A E, t he S A E m u st be rec or de d o n 
t he C R F a n d re p orte d, as a p pr o priate, o n t he C T S A E Re p ort F or m, i n acc or da nce wit h t he 
Re q uire me nts secti o n a b o ve.


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8. 1. 4. Ti me Peri o d f or C ollecti n g A E/ S A E I nf or m ati o n
T he ti me peri o d f or acti vel y  eliciti n g a n d c ollecti n g A Es a n d S A Es (“acti ve c ollecti o n 
peri o d”) f or eac h s u bject be gi ns fr o m t he ti me t he s u bject, le gall y acce pta ble 
re prese ntati ve/ pare nt(s) or le gal g uar dia n, if a p plica ble, pr o vi des i nf or m e d c o nse nt, w hic h is 
o bta i ne d bef ore t he s u bject’s partici pati o n in t he st u d y  (ie, bef ore u n der g oi n g a ny 
st u d y-relate d pr oce d ure a n d/ or recei vi n g i n vesti gati o nal pr o d uct), t hr o u g h a n d i ncl u di n g a 
mi ni m u m of 2 8 cale n dar da ys; e xce pt as i n dicate d bel o w after t he last a d mi nistrati o n of t he 
i n vesti gati o nal pr o d uct.
F or s u bje cts w h o are scree n fail ures, t he acti ve c ollecti o n peri o d e n ds w he n scree n fail ure 
stat us is deter mi ne d.
8. 1. 4. 1. Re p orti n g S A Es t o Pfizer S afet y
All S A Es occ urri n g i n a s u bject d uri n g t he acti ve c ol lecti o n peri o d are re p orte d t o Pfizer 
Safet y  o n t he C T S A E Re p ort F or m.
S A Es occ urri n g i n a s u bject after t he acti ve c ollecti o n peri o d has e n de d are re p orte d t o Pfizer 
Safet y  if t he i n vesti gat or bec o mes a ware of t he m; at a mi ni m u m, all S A Es t hat t he 
i n vesti gat or belie ves ha ve at l east a reas o na ble p oss i bilit y of bei n g relate d t o i n vesti gati o nal 
pr o d uct m ust be re p orte d t o Pfizer Safet y .
F oll o w u p b y  t he i n vesti gat or c o nti n ues t hr o u g h o ut a n d after t he acti ve c ollecti o n peri o d a n d 
u ntil t he e ve nt or its se q ue lae res ol ve or sta bilize at a le vel acce pta ble t o t he i n vesti gat or, a n d 
Pfizer c o nc urs wit h t hat assess me nt.
8. 1. 4. 2. Rec or di n g N o n -seri o us A Es a n d S A Es o n t he C R F
D uri n g t he acti ve c ollecti o n peri o d, b ot h n o n-seri o us A Es a n d S A Es are rec or de d o n t he 
C R F.
F oll o w - u p b y  t he i n vesti gat or ma y be re q uire d u ntil t he e ve nt or its se q uel ae res ol ve or 
sta bilize at a le vel acce pta ble t o t he i n vesti gat or, a n d Pfizer c o nc urs wit h t hat assess me nt.
8. 1. 5. C a us alit y Assess me nt
T he i n vesti gat or’s assess me nt of ca usali t y m ust be pr o vi de d for all A Es (seri o us a n d 
n o n -seri o us); t he i n vesti gat or m ust rec or d t he ca usal relati o ns hi p o n t he C R F, a n d re p ort s uc h 
a n assess me nt i n acc or da nce wit h t he S A E re p orti n g re q uire me nts, if a p plica ble.  A n 
i n vesti gat or’s ca usality assess m e nt is t he deter mi nati o n of w het her there e xis ts a reas o na ble 
p ossi b ilit y t hat t he i n vesti gati o nal pr o d uct ca use d or c o ntri b ute d t o a n A E; ge nerall y t he facts 
(e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p s h o ul d be pr o vi de d.  If t he 
i n vesti gat or d oes n ot k n o w w het he r or n ot t he i n vesti gati onal pr o d uct ca use d t he e ve nt, t he n 
t he e ve nt will be ha n dle d as “relate d t o i n vesti gati o nal pr o d uct” f or re p orti n g p ur p oses, as 
defi ne d b y t he s p o ns or.  If t he i n vesti gat or's ca usalit y assess me nt is “ u n k n o w n b ut n ot 
relate d” t o i n vesti gati o nal pr o d uct, t hi s s h o ul d be clearly d o c u me nte d o n st u d y rec or ds. 


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I n a d diti o n, if t he i n vesti gat or deter mi nes t hat a n S A E is ass ociate d wit h st u d y pr oce d ures, 
t he i n vesti gat or m ust rec or d t his ca usal relati o ns hi p i n t he s o urce d oc u me nts a n d C R F, a n d 
re p ort s uc h an assess m e nt i n t he de dicate d s ecti o n of t he C T S A E Re p ort F or m a n d i n 
acc or da nce wit h t he S A E re p orti n g re q uire me nts.
8. 1. 6. S p o ns or’s Re p orti n g Re q uire me nts t o Re g ul at or y A ut h orities
A E re p orti n g, i ncl u di n g s us pecte d u ne x pec te d seri o us a d verse reacti o ns, will be carrie d o ut 
i n acc or da nce with a p plica ble l ocal re g ulati o ns.
8. 2. Defi niti o ns
8. 2. 1. A d verse E ve nts
A n A E is a n y u nt o war d me dical occ urre nce i n a st u d y s u bject a d mi nistere d a pr o d uct or 
me dical de vice; t he e ve nt nee d n ot necessar il y ha ve a ca usal relati o ns hi p wit h t he treat m e nt 
or usa ge.  E xa m ple s of A Es i ncl u de, but are n ot li mite d t o: 

A b n or mal test fi n di n gs;

Cli nicall y  si g nifica nt si g ns a n d s ym pt o ms;

C ha n ges i n p h ys ical e xa mi nati o n fi n di n gs;

H y perse nsiti vit y ;

Pr o gressi o n/ w orse n i n g of u n derlyi n g dis ease; 

Dr u g a b us e;

Dr u g d e pe n de nc y.
A d diti o nall y, A Es ma y i ncl u de si g ns a n d sy m pt o ms res ulti n g fr o m:

Dr u g o ver d ose;

Dr u g wit h dra wal;

Dr u g mis use; 

Dr u g i nteracti o ns;

E xtra vasati o n;

E x p os ure d uri n g pre g na nc y  ( E D P);

E x p os ure via breastfe e di n g;

Me dicati o n err or;


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
Occ u pati o nal e x p os ure.
8. 2. 2. A b n or m al Test Fi n di n gs
A b n or mal o bjecti ve test fi n di n gs s h o ul d be rec or de d as A Es w he n a n y of t he f oll o wi n g 
c o n diti o ns are met: 

Test res ult is ass ociate d wit h acc o m pa n yi n g s y m pt o ms; a n d/ or

Test res ult re q uir es a d diti o nal dia g n os tic testi n g or me dical/s ur gical i nter ve nti o n; 
an d/ or

Test res ult l ea ds t o a c ha n ge i n st u d y d osi n g ( o utsi de of a n y pr ot oc ol -s pecifie d d ose 
a dj ust me nts) or disc o nti n uati o n fr o m t he st u d y , si g nifica nt a d diti o nal c o nc o mita nt 
dr u g treat me n t, or ot her t hera p y; a n d/ or

Test res u lt is c o nsi dere d t o be a n A E by t he i n vesti gat or or s p o ns or.
Merel y re peati n g a n a b n or mal test, i n t he a bse nce of a n y of t he a b o ve c o n diti o ns, d oes n ot 
c o nstit ute a n A E.  A n y a b n or mal test res ult t hat is deter mi ne d t o b e a n err or d oes n ot r e q uire 
rec or di n g as a n A E.
8. 2. 3. Seri o us A d verse E ve n ts
A seri o us a d vers e e ve nt is a n y u nt o war d me dical occ urre nce at a n y d ose t hat:

Res ults i n deat h;

Is life-t hreate ni n g (i m me diate ris k of deat h);

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;

Res ults i n persiste nt or si g nif ica nt disa bilit y/i nca pacit y (s u bsta ntial disr u pti o n of t he 
a bilit y t o c o n d uct n or mal life f u ncti o ns);

Res ults i n c o n ge nital a n o mal y / birt h defect.
Or t hat is c o nsi dere d t o be:

A n i m p orta nt me dical e ve n t.
Me dica l a n d scie ntific j u d g me nt is e xercise d i n determi ni n g w het her a n e ve nt is a n i m p orta nt 
me dical e ve nt.  A n i m p orta nt me dical e ve nt ma y  n ot be i m me diatel y life-t hreate ni n g a n d/ or 
res ult i n deat h or h os pitalizati o n.  H o we ver, if it is deter mi ne d t hat t he e ve nt ma y je o par dize
t he s u bject or ma y re q uire i nter ve nti o n t o pre ve n t o ne of t he ot her A E o utc o mes, t he 
i m p orta nt me dical e ve nt s h o ul d be re p orte d as seri o us.


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E xa m ples of s uc h e ve nts are 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 hos pas m; bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os p italizati o n; 
or de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use.
8. 2. 4. H os pit aliz ati o n
H os pitalizati o n is defi ne d as a n y i nitial a d missi o n (e ve n less t ha n 2 4 h o urs) i n a h os pital or 
e q ui vale nt healt h care facilit y, or a n y pr ol o n gati o n of a n e xistin g a d missi o n.  A d mi ssi o n als o 
i ncl u des tra nsfer wit hi n t he h os pital t o a n ac ute/i nte nsi ve care u nit (e g, fr o m t he ps yc hiatric 
wi n g t o a me dical fl o or, me dical fl o or t o a c or o nar y  care u nit, or ne ur ol o gical fl oor t o a 
t u berc ulosis u nit).  A n e mer ge nc y  r o o m visit d oes n ot nece ssarily c o nstit ute a h os pitalizati o n; 
h o we ver, t he e ve nt lea di n g t o t he e mer ge nc y  r o o m visit is assesse d f or me dical i m p orta nce.
H os pitalizati o n d oes n ot i ncl u de t he f ol l o win g:

Re ha bilitati o n facilities;

H o s pice facilities;

Res pite care (e g, care gi ver relief);

S kille d n ursi n g facilities;

N ursi n g h o mes;

Sa me -d a y  s ur geries (as o ut patie nt/sa me-d a y /a m b ulat or y pr oce d ures).
H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n t he a bse nce of a preci pitati n g cli nical 
A E is n ot i n itself a n S A E. E xa m ples i ncl u de:

A d missi o n f or treat me nt of a pree xisti n g c o n diti o n n ot ass ociate d wit h t he 
de vel o p me nt of a ne w A E or wit h a w orse ni n g of t he pree xisti n g c o n diti o n (e g, f or 
w or k u p of a pers iste nt pretreat ment la b orat or y  a bn or malit y );

S ocial a d missi o n (e g, s u bject has n o p lace t o slee p);

A d mi nistrati ve a d missi o n (e g, f or ye arl y p h ys ical e xa mi nati o n);

Pr ot oc ol -s pecifie d a d missi o n d uri n g a st u dy (e g, f or a pr oce d ure re q uire d b y t he st u d y 
pr ot oc ol);

O pti o nal a d m issi o n n ot ass ociate d wit h a preci pitati n g cli nical A E (e g, f or electi ve 
c os metic s ur ger y);

H os pitalizati o n f or o bser vati o n wit h o ut a me dical A E;

Pre pla n ne d treat me nts or s ur gical pr oce d ures.  T hese s h o ul d be n ote d i n t he baseli ne 
d oc u me nt ati o n f or t he e nt ire pr ot oc ol a n d/ or f or t he i n di vi d ual s u bject.


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Dia g n ostic a n d t he ra pe utic n o ni n vasi ve a n d i n vasi ve pr oce d ures, s uc h as s ur ger y, s h o ul d n ot 
be re p orte d as S A Es.  H o we ver, t he me dical c o n diti o n f or w hic h t he pr oce d ure was 
perf or me d s h o u l d be re p orte d if it meets t he defi niti o n of a n S A E.  F or e xa m ple, a n ac ute 
a p pe n diciti s t hat be gi ns d uri n g t he re p orti n g peri o d s h o ul d be re p orte d if t he S A E 
re q uire me nts are met, a n d t he res ulti n g a p pe n dect o m y s h o ul d be rec or de d as treat me nt of t he 
A E.
8. 3. S e verit y Assess me nt
If re q uire d o n t he A E pa ge of t he C R F, t he i n vesti gat or will use t he a djecti ves MI L D, 
M O D E R A T E, or S E V E R E t o descri be t he ma xi m u m i nte nsit y  of t he A E.  F or p ur p oses of 
c o nsiste nc y, t hese i nte nsit y gra des are defi ne d as f oll o ws:
MI L D
D oe s n ot i nterfere wit h s u bject's us ual f u ncti o n.
M O D E R A T E
I nterferes t o s o me e xte nt wit h s u bject's us ual f u ncti o n.
S E V E R E
I nterferes si g nifica ntly wit h s u bject's us ual f u ncti o n.
N ote t he disti ncti o n bet wee n t he se verit y a n d t he seri o us ness of a n A E.  A se vere e ve nt is n ot 
nec essaril y a n S A E.  F or e xa m ple, a hea dac he ma y  be se vere (i nterfere s si g nifica ntl y wit h 
t he s u bject's us ual f u ncti o n) b ut w o ul d n ot be classifie d as seri o us u nless it met o ne of t he 
criteria f or S A Es, liste d a b o ve.
8. 4. S peci al Sit u ati o n s
8. 4. 1. Pr ot oc ol -S pecifie d Seri o us A d verse E ve n ts
T here are n o pr ot oc ol -s pecifie d S A Es i n t his stu d y.  All S A Es will be re p orte d t o Pfizer 
Safet y  b y t he i n vesti gat or as descri be d i n pre vi o us secti o ns, a n d will be ha n dle d as S A Es i n 
t he safety data base. 
8. 4. 2. P ote nti al C a ses of Dr u g-I n d uce d Li ver I nj ur y
H u ma ns e x p ose d t o a dr u g w h o s h o w no si g n of li ver i nj ur y  (as deter mi ne d b y ele vati o ns i n 
tra nsa mi nases) are ter me d “t olerat ors,” w hile t h ose w h o s h o w tra nsie nt li ver i nj ur y, b ut a da pt 
are ter me d “a da pt ors.”  I n s o me s u bjects, tra nsa mi nase ele vati o ns are a har bi n ger of a m ore 
seri o us p ote ntial o utc o me.  T hese s u bjects fail t o a da pt a n d t heref ore are "s usce pti ble" t o 
pr o gressi ve a n d seri o us li ver i nj ur y , c o m m o nl y referre d t o as dr u g-i n d uce d li ver i nj ur y 
( DI LI).  S u bjects w h o e x perie nce a tra nsa mi nase ele vati o n a b o ve 3 ti mes t he u p per limit of
n or mal ( × U L N) s h o ul d be m o nit ore d m ore fre q ue ntl y  t o deter mi ne if t he y are a n “a da pt or” 
or are “s usce pti ble.”
I n t he maj orit y of DI LI cases, ele vati o ns i n as partate a mi n otra nsferase ( A S T) a n d/ or ala ni ne 
a mi notra nsferase ( A L T) prece de t otal bilir u bi n ( T Bi li) ele vati o ns ( > 2 × U L N) b y  se veral 
da y s or wee ks.  T he i ncrease i n T Bili t ypicall y occ urs w hile A S T/ A L T is/are still ele vate d 
a b o ve 3 × U L N (ie, A S T/ A L T a n d T Bili val ues will be ele vate d wit hi n t he sa me la b sa m ple).  
I n rare i nsta nces, b y t he ti me T Bili ele vati o ns are dete cte d, A S T/ A L T val ues mi g ht ha ve 
decrease d.  T his occ urre nce is still re gar de d as a p ote ntial DI LI.  T heref ore, a b n or mal 
ele vati o ns i n eit her A S T O R A L T i n a d diti o n t o T B ili t hat meet t he criteria o utli ne d bel o w 


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are c o nsi dere d p ote n tial DI LI (assesse d per Hy’s la w criteria) cases a n d s h o ul d al wa ys be 
c o nsi dere d i m p orta nt me dical e ve nts, e ve n bef ore all ot her p ossi ble ca uses of li ver i nj ur y 
ha ve bee n e xcl u de d.
T he t hres h ol d of la b orat or y  a b n or malities f or a p o te ntial DI LI case de pe n ds o n t h e s u bject’s 
i n di vi dual baseli ne val ues a n d u n derl yi n g c o n diti o ns.  S u bjects w h o prese nt wit h t he 
f oll o wi n g la b orat or y a b n or malities s h o ul d be e val uate d f urt her as p ote ntial DI LI ( H y’s la w)
cases t o defi niti vel y deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y val ues:

S u bjec ts wit h A S T/ A LT a n d T Bili baseli ne val ues wit hi n t he n or mal ra n ge w h o 
s u bse q ue ntl y prese nt wit h A S T O R A L T val ues > 3 × U L N A N D a T Bili val ue 
> 2 × U L N wit h n o e vi de nce of he m ol ys is a n d a n al kali ne p h os p hatas e val ue 
< 2 × U L N or n ot a vaila b le;

F or s u bjects wi t h baseli ne A S T O R A L T O R T Bili val ues a b o ve t he U L N, t he 
f oll o wi n g t hres h ol d val ues are use d i n t he defi niti o n me nti o ne d a b o ve, as nee de d, 
de pe n di n g o n w hic h val ues are a b o ve t he U L N at bas eli ne:

Pree xisti n g A S T or A L T baseli ne va l ues ab o ve t he n or mal ra n ge: A S T or A L T 
val ues > 2 ti mes t he baseli ne val ues A N D > 3 × U L N; or > 8 × U L N ( w hic he ver is 
s maller).

Pree xisti n g val ues of T Bili a b o ve t he n or mal ra n ge: T Bili le vel i ncr ease d fr o m 
baseli ne v al ue b y a n a m o u nt of at least 1 × U L N or if t he val ue reac hes > 3 × U L N 
( w hic he ver is s maller).
Rises i n A S T/ A L T a n d T Bili se parate d b y m ore t ha n a fe w wee ks s h o ul d be assesse d 
i n di vi d uall y base d o n cli nical j u d g me nt; a n y case w here u ncertai nt y re mai ns as to w het her it 
re prese nts a p ote ntial H y’s la w case s h o ul d be re vie we d wit h t he s p o ns or.
T he s u bject s h o ul d ret ur n t o t he i n vesti gat or site a n d be e val uate d as s o o n as p ossi ble, 
prefera bl y wit hi n 4 8 h o urs fr o m a ware ness of t he a b n or mal r es ults.  T his e val uat i o n s h o ul d 
i ncl ude la b orat or y  tests, detaile d hist or y, a n d p h ysical assess me nt. 
I n a d diti o n t o re peati n g meas ure me nts of A S T a n d A LT a n d T Bili, la b orat or y  tests s h o ul d 
i ncl u de al b u mi n, creati ne ki nase ( C K), direct a n d i n direct bilir u bi n, ga m ma-gl uta m yl  
tra nsferase ( G G T), pr ot hr o m bi n ti me ( P T)/i n ter nati o nal n or malize d rati o (I N R), t otal bile 
aci ds, al kali ne p h os p hatase a n d aceta mi n o p he n dr u g a n d/ or pr otei n a d d uct le vels.  
C o nsi derati o n s h o ul d als o be gi ve n t o dra wi n g a se parate t u be of cl otte d bl o o d a n d a n 
a ntic oa g ulate d t u be of bl o o d f or f urt her testi ng, as nee de d, f or f urt her c o nte m p ora ne o us 
a nal ys es at t he ti me of t he rec o g nize d i nitial a b n or malities t o deter mi ne eti ol o g y .  A detaile d 
hist or y , i ncl u di n g rele va nt i nf or mati o n, s uc h as re vie w of et ha n ol, aceta mi n o p he n (eit her b y 
itself or as a c o-for m ula te d pr o d uct i n prescri pti o n or o ver-t he-c o u nter me dicati o ns) , 
recreati o nal dr u g, s u p ple me nt ( her bal) use a n d c o ns u m pti o n, fa mil y hist or y, se x ual hist or y, 
tra vel hist or y, hist or y of c o ntact wit h a ja u n dice d per s o n, s ur ger y, blo o d tra nsf usi o n, hist or y  
of li v er or aller gic disease, a n d p ote ntial occ u pati o nal e x p os ure t o c he micals, s h o ul d be 


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c ollecte d.  F urt her testi n g f or ac ute he patitis A, B, C, D, a n d E i nfecti o n a n d li ver i ma gi n g 
(e g, biliar y tract) ma y be warra nte d. 
All case s de m o nstrate d o n re peat testi ng as meeti n g t he la b orat or y  criteria of A S T/ A LT a n d 
T Bili ele vati o n defi ne d a b o ve s h o ul d be c o nsi dere d p ote ntial DI LI ( H y ’s la w) cases if n o 
ot her reas o n f or t he li ver f u ncti o n test ( L F T) a b n or malities has yet bee n f o u n d.  S u c h 
p ote nti al DI LI ( H y’s l a w) c a ses are t o be re p orte d as S A Es, irres pecti ve of a v ail a bilit y 
of all t he res ults of t he i n vesti g ati o ns perf or me d t o deter mi ne eti ol o g y of t he L F T 
a b n or m alities.
A p ote ntial DI LI ( H y ’s la w) case bec o mes a c o nfi r me d case o nly a fter all res ults of 
reas o na ble i n vesti gati o ns ha ve bee n recei ve d a n d ha ve e xcl u de d a n alter nati ve eti ol o g y .
8. 4. 3. E x p os ure t o t he I n vesti g ati o n al Pr o d uct D uri n g Pre g n a nc y or Bre astfee di n g, a n d 
Occ u p ati o n al E x p os ure
E x p os ure t o t he i n vesti gati o nal pr o d uct u n der s t u d y d uri n g pre g na ncy or breast fee di n g a n d 
occ u pat i o nal e x p os ure are re p orta ble t o Pfizer Safet y wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness.
8. 4. 3. 1. E x p os ure D uri n g Pre g n a nc y
F or b ot h u na p pr o ve d/ u nlice nse d pr o d ucts a n d f or mar ke te d pr o d ucts, a n e x p os ure d uri n g 
pre g na nc y  ( E D P) occ urs if:

A fe male bec o mes, or is f o u n d t o be, pre g na nt eit her w hile recei vi n g or ha vi n g bee n 
e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he i n vesti gati o nal 
pr o d uct; or t he fe male bec o m es or is f o u n d t o be pre g na nt after d isc o nti n ui n g a n d/ or 
bei n g e x p os e d t o t he i n vesti ga ti o nal pr o d uct;

A n e xa m ple of e n vir o n me ntal e x p os ure w o ul d be a case i n v ol vi n g direct c o ntact 
wit h a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a n urse re p orts t hat s he is pre g na nt 
a n d has bee n e x p ose d t o c he m ot hera pe utic pr o d uct s);

A male has bee n e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he 
i n vesti gati o nal pr o d uct pri or t o or ar o u n d t he ti me of c o nce pti o n a n d/ or is e x p ose d 
d uri n g his part ner’s pre g na n c y . 
If a s u bject or s u bject’s part ner bec o mes or is f o un d t o be pr e g na nt d uri n g t he s u bject’s 
treat me nt wit h t he i n vesti gati o nal pr o d uct, t he i n vesti gat or m ust re p ort t his i nf or mati o n t o 
Pfizer Safet y  o n t he C T S A E Re p ort F or m a n d a n E D P s u p ple me ntal f orm, re gar dless of 
w het her a n S A E has o cc urre d.   I n a d diti o n, t he i n vesti gat or m ust s u b mit i nf or mati o n 
re gar di n g e n vir o n me ntal e x p os ure t o a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a s u bject 
re p orts t hat s he is pre g na nt a n d has bee n e x p ose d t o a c yt ot o xic pro d uct b y i n halati o n o r 
s pilla ge) t o Pfizer Safet y usi n g the E D P s u p p le me ntal f or m.  T his m ust be d o ne irres pecti ve 
of w het her a n A E has occ urre d a n d wit hi n 2 4 h o urs of a ware ness of t he e x p os ure.  T he 
i nf or mati o n s u b mitte d s h o ul d i ncl u de t he a ntici pate d date of deli ver y (see bel o w f or 
i nf or mati o n relate d t o ter minati o n of p re g na nc y).


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F oll o w - up is c o n d ucte d t o o btai n ge neral i nf or mati o n o n t he pre g na nc y  a n d its o utc o me f or 
all E D P re p orts wit h a n u n k n o w n o utc o me.  T he i n vesti gat or will f oll o w t he pre g na nc y  u ntil 
c o m pleti o n ( or u ntil pre g na nc y ter mi nati o n) a n d n otify Pfizer Sa fety of t he o utc o me as a 
f oll o w- u p t o t he i nitial E D P s u p ple me ntal f or m.  I n t he case of a li ve birt h, t he str uct ural 
i nte grity of t he ne o nate ca n be assesse d at t he ti me of birt h.  I n t he e ve nt of a ter mi nati o n, t he 
reas o n(s) f or ter mi nati o n s ho ul d be s pe cifie d a n d, if cli n icall y p ossi ble, t he str uct ural 
i nte grity of t he ter mi nate d fet us s h o ul d be assesse d b y gr oss vis ual i ns pecti o n ( u nless 
pre -pr oce d ure test fi n di n gs are c o ncl usi ve f or a c o n ge nital a n o mal y a n d t he fi n di n gs a re 
re p orte d).
If t he o utc o me of t he pre g na nc y meets t he criteria f or a n S A E (ie, ect o pic pre g na nc y, 
s p o nta ne o us a b orti o n, i ntra uteri ne fetal de mise, ne o natal deat h, or c o n ge nital a n o mal y [i n a 
li ve-b or n ba b y, a ter mi nat e d fet us, a n i ntra ute ri ne fetal de mise, or a ne o natal deat h]), t he 
in vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es.
A d diti o nal i nf or mati o n a b o ut pre g na nc y  o utc o mes t hat are re p orte d t o Pfizer Safety as S A Es 
f oll o ws: 

S p o nta ne o us a b orti o n i ncl u des miscarria ge a n d m isse d a b orti o n;

Ne o natal deat hs t hat occ ur wit h i n 1 m o nt h of birt h s h o ul d be re p orte d, wit h o ut re gar d 
t o ca usalit y, as S A Es.  I n a d diti o n, i nfa nt deat hs after 1 m o nt h s h o ul d be re p orte d as 
S A Es w he n t he i n vesti gat or assesses t he i nfa nt deat h as relate d or p ossi bl y  relate d t o 
e x p os ure t o t he i n vesti gatio nal pr o d uct;
A d dit i o nal i nf or mati o n re gar di n g t he E D P ma y be re q ueste d b y t he s p o ns or.  F urt her 
f oll o w- u p of birt h o utc o mes will be ha n dle d o n a case-b y -case basis (e g, f oll o w- u p o n 
prete r m i nfa nts t o i de ntify de vel o p me ntal dela y s).  In t he cas e of pater n al e x p os ure, t he 
i nvesti gat or will pr o vi de t he s u bject wit h t he Pre g na nt Part ner Release of I nf or mati o n F or m 
t o deli ver t o his part ner.  T he i n vesti gat or m ust d oc u me nt i n t he s o urce d oc u ments t hat t he 
s u bject was gi ve n t he Pr e g na nt Part ner Relea se of I nf ormati o n F or m t o pr o v i de t o his 
part ner.
8. 4. 3. 2. E x p os ure D uri n g Bre astfee di n g
Sce nari os of e x p os ure d uri n g breastfee di n g m ust be re p orte d, irres pecti ve of t he prese nce of 
a n ass ociate d S A E, t o Pfiz er Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s a ware ness, usi n g t he
C T S A E Re p ort F or m .  A n e x p os ure d uri n g breastfee di n g re p ort is n ot create d w he n a Pfizer 
dr u g s pecificall y  a p pr o ve d f or use i n breastfee di n g w o me n (e g, vita mi ns) is a d mi nistere d i n 
acc ord wit h a ut h orize d use .  H o we ver, if the i nfa nt e x perie nces a n S A E as s ociate d wit h s uc h 
a dr u g’s a d mi nistrati o n, t he S A E is re p orte d t o get her wit h t he e x p os ure d uri n g breastfee di n g.
8. 4. 3. 3. Occ u p ati o n al E x p os ure
A n occ u pati o nal e x p os ure occ urs w he n, d uri n g t he perf or ma nce of j o b d uties , a pers o n 
(w het her a healt hcare pr ofessi o nal o r ot her wise) gets in u n pla n ne d direct c o ntact wit h t he 
pr o d uct, w hic h ma y  or ma y n ot lea d t o t he occ urre nce of a n A E.


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A n occ u pati o nal e x p os ure is re p orte d t o Pfizer Safet y  wit hi n 2 4 h o urs of t he i n vesti gat or’s
a ware ness, usi n g t he C T S A E Re p ort F or m, re gar dless of w het her t h ere is a n ass ociate d 
S A E.  Si nce t he i nf or mati o n d oes n ot pertai n t o a s u bject e nr olle d i n t he st u d y , t he 
i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y of t he c om plete d C T S A E Re p ort
F or m is mai ntai ne d i n t he i n vesti gat or site fi le.
8. 4. 4. Me dic ati o n Err o rs 
Ot her e x p os ures t o t he i n vesti gati o nal pr o d uct u n der st u d y  m a y occ ur i n cli nical trial setti n gs, 
s uc h as me dicati o n err ors.
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E 
Re p ort F or m t o Pfi zer 
S afet y Wit hi n 2 4 H o urs of 
A w are ness
Me dicati o n er r ors
All (re gar dless of w het her 
ass ociate d wit h a n A E)
O nl y  if ass ociate d wit h a n 
S A E
8. 4. 4. 1. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult fr o m t he a d mi nistrati o n or c o ns u m pti o n of t he i n vesti gati o nal 
pr o d uct b y t he wr o n g s u bject, or at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h. 
Me dicati o n err ors i ncl u de :

Me dicati o n err ors i n v ol vi n g s u bject e x p os ure t o t he i n vesti gati o nal pr o d uct;

P ote ntial me dicati o n err ors or uses o ut si de of w hat is f oresee n i n t he pr ot o c ol t hat d o 
or d o n ot i n v ol ve t he partici pati n g s u bject;

Refer t o Secti o n 5. 4 f or e xa m ples of me dicati o n err ors relate d t o c o m plia nce wit h 
i n vesti gati o nal pr o d uct.
S uc h me dicati o n err ors occ urr i n g t o a st u d y partici pa nt are t o be ca pt ure d o n t he me dicati o n 
err or pa ge of t he C R F, w hic h is a s pecific versi o n of t he A E pa ge.
I n t he e ve nt of a me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d i m me diatel y.
W het her or n ot t he me d icati o n err or is acc o m pa nie d b y a n A E, as determi ne d b y  t he 
i n vesti gat or, t he me dicati o n err or is rec or de d on t he me dicati o n err or pa ge of t he C R F a n d, if 
a p plica ble, a n y ass ociate d A E(s), seri o us a n d n o n -seri o us, are rec or de d o n a n A E pa ge of t he 
C R F.
M e dicati o n err ors s h o ul d be re p orte d t o Pfizer Safet y wit hi n 2 4 h o u rs o n a C T S A E Re p ort 
F or m o nl y w he n ass oc i ate d wit h a n S A E.


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9. D A T A A N A L Y SI S/ S T A TI S TI C A L M E T H O D S
Detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nalys es of t he data c oll ecte d i n t his st u d y 
is o utli ne d here a n d f urt her detaile d i n a stati stical a nalys is plan ( S A P), w hic h will be 
mai ntai ne d b y  t he s p o ns or.  T he S A P ma y m o dif y w hat is o utli ne d i n t he pr ot oc ol w here 
a p pr o priate; h o we ver, a n y maj or m o dificati o ns of t he c o-pri m ar y e n d p oi nt defi niti o ns or t heir 
a nal yses will als o be reflecte d i n a pr ot oc ol a me n d ment.
9. 1. S a m ple Size Deter mi n ati o n
A t otal of 6 0 0 s u bjects wit h 2 0 0 recei vi n g P F-0 4 9 6 5 8 4 2 2 0 0 m g Q D, 2 0 0 recei vi n g 
P F - 0 4 9 6 5 8 4 2 1 0 0 m g Q D, a n d 2 0 0 recei vi n g place b o ( 1: 1: 1 ra nd o mizati o n) will pr o v i de 
9 4 % p o wer t o detect a rati o of me dia n ti me t o flare of at least 1. 5 ti mes bet wee n eit her d ose 
of P F -0 4 9 6 5 8 4 2 ( 2 0 0 m g or 1 0 0 m g) a n d place b o.  T he T y pe I err or rate is set at
5 % ( 2-si de d).  Ass u mi n g base d o n pri or data, t hat a b o ut 44 % of s u bjects w o ul d meet t he 
pr ot oc o l- defi ne d criteria t o be a res po n der at Wee k 1 2, a p pr o xi matel y  1 3 7 0 s u bjects w o ul d 
nee d t o e nter t he o pe n la bel r u n -i n peri o d of t he st u d y t o e ns ure t hat 6 0 0 s u bjects are 
a vaila ble f or ra n d o mizati o n.
9. 2. Effic ac y A n al ysis
9. 2. 1. A n al ysis Sets 
T he sta tistical o bjective of t he st u d y  is t o c haracterize t he l oss of res p o nse wit h eac h 
ra n d o mize d gr o u p after ac hie vi n g res p o nse at Wee k 1 2 f oll o wi n g o pe n -la bel treat me nt wit h 
2 0 0 m g P F - 0 4 9 6 5 8 4 2 Q D. 
T he pri mar y  a nalys is p o p ulati o n f or efficac y data will be t he F ull A nal ys is Set ( F A S -R A) 
defi ne d as all ra n d o mize d s u bjects w h o are dis pe nse d at least o ne d ose of st u d y  me dicati o n.  
T his is a res p o n der -e nric he d p o p ulati o n w h o are eli gi ble t o e nter t he ra n d o mize d, 
d o u ble -bli n d peri o d of t he st u d y .  All a nal yses will be re p orte d b y t reat me nt 
re gi me n/se q ue nce.  T he pri mar y  efficac y en d p oi nt a n d t he ke y  seco n dar y  efficac y e n d p oi nts 
will als o be a nal yz e d f or t he Per-Pr ot oc ol A nal ys is Set ( P P A S) defi ne d as a s u bset of 
F A S - R A w h o ha d n o maj or pr ot oc ol vi olati o ns.  Maj or pr o t oc ol vi olati o ns w o ul d c o nsist of 
n ot meeti n g i nclusi o n criteria or meeti n g a n e xcl usi o n crtieria or n ot ha vi n g ta ke n t he c orrect 
ra n d o mize d treat me nt f or at least 8 0 % of t he assi g ne d a m o u nt or ha vi n g ta ke n a pr o hi bite d 
c o nc o mita nt me dicati o n (as detaile d i n Secti o n 5. 9. 2 ) or a ny ot her maj or pr ot oc ol vi olati o n as 
deter mi ne d b y t he cli nical tea m or me dical m o nit or pri or t o data base l oc k. T he s u b jects 
e xcl u de d fr om t he P P A S will be deter mi ne d a n d d oc u me nte d bef ore t he st u d y  is u n- bli n de d.  
F or all a nal y ses, baseli ne val ue will be base d o n o bser vati o ns c ollecte d pre-d ose.
A n a d diti o nal s u b gr o u p of s u bjects w h o ha ve recei ve d at least o ne d ose of resc ue treat me nt 
(f oll o wi n g a pr ot oc ol-defi ne d flare d uri n g t he ra n d o mize d, d o u ble -bli n d peri o d) will als o be 
defi ne d as t he F A S -R E s u b gr o u p.  I n a d diti o n t o t hese s u b gr o u ps, a nal yses will als o be 
perf or me d f or all s u bjects parti ci pati n g i n t he o pe n -la bel r u n-i n peri o d ( defi ne d as t he 
F A S -O L s u b gr o u p).


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9. 2. 2. Testi n g Pr oce d ure f or M ulti ple C o m p aris o ns
T here are si x ke y  h yp ot heses t o be teste d f or eac h pair wise c o m paris o n bet wee n t w o 
P F -0 4 9 6 5 8 4 2 d oses ( 2 0 0 m g Q D a n d 1 0 0 m g Q D) a n d place b o , f or t he pri mary a n d ke y 
sec o n dar y e n d p oi nts. F or t hese h y p ot hes es, t he fa mil ywise T y pe- I err or rate will be str o n gly 
c o ntr olle d at 5 % usi n g a se q ue ntial, gate kee pi n g pr oce d ure. 
T he pr oce d ure will first test t he h y p ot hesis of n o dif fere nce f or t he pri mar y e n d p oi nt bet w ee n
2 0 0 m g Q D a n d place b o at 5 % le vel of si g nificance. If t his hy p ot hesis is rejecte d, statistical 
si g nifica nce will be assesse d f or t he hy p ot hesis of n o differe nce f or t he ke y sec o n dar y 
e n d p oi nt bet wee n 2 0 0 m g  Q D a n d place b o at 5 % le vel o f si g nifica nce. If rejected, t he 
pr oce d ure wil l c o nti n ue wit h t he h y p ot hesis of n o differe nce f or t he pri mar y  e n d p oi nt 
bet wee n 1 0 0 m g  Q D a n d place b o a n d if rejecte d, c o nti n ui n g wit h t he hy p ot hesis of n o 
differe nce bet wee n 1 0 0 m g Q D a n d place b o f or t he ke y sec o n dar y e n d p oi nt. Fi nal l y, if all 
t he a b o ve h y p ot heses are rej ecte d, t he pr oce d ure will c o nti n ue wit h t he h y p ot hesis of n o 
differe nce bet wee n 2 0 0 m g Q D a n d 1 0 0 m g Q D f or t he pri mar y  e n d p oi nt a n d if rejecte d, 
c o nti n ui n g wit h t he h y p ot hesis of n o differe nce bet wee n 2 0 0 m g  Q D a n d 10 0 m g Q D f or t he 
ke y sec o n dar y e n d p oi nt. All tests will be c o n d ucte d at 5 % le vel of si g nifica nce.  Statistical 
si g nifica nce f or s u bse q ue nt tests will n ot be f or mall y clai me d if t he pre vi o us h yp ot hesis has 
n o t bee n rejecte d.
H y p o t heses f or all ot her e n d p oints n ot descri be d he re are t o be teste d at t he n o mi nal
5 % le vel, wit h o ut ma ki n g a dj ust me nts f or m ulti ple c o m paris o ns.
9. 2. 3. A n al ysis of t he Pri m ar y a n d Ke y Sec o n d ar y E n d p oi nts 
T he pri mar y  a nalys es f or b ot h e n d p oints will be base d o n t he F A S -R A s u b set.  Sec o n dar y 
a nal ys es will be base d o n t he P P A S. F or a nal ys is of t he pri mar y a n d ke y sec o n dar y 
e n d p oi nts, a c o m bi nati o n of gra p hical a n d a nal ytical met h o ds will be use d.  T he ti me 
(i n wee ks) t o pr ot oc ol -defi ne d flare will be use d t o e val ua te t he pri mar y en d p oi nt w hile t he 
ti me (i n weeks) t o ac hie ve a n IG A sc ore of 2 will be use d t o e val uate t he ke y  sec o n dar y 
e n d p oi nt.  S u bjects w h o d o n ot re p ort a n e ve nt (ie pr ot oc ol-defi ne d flare or I G A 2) or 
disc o nti n ue t he st u d y  duri n g t he d o u ble- bli n d ra n d o mize d peri o d will ha ve t heir ti me t o e vent 
ce ns ore d at t heir last k n o w n visit i n t his peri o d.  Ka pla n-Meier c ur ves will be use d t o dis pla y  
t he ti me t o e ve nt a n d re p ort t he me dia n ti me t o e ve nt (a n d its 9 5 % c o nfi de nce i nter val) 
am o n g t he t hree ra n d o mi ze d gr o u ps.  T h e l o g-ra n k test will be use d t o c o m pare t hese c ur v es.  
Pr o p orti o ns of s u bjects wit h a n e ve nt a n d c o nfi de nce i nter vals will als o be re p orte d b y  
ra n d o mize d gr o u p.
9. 2. 4. A n al ysis of Sec o n d ar y E n d p oi nts
I n ge neral, bi nar y e n d p oi nts (s uc h as E A SI- 5 0, EA SI -9 0 or t he p ro p orti o n of s u bjects 
ac hie vi n g 4 p oi nt i m pr o ve me nt i n se verit y of pr urit us N R S meas ure) will be a nal yz e d usi n g 
t he ( C oc hra n-Ma ntel -Hae nszel) test a dj uste d b y  ra n d o mizati o n strata (a ge gr o u ps) a n d 
baseli ne disease se ve rity .  T he differe nce bet wee n treat ment gr o u ps i n t he pr o p orti o n of 
s u bjects ac hie vi n g a res p o nse al o n g wit h its 9 5 % c o nfi de nce i nter val ( usi n g t he n or mal 
a p pr o xi mati o n f or t he differe nce i n bi n o mial pr o p orti o ns) will be re p orte d.  If a s u bject 
wit h dra ws f r o m t he st u d y, t he n t his s u bject will be c o u nte d as a n o n -res p o n der f or e n d p oi nts 


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after wit h dra wal.  I n a d diti o n, a s u bject i n t he F A S-R A s u b set w h o recei ves resc ue treat me nt 
d ue t o pr ot oc ol - defi ne d flare will be c o nsi dere d a n o n -res p o n der.
F or c o nti n u o us e n d p oi nts, s uc h as per ce nt c ha n ge fr o m baseli ne i n t he E A SI t otal sc ore a n d 
B S A or c ha n ge fr o m baseli ne i n S C O R A D, P S A A D, D L QI/ C D L QI, P O E M, H A D S, a n d 
c ha n ge fr o m baseli ne i n t he pr urit us se verit y usi n g t he N R S meas ure , a mi xe d-effect m o del 
wit h re peate d me as ures ( M M R M) will be use d.  T his m o d el will i ncl u de t he fact ors (fi xe d 
effects) f or treat me nt gr o u p, ra n d o mizati o n strata (a ge gr o u ps ), a n d baseli ne disease se verit y,
visit, treat me nt -b y - visit i nteracti o n, a n d rele va nt baseli ne val ue.  Wit hi n t he fra me w ork of 
M M R M, differe nces
bet wee n gr o u ps will be teste d usi n g esti mates fr o m t he M M R M m o del.
F or all bi nar y  e n d p oi nts, missi n g data will be ha n dle d b y c o nsi deri n g s u bjects w h o w it h dra w 
or ra n d o mize d s u bjects recei vi n g resc ue treat me nt as n o n-res p o n ders. N o i m p utati o ns will 
be ma d e f or c o nti n u o u s data a n d missi n g data will be c o nsi dere d t o be M A R.
I n ge neral all sec o n dar y e n d p oi nts will be a nal yse d f or t he F A S-R A s u b set.  F or t he s u bjects 
re q uiri n g resc ue t hera py ( F A S-R E s u b set), t he res p o nse ac hie ve d at t he en d of t he resc ue 
peri o d will be asses se d i n relati o n t o t he start of t he resc ue peri o d.  I n a d diti o n t o t hese t w o
a nal ys is sets, sec o n dar y e n d p oi nts will als o be s u m marize d f or all s u bjects partici pati n g i n 
t he o pe n-la bel r u n-i n peri o d ( F AS- O L s u b set).
H y p ot heses f or all rele va nt sec o n dar y e nd p oi nts will be teste d at t he n o mi nal 5 % le vel of 
si g nifica nce, wit h o ut a dj ust me nts f or m ulti ple c o m paris o ns.
9. 3. S afet y A n al ysis
T he safet y data will be s u m marize d i n acc or da nce wit h Pfizer Dat a Sta n dar ds.  All s u bjects 
w h o recei ve i n vesti gati o nal pr o d uct (sa fety p o p ulati o n) will be i ncl u de d i n t he safet y 
a nal ys es.  All safet y data will be s u m marize d descri pti vel y t hr o u g h a p pr o priate data 
ta b ulati o ns, descri pti ve statistics, cate g orical s u m maries, a n d gra p hical prese ntati o ns.  Safet y 
e n d p oi nts for t he st u d y i ncl u de:

Treat me nt -e mer ge nt A Es a n d S A Es;

Wit h dra wals fr o m acti ve treat me nt d ue t o A Es;

Seri o us i nfecti o ns, defi ne d as a n y i nfecti o n ( viral, bacterial, a n d f u n gal) re q uiri n g 
h os pitalizati o n or pare nteral a nti micr o bials or meets ot her criteria t hat re q uire it t o be
classifie d as a seri o us a d vere e ve nt, will be s u m marize d;

Safet y  la b orat or y tests (e g, he mat ol o g y [i ncl u di n g c oa g ulati o n pa nel], c he mistr y a n d 
li pi d pr ofiles);

Vital si g ns;

E C G para meters if a p plica ble.


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C ha n ge fr o m baseli ne o n la b orat or y data a n d vi tal sig ns will be a d diti o nall y s u m marize d.
S u bject listi n gs will als o be pr o d uce d f or t hese safet y  e n d p oi nts.
All safet y data will be s u m marize d se paratel y f or eac h of t he f oll o wi n g ke y s u b gr o u ps:

S u bjects w h o ha ve rece i ve d at least o ne d ose o f st u d y dr u g d uri n g t he o pe n la bel 
r u n-i n peri o d.  T hese s u bjects w o ul d ha ve a c u m ulati ve e x p os ure t o 2 0 0 m g Q D 
P F - 0 4 9 6 5 8 4 2 of u p t o 1 2 wee ks;

S u bjects w h o ha ve bee n ra n d o mize d a n d ha ve recei ve d at least o ne d ose of 
ra n d o mize d st u d y treat me nt.  S u m maries o f safety data will be re p orte d f or t hese 
s u bjects b y ra n d o mize d treat me nt re gi me n;

S u bjects w h o meet l oss of res p o nse criteria d uri n g t he ra n d o mize d, d o u ble -bli n d 
peri o d a n d recei v e at least o ne d ose of resc ue treat me nt.  S u m maries of safet y  data 
will be re p orte d f or these s u bjects b y  ra n d o mize d treat me nt re gi me n.
9. 4. A n al ysis of P h ar m ac o ki netic E n d p oi nts 
P o p ulati o n P K data f or P F- 0 4 9 6 5 8 4 2 will be s u m marize d t hr o u g h a p pr o priate data 
tab ulati o ns, descri pti ve statistics, a n d gra p hical prese ntati o n.  A p o p ulati o n P K m o del wil l be 
d e vel o pe d f or t he p ur p ose of esti mati n g P K para meters.  A d diti o nal details of t he 
met h o d ol o g y  will be ca pt ure d i n a se parate m o deli n g pla n a n d t he res ults will als o be 
re p orte d se parately.
9. 5. E xter n al D at a M o nit ori n g C o m mittee 
T his st u d y  wi ll use a n e xter nal data m o nit ori n g c o m mittee ( E -D M C ).  T he E-D M C will be 
res p o nsi ble f or o n g oi n g m o nit ori n g of t he efficac y, safety a n d P Ks of s u bjects i n t he st u d y 
acc or di n g t o t h e c harter.  T he rec o m me n dati o ns ma de b y  t he E-D M C t o alter t he c o n d uct of 
t he st u d y will be f or war de d t o Pfizer f or fi nal decisi o n.  Pfizer will f or war d s uc h decisi o ns, 
w hic h ma y  i ncl u de s u m maries of a g gre gate a nal yses of e n d p oi nt e ve nts a n d of safety data
t hat are n ot e n d p oi nts, t o re g ulat or y a ut h orities, as a p pr o priate.  C o m p o siti o n of t he E-D M C 
an d pr ocesses u n der w hic h t he E -D M C o perates will be d oc u me nte d i n t he E -D M C c harter.
9. 6. S afet y A dj u dic ati o n C o m mittees
T o hel p assess t he s pecific, c o m ple x safet y e ve nts relate d t o mali g na ncies, car di o vasc ular 
e ve nts, a n d o p p ort u nistic i nfecti o n (i ncl u di n g ecze ma her petic u m a n d ot her i nfecti o ns of 
s pecial i nterest) i n t his st u d y, Safety A dj u dicati o n C o m mittees, c o nsisti n g of cli nical e x perts 
i n eac h of t he rele va nt cli nical areas, will be set u p t o har m o nize a n d sta n dar dize 
assess me nts.  In or der t o all o w f or a n u n biase d safet y assess me nt, t he me m bers of t hese 
c o m mittees will be bli n de d t o treat me nt assi g n me nt.  F urt her i nf or mati o n a b o ut t he Safet y  
A dj u dicati o n C o m mit tees ca n be f o u n d i n t heir res pecti ve c harters, i nclu di n g a s pecific 
descr i pti o n of t he sc o pe o f t heir res p o nsi bilities, a pla n w here c o m m u nicati o n ti meli nes are 
defi ne d, a n d t he e xact pr ocess a n d defi niti o ns use d b y  eac h c o m mittee t o a dj u dicate t he 


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safety e ve nts t hat t he y will a dj u dicate.  Ot her safet y  e vents f or a dj u dicati o n m a y be i de ntifie d 
a n d i ncl u de d i n t he re mit of t he Safety A dj u dicati o n C o m mittees as a p pr o priate.
1 0. Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
Pfizer or its a ge nt will c o n d uct peri o dic m o nit ori n g visits d uri n g st u d y c o n d uct t o e ns ure t hat 
t he pr ot oc ol a n d G o o d Cli ni cal Practices ( G C Ps) are bei n g f oll o we d.  T he m o nit ors ma y 
re vie w s o urce d oc u me nts t o c o nfir m t hat t he data rec or de d o n C R Fs are acc urate.  T he 
i n vesti gat or a n d i nstit uti o n will all o w Pfizer m o nit ors/a u dit ors or its a ge nts a n d a p pr opriate 
re g ulat or y a ut hor ities direct access t o s o urce d oc u me nts t o perf or m t his verificati o n.  T his 
verificati o n ma y  als o occ ur after st u d y c o m pleti o n.
D uri n g st u d y c o n d uct a n d/ or after st u d y c o m pleti o n, t he i n vesti gat or site ma y be s u bject t o 
re vie w by t h e I RB/ E C, a n d/ or t o q u alit y ass ura nce a u dits perf or me d by Pfizer, or c o m pa nies 
w or ki n g wit h or o n be half of Pfizer, a n d/ or t o i ns pecti o n b y  a p pr o priate re g ulat or y 
a ut h orities.
T he i n vesti gat or(s) will n ot if y Pfizer or its a ge nts i m me diatel y of a n y re g ulat or y i ns pecti o n 
n otifica tio n i n relati o n t o t he st u d y .  F urt her m ore, t he i n vesti gat or will c o o perate wit h Pfizer 
or its a ge nts t o pre pare t he i n vesti gat or site f or t he i ns pecti o n a n d will all o w Pfizer or it s 
a ge nt, w he ne ver feasi ble, t o be prese nt d uri n g t he i ns pecti o n.  T he i n vesti gat or site an d 
i n vesti gat or will pr o m ptl y res ol ve a n y discre pa ncies t hat are i de ntifie d bet wee n t he st u d y 
data a n d t he s u bject's me dical rec or ds.  T he i n vesti gat or will pr o m ptl y p r o vi de c o pies of t he 
i ns pecti o n fi n di n gs t o Pfizer or its a ge nt.  Bef ore resp o nse s u b miss i o n t o t he re g ulat or y 
a ut h orities, t he i n vesti gat or will pr o vi de Pfizer or its a ge nts wit h a n o p p ort u nit y  t o re vie w 
a n d c o m me nt o n res p o nses t o a n y  s uc h fi n di n gs.
It is i m p orta nt t hat t he i n vesti gat or(s) a n d t heir rele va nt pers o n nel are a vai l able d uri n g t h e 
m o ni t ori n g visits a n d p ossi ble a u dits or i ns pecti o ns a n d t hat s ufficie nt ti me is de v ote d t o t he 
pr ocess.
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G
1 1. 1. C ase Re p ort F or ms ( C R F)/ D at a C ollecti o n T o ols ( D C Ts)/ Electr o nic D at a Rec or d
As use d i n t his pr ot oc ol, t he ter m C R F/ D C T s h o ul d be u n derst o o d t o refer t o eit her a pa per 
f or m or a n electr o nic data rec or d or b ot h, de pe n di n g o n t he data c ollecti o n met h o d use d i n 
t his st u d y.
A C R F/ D C T is re q uire d a n d s h o ul d be c o m plete d f or eac h i ncl u de d su bject.  T he c o m plete d
o ri gi nal C R Fs/D C Ts a re t he s ole pr o perty of Pfizer a n d s h o ul d n ot be ma de a vaila ble i n a n y 
f or m t o t hir d parties, e xce pt f or a ut h orize d re prese ntati ves of Pfizer or a p pr o priate re g ulat or y 
a ut h orities, wit h o ut writte n per missi o n fr o m Pfizer.   T he i n vesti ga t or s hall e ns ure t hat t he 
C R Fs/ D C Ts are sec urel y st ore d at t he st u d y site i n e ncr y pte d electr o nic a n d/ or pa per f or m 
a n d will be pass w or d pr otecte d or sec ure d i n a l oc ke d r o o m t o pre v e nt access b y 
u na ut h orize d t hir d parties.


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T he i n vest i gat or has ulti mate res po nsi bilit y  f or t he c ollecti o n a n d re p orti n g of all cli nical, 
safety, a n d la b orat or y data e ntere d o n t he C R Fs/ D C Ts a n d a n y ot her data c ollecti o n f or ms 
(s o urce d oc u me nts) a n d e ns uri ng t hat t he y  are acc urate, a ut he ntic/ ori gi nal, attri buta ble, 
c o m plete, c o ns iste nt, le gi ble, ti mel y (c o nte m p ora ne o us), e n d uri n g, a n d a vaila ble w he n 
re q uire d.  T he C R Fs/ D C Ts m ust be si g ne d by t he i n vesti gat or or b y a n a ut h orize d staff 
me m ber t o attest t hat t h e data c o ntai ne d o n t he C R Fs/ D C Ts are tr ue.  A n y c or recti o ns t o 
e ntries made i n t he C R Fs/D C Ts o r s o urce d oc u me nts m ust be date d, i nitiale d, a n d e x plai ne d 
(if necessar y) a n d s h o ul d n ot o bsc ure t he ori gi nal e ntr y. 
I n m ost cases, t he s o urce d oc u me nts are t he h os pital or t he p hys icia n s u bject c hart.  I n t hese 
cases, data c ollecte d o n t he C R Fs/ D C Ts m ust matc h t he data i n t h ose c harts. 
I n s o me cases, t he C R F/ D C T ma y als o ser ve as t he s o urce d oc u me nt.  I n t hese cases, a 
d oc u me nt s h o ul d be a vaila ble at t he i n vest i gat or site a n d at Pfizer t hat clearl y i de ntifies t hose 
data t hat will be rec or de d o n t he C R F/ D C T, a n d f or w hic h t he C R F/ D C T will sta n d as t he 
s o urce d oc u me nt.
1 1. 2. Rec or d Rete nti o n
T o e na ble e val uati o ns a n d/ or i ns pecti o ns/a u dits fr o m re g ulat or y a ut h orities or Pfizer, t he 
i n vesti gat or a grees t o kee p rec or ds, i ncl u di n g t he i de ntit y of all partici pati n g s ubjects 
(s ufficie nt i nf or mati o n t o li n k rec or ds, e g, C R Fs/ D C Ts a n d h os pital rec or ds), all ori gi nal 
si g ne d i nf or me d c o nse nt/asse nt d oc u me nts, c o pies of all C R Fs/ D C Ts, safet y re p orti n g f or ms, 
s o urce d oc u me nts, a n d detaile d rec or ds of treat me nt dis p ositi o n, a n d a de q uate d oc u me ntati o n 
of rele va nt c orres p o n de nce (e g, letters, meeti n g mi n utes, a n d tele p h o ne call re p orts).  T he 
rec or ds s h o ul d be retai ne d b y t he i n vesti gat or acc or di n g t o t he I C H g ui deli nes, acc or di n g t o 
l ocal re g ulati o ns, or as s pecifie d i n t h e cli nical st u d y a gree me nt ( C S A), w hic he ver is l o n ger. 
T he i n vesti gat or m ust e ns ure t ha t t he rec or ds c o nti n ue t o be st ore d sec urely f or s o l o n g as 
t he y are retai ne d.
If t he i n vesti gat or bec o mes u na ble f or a ny reas o n t o c o nti n ue t o retai n stu d y rec or ds f or t he 
re q uire d peri o d (e g, retire me nt, rel ocati o n), Pfizer s h o ul d be pr os pecti vel y n otifie d.  T he 
st u d y rec or ds m ust be tra nsferre d t o a desi g nee acce pta ble t o Pfizer, s uc h as a n ot her 
i n vesti gat or, a n ot her i nstit uti o n, or a n i n de pe n de nt t hir d p art y arra n ge d b y  Pfizer. 
I n vesti gat or rec or ds m ust be ke pt f or a mi ni m u m of 1 5 ye ars after c o m pleti o n or 
disc o nti n uati o n of t he st u d y or f or l o n ger if re q uire d b y  a p plica ble l ocal re g ulati o ns.
T he i n vesti gat or m ust o btai n Pfizer' s writte n per missi o n before dis p osi n g of a n y rec or ds, 
e ve n if rete nti o n re q uire me nts ha ve bee n met.
1 2. E T HI C S
1 2. 1. I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee


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It is t he res p o nsi bilit y of t he i n vesti gat or t o ha ve pr os pecti ve a p pr o val of t he st u d y  pr ot oc ol, 
pr ot oc ol a me n d me nts, i nf or me d c onse nt/asse nt d oc u me nts, a n d ot her rele va nt d oc u me nts, 
e g, recr uit me nt a d vertise me nts, if a p plica ble, fr o m t he IR B/ E C.  All c orres p o n de nce wit h t he 
I RB/ E C s h o ul d be retai ne d i n t he i n vesti gat or file.  C o pies of IR B/ E C a p pr o vals s h o ul d be 
f or war de d t o Pfizer.
T he o nl y  circ u msta nce i n w hic h a n a me n d me nt ma y  be i nitiate d pri or t o I R B/ E C a p pr o val is 
w here t he c ha n ge is necessar y  t o eli mi nate a p pare nt i m me diate hazar ds t o t he s u bjects.  In 
t hat e ve nt, t he i n vesti gat or m ust n otif y t he I R B/ EC a n d Pfizer i n writi n g i m me diatel y after 
t he i m ple me ntati o n.
1 2. 2. Et hic al C o n d uct of t he St u d y
T he st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol, le gal a n d re g ulat or y 
re q uire me nts, a n d t he ge neral pri nci ples set f ort h i n t he Inter nati o nal Et hical G ui deli nes f or 
Bi o me dical R esearc h I n v ol vi n g H u ma n S u bjects ( C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dical Scie nces 2 0 0 2), I C H G ui deli ne f or G o o d Cli nical Practice, a n d t he Declarati o n of 
Helsi n ki.
1 2. 3. S u bj ect I nf or m ati o n a n d C o nse nt
All parties will c o m pl y  wit h all a p plica ble la ws , i ncl u di n g la ws re gar di n g t he i m ple me ntati o n 
of or ga nizati o nal a n d tec h nical meas ures t o e ns ure pr otecti o n of s u bject pers o nal data.  S uc h 
meas ures will i ncl u de o mitti n g s u bject n a mes or ot her directl y i de ntifia ble data i n a n y 
re p orts, p u blicati o ns, or other discl os ur es, e x ce pt w here re q uire d b y a p plica ble la ws. 
T he pers o nal data will be st ore d at t he st u d y  site i n e ncr ypte d electr o nic a n d/ or pa per f or m 
a n d will be pass w or d pr otec te d or sec ure d i n a l oc ke d r o o m t o e ns ure t hat o nl y a ut h orize d 
st u d y staff h a ve access.  T he st u d y  site will i m ple me nt a p pr o priate tec h nical a n d 
or ga nizati o nal meas ures t o e ns ure t hat t he pers o nal data ca n be rec o vere d i n t he e ve nt of 
disaster.  I n t he e ve nt of a p ote ntial pers o nal data breac h, t he st u d y si te s hall be res p o nsi ble 
f or deter mi nin g w he t her a pers o nal data breac h has i n fact occ urre d a n d, if s o, pr o vi di n g 
breac h n otificati o ns as re q uire d b y  la w.
T o pr otect t he ri g hts a n d free d o ms of nat ural per s o ns wit h re gar d t o t he pr ocessi n g of 
pers o nal data, w he n st u d y  data are co m pile d f or tra nsfer t o Pfizer a n d ot her a ut h orize d 
parties, s u bject na mes will be re m o ve d a n d will be re place d b y a si n gle, s pecific, n u merical 
c o de, base d o n a n u m beri n g s ys te m defi ne d by Pfizer.  All ot her i de ntifia ble data tra nsfe rre d 
t o Pfizer or ot her a ut h orize d parties will be i de ntifie d b y  t his si n gle, s u bject-s pecific c o de.  
T he i n vesti gat or site will mai ntai n a c o nfi de ntial list of s u bjects w h o partici pate d i n t he 
st u d y, li nki n g eac h s u bject’s n u merical c o de t o his or her act ual i de ntit y .  I n case o f data 
tra nsfer, Pfizer will mai ntai n hi g h sta n dar ds of c o nfi de ntialit y a n d pr otecti o n of s u bjects’ 
pers o nal data c o nsiste nt wit h t he Cli nical St u d y A gree me nt a n d a p plica ble pri vac y la ws.
T he i nf or me d c o nse nt /asse nt d oc u me nts a n d a n y s u bject recr uit me nt ma terials m ust be i n 
c o m plia nce wit h I C H G C P, l ocal re g ulat or y  re q uire me nts, a n d le gal re q uire me nts, i ncl u di n g 
a p plica ble pri vac y la ws.


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Pa ge 1 3 4
T he i nf or me d c o nse nt /asse nt d oc u me nts use d d ur i n g t he i nf or me d c o nse nt pr ocess a n d a n y 
s u bject recr uit me nt materials m ust be re vie we d a n d a p p r o ve d by Pfizer, a p pr o ve d b y t he 
I RB/ E C bef ore use, a n d a vaila ble f or i ns pecti o n.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  s u bject, or his or her le gall y acc e pta ble 
re prese ntati ve, or pare nt(s) or le gal g uar dia n if a mi n or, is f ully i nf or me d a b o ut t he nat ure 
a n d o bjecti ves of t he st u d y, t he s hari n g of data relati n g t o t he st u d y a n d p ossi ble ris ks 
ass ociate d wit h partici pati o n, i ncl u di n g t he ris ks ass ociate d wit h t he pr ocessi n g of t he 
s u bject’s pers o nal data.  The i n vesti gat or f urt he r m ust e ns ure t hat ea c h st u d y s u bject, or his 
or her le gall y  acce pta ble re prese ntati ve, or pare nt(s) or le gal g uar dia n if a mi n or, is f ull y 
i nf or me d a b o ut his or her ri g ht t o access a n d c orrect his or her pers o nal data a n d t o wit h dra w
c o nse nt f or t he pr ocessi n g of his or her p ers o nal data.
W he ne ver c o nse nt is o btai ne d fr o m a s u bject’s le gally acce pta ble re prese ntati ve/ pare nt(s) or 
le gal g uar dia n, t he s u bject’s asse nt (affir mative a gree me nt) m ust s u bse q ue ntl y  be o btai ne d 
w he n t he s u bjec t has t he ca pacit y t o pr o vi de asse nt, as deter mi ne d by t he I R B/ E C.  If t he 
i n vesti gat or deter mi nes t hat a s u bject’s decisi o nal ca pacit y is s o li mite d t hat he or s he ca n n ot 
reas o na bly be c o ns ulte d, t he n, as per mitte d by t he I R B/ E C a n d c o nsiste nt wit h l ocal 
re g ulat or y a n d le gal re quire me nts, t h e s u bj ect’s asse nt ma y be wai ve d wit h s o urce 
d oc u me ntati o n of t he reas o n asse nt was n ot o btai ne d.  If t he st u d y s u bject d oes n ot pr o vi de 
his or her o w n c o nse nt, t he s o urce d oc u me nts m ust rec or d w hy t he s u bject di d n ot p r o vi de 
c o nse nt (e g, mi n o r, decisi o nall y i m paire d a d ult), h o w t he i n vesti gat or deter mi ne d t hat t he 
pers o n si g ni n g t he c o nse nt was t he s u bject’s le gall y acce pta ble re prese ntati ve, t he c o nse nt 
si g ner’s relati o ns hi p t o t he st u d y s u bject (e g, pare nt, s p o use), a n d t hat t he s u bject’s asse nt 
was o bta i ne d or wai ve d.  If asse nt is o btai ne d ver ball y, it m ust be d oc u me nte d i n t he s o urce 
d oc u me nts .
If t he st u dy i ncl u des mi n or s u bjects w h o reac h t he a ge of maj ori t y d uri n g t he st u d y, as 
rec o g nize d u n der l ocal la w, t he y m ust rec o nse nt as a d ults to re mai n i n t he st u d y .  If t he 
e nr oll me nt of e ma nci pate d mi n ors is per mitte d b y  t he st u d y a ge criteria, t he IR B/ E C, a n d 
l ocal la w, t he y m ust pr o vi de d oc u me ntati o n of le gal stat us t o gi ve c o nse nt wit h o ut t he 
per missi o n of a pare nt or le gal g uar dia n. 
T he i nvesti gat or, o r a pers o n desi g nate d b y t he i n vesti gat or, will o btai n writte n i nf or me d 
c o nse nt fr o m eac h s u bject or t he s u bject's le gall y acce pta ble re prese ntati ve, pare nt(s), or le gal 
g uar dia n a n d t he s u bject’s asse nt, w he n a p plica bl e, bef ore a n y st u d y- s pecific acti vit y is 
pe rf or me d, u nless a wai ver of i nf or me d c o nse nt has bee n gra nte d by a n I RB/ E C.  T he 
i n vesti gat or will retai n t he ori gi nal of eac h s u bject's si g ne d c o nse nt/asse nt d oc u me nt.
1 2. 4. Re p orti n g of S afet y Iss ues a n d Seri o us Bre ac hes of t he Pr ot oc ol or IC H G C P
I n t he e ve nt of a n y  pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) b y a n a p plica ble 
re g ulat or y a ut h ority i n a n y area of t he w orl d, or if t he i n vesti gat or is a ware of a n y  ne w 
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be nefits an d ris ks of t he i n vesti gati o nal 
pr o d uct, Pfizer s h o ul d be i nf or me d i m me diatel y. 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
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Pa ge 1 3 5
I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety meas ures 
ta ke n b y t he i n vesti gat or t o pr otect t he st u d y s u bjects a gai ns t a ny i m me diate hazar d , a n d of 
a n y seri o us breac hes of t his pr ot oc ol or of I C H G C P t hat t he i n vesti gat or bec o mes a ware of.
1 3. D E FI NI TI O N O F E N D O F T RI A L
1 3. 1. E n d of Tri al i n All P artici p ati n g C o u ntries
E n d of trial i n all c o u ntries is defi ne d as t he last s u bject l ast visit ( LS L V).
1 4. S P O N S O R DI S C O N TI N U A TI O N C RI T E RI A
Pre mat ure ter mi nati o n of t his st u d y  ma y occ ur beca use of a re g ulat or y a ut h orit y decisi o n, 
c ha n ge i n o pi ni o n of t he I R B/ E C, or i n vesti gati o nal pr o d uct safet y pr o ble ms, or at t he 
discreti o n of Pfizer.  I n a d diti o n, Pfizer retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of 
P F -0 4 9 6 5 8 4 2 at a n y ti me.
If a st u dy is pre mat urel y ter mi nate d, Pfizer will pr o m ptl y n otif y t he i n vesti gat or.  After 
n otificati o n, t he i n vesti gat or m ust c o ntact all partici pati n g s u bjects a n d t h e h os pital p har mac y 
(if a p plica ble) wit hi n 7 da y s.  As directe d b y Pfizer, all st u d y materials m ust be c ollecte d a n d 
all C R Fs c o m plete d t o t he greatest e xte nt p ossi ble.
1 5. P U B LI C A T I O N O F S T U D Y R E S U L T S
1 5. 1. C o m m u nic ati o n of Res ults b y Pfizer
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical trial res ults t hr o u g h p osti n g t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E ur o pea n Cli nical Trials 
Data base ( E u dra C T), a n d/ or w w w. pfizer.c o m, a n d ot her p u blic re gistries i n acc or da nce with 
a p plica ble l ocal la ws/re g ulati o ns. 
I n all cases, st u dy res ults are re p orte d b y Pfizer i n a n o bjecti ve, acc urate, bala nce d, a n d 
c o m plete ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y or t he c o u ntr y i n 
w hic h t he st u d y  was c o n d ucte d.
w w w.c li nicaltrials. g o v
Pfiz er p osts cli nic al trial U S Basic Res ults o n w w w.cli nicaltrials. g o v f or Pfizer- s p o ns ore d 
i nter ve nti o nal st u dies (c o n d ucte d i n patie nts) t hat e val uate t he safety a n d/ or efficac y of a 
Pfizer pr o d uct, re gar dless of t he ge o gra p hical l ocati o n i n w hic h t he st u d y  is c o n d ucte d.  U S 
Bas ic Res ults are s u b mitte d f or p osti n g wit hi n 1 year of t he pri mar y c o m pleti o n date ( P C D) 
f or st u dies i n a d ult p o p ulati o ns or wit hi n 6 mo nt hs of t he P C D f or st u dies i n pe diatric 
p o p ulati o ns.
P C D is defi ne d as t he da te t hat t he fi nal s u bject was e xa mi ned or r ecei ve d a n i nter ve nti o n f or 
t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y o utc o me, w het her t he cli nical st u d y 
c o ncl u de d acc or di n g t o t he pre -s pecifie d pr ot oc ol or was ter mi nate d.


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B 7 4 5 1 0 1 4
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E u dra C T
Pfizer p osts E u r o pea n U ni o n ( E U) Basic Res ults o n E u dra C T f or all Pfizer-s p o ns ore d 
i nter ve nti o nal st u dies t hat are i n sc o pe of E U re q uire me nts.  E U Basic Res ults are s u b mitte d 
f or p osti n g wit hi n 1 year of t he P C D f or st u dies i n a d ult p o p ulati o ns or wit hi n 6 m o nt hs of 
t he P C D f or st u dies i n pe di atric p o p ulat i o ns.
w w w. pfizer.c o m
Pfizer p osts P u blic Discl os ure S y n o pses (cli nical st u d y  re p ort s yn o pses i n w hic h a n y  data 
t hat c o ul d be use d t o i de ntify i n di vi d ual patie nts has bee n re m o ve d) o n w w w. pfizer.c o m f or 
Pfizer -s p o ns ore d i nter ve nti o nal st u dies at t he sa me time t he U S Basic Res ults d oc u me nt is 
p oste d t o w w w.cli nicaltrials. g o v.
1 5. 2. P u blic ati o ns b y I n vesti g at ors
Pfizer s u p p orts t he e xercise of aca de mic free d o m a n d has n o o bjecti o n t o p u blicati o n b y t he 
pri nci pal i n vesti gat or ( PI) of t he res ults of t he st u d y base d o n i nf ormati o n c ollecte d or 
ge nerate d b y t he PI, w het her or n ot t he res ults are fa v ora ble t o t he Pfizer pr o d uct.  H o we ver, 
t o e ns ure a gai nst i na d verte nt discl os ure of c o nfi de ntial i nf or mati o n or u n pr otecte d 
i n ve nti o ns, t he i n vesti gat or will pr o v i de Pfizer a n o p p or t u nit y t o re vie w a n y pr o p ose d 
p u blicati o n or ot her t y pe of discl os ure of t he res ults of t he st u d y (c ollecti vel y, “ p u blicati o n”) 
bef ore it is s u b mitte d or ot her wise discl ose d.
T he i n vesti gat or will pr o vi de a n y  p u blicati o n t o Pfizer at least 3 0 d a y s bef ore it is s u b mitte d 
f or p u blicati o n or ot her wise discl ose d.  If a n y pate nt acti o n is re q uire d t o pr otect i ntellect ual 
pr o pert y ri g hts, t he i n vesti gat or a grees t o dela y t he discl os ure f or a peri o d n ot t o e xcee d a n 
a d diti o nal 6 0 da y s.
T he i n v esti gat or will, o n re q uest, re m o ve a n y pre vi o usl y  u n discl ose d c o nfi de ntial 
i nf or mati o n bef ore discl os ure, e xce pt f or a ny st u d y - or Pfizer pr o d uct -relate d inf or mati o n 
necessar y  t o t he a p pr o priate scie ntific prese ntati o n or u n dersta n di ng of t he st u d y  res ults.
If t he st u dy is part of a m ultice nter st u d y, t he i n vesti gat or a grees t hat t he first p u blicati o n is 
t o be a j oi nt p u blicati o n c o veri n g all i n vesti gat or sites, a n d t hat a ny s u bse q ue nt p u blicati o ns 
b y  t he PI will refere nce t hat pri mar y p u blicati o n.  H o we ver , if a j oi nt man uscri pt has n ot 
bee n s u b mitte d f or p u blicati o n wit hi n 1 2 m o nt hs of c o m pleti o n or ter mi nati o n of t he st u d y  at 
all partici pati n g sites, t he i n vesti gat or is free t o p u blis h se paratel y, s u bject t o t he ot her 
re q uire me nts of t his secti o n.
F or all p u blicati o ns r elati ng t o t he st u d y, t he i nstit uti o n will c o m pl y  wit h rec o g nize d et hical 
sta n dar ds c o ncer ni n g p u blicati o ns a n d a ut h ors hi p, i ncl u di n g Secti on II - “ Et hical 
C o nsi derati o ns i n t he C o n d uct a n d Re p orti n g of Researc h” of t he U nif or m Re q uire me nts f or 
Ma n uscri pts
S u b mi tte d t o Bi o me dical J o ur nals, htt p:// w w w.ic mje. or g/i n de x. ht ml #a ut h ors hi p, 
esta blis he d b y t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors.


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B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 7
P u blicati o n of st u d y  res ults is als o pr o vi de d f or i n t he C S A bet wee n Pfizer a n d t he 
i nstit utio n.  I n t his secti on e ntitle d P u blicati o ns b y  In vesti gat ors , t he defi ne d ter ms s hall ha ve 
t he mea ni n gs gi ve n t o t he m i n t he C S A.
If t here is a ny c o nflict bet wee n t he C S A a n d a n y attac h me nts t o it, t he ter ms of t he C S A 
c o ntr ol.  If t here is a n y c o nflict bet wee n t his pr ot oc ol a n d t he C S A, t his pr ot oc ol will c o ntr ol 
as t o a n y iss ue re gar di n g treat me nt of st u d y s u bjects, a n d t he C S A will c o ntr ol as t o all ot her 
iss ues.


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B 7 4 5 1 0 1 4
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Pa ge 1 3 8
1 6. R E F E R E N C E S
1.
Eic he nfiel d L F, Ellis C N, Ma nci n i AJ, et al. At o pic der matitis: e pi demi ol o g y a n d 
pat h o ge nesis u p date. Se mi n C uta n Me d S ur g 2 0 1 2; 3 1( 3 S u p pl)( Se p): S 3 - 5.
2.
Leic ht S, Ha n g gi M. At o pic der matitis. H o w t o i nc or p orate a d va nces i n ma na ge me nt. 
P ost gra d Me d 2 0 0 1; 1 0 9( 6)(J u n): 1 1 9- 2 7.
3.
Mar g olis J S, A b ua bara K, Bil ker W, et a l. Persiste nce of mil d t o m o derate at o pic 
der matitis. J A M A Der mat ol 2 0 1 4; 1 5 0( 6): 5 9 3- 6 0 0.
4.
Slater N A, M orrell D S. S y ste mic t hera p y of c hil d h o o d at o pic der matitis. Cli n Der mat ol 
2 0 1 5; 3 3( 3): 2 8 9 - 2 9 9.
5.
Le u n g D Y, Bie ber T. At o pic der matitis. La ncet 2 0 0 3; 3 6 1( 9 3 5 2) : 15 1 - 1 6 0.
6.
Ri n g J, Al o mar A, Bie ber T, et al. G ui deli nes f or treat me nt of at o pic ecze ma (at o pic 
der matitis) part I. J E ur Aca d Der mat ol Ve nere ol 2 0 1 2; 2 6( 8): 1 0 4 5 - 6 0.
7.  
A urie m ma M, Via nale G, A meri o P, et al. C y t o ki nes a n d T cells i n at o pic der matitis E ur 
C y t o ki ne Net w 2 0 1 2; 2 4( 1): 3 7 - 4 4.
8.  
M ortz C, A n derse n K, Dell gre n C, et al. At o pic der matitis fr o m a d olesce nts t o 
a d ult h o o d i n t he T O A C S c o h ort: pre vale nce, persiste nce a n d c o m or bi dities. Aller g y  
2 0 1 5; 7 0: 8 3 6 - 4 5. 
9.
Sa n dstr o m M., Faer ge ma n n J. P r o g n osis a n d pr o g n ostic fact ors i n a dult pa tie nts wit h 
at o pic der matitis: a l o n g -ter m f oll o w-u p q uesti o n naire st u d y . Britis h J. of Der mat ol o g y 
2 0 0 4; 1 5 0: 1 0 2 - 1 0.
1 0.
Dec kers I, Mc Lea n A S, Li nsse n S, M o m mers M, et al. I n vesti gati n g i nter nati o nal ti me 
tre n ds i n t he i nci de nce a n d pre vale n ce of at o pic ecz e ma 1 9 9 0 -2 0 1 0: a s y ste matic re vie w 
of e pi de mi ol o gical st u dies P L o S O ne 2 0 1 2; 7( 7):e 3 9 8 0 3.
1 1.
Sil ver ber g J I, Ha nifi n J M. A d ult ecze ma pre vale nce a n d ass ociati o ns wit h ast h ma a n d 
ot her healt h a n d de m o gra p hic fact ors: a U S p o p ulati o n -base d st u d y . J Aller g y Clin 
Im m u n ol 2 0 1 3; 1 3 2( 5): 1 1 3 2 - 1 1 3 8.
1 2.
Lee C H, C h ua n g H Y, H o n g C H, H ua n g S K, et al. Lifeti me e x p os ure t o ci garette 
s m o ki n g a n d t he de vel o p me nt of a d ult-o nset at o pic der matitis. Br J Der mat ol 
2 0 1 1; 1 6 4( 3): 4 8 3 - 9.
1 3.
H o me y  B, Stei nh off M, R uzic ka T, et al. C yt o ki nes an d c hem o ki nes orc hestrate at o pic 
s ki n i nfla m mati o n.J Aller g y Cli n I m m u n ol 2 0 0 6; 1 1 8( 1): 1 7 8- 8 9.
1 4.
C or nelisse n C, L usc her -Firzlaff J, Bar o n J M, et al. Si g nali n g b y I L-3 1 a n d f u ncti o nal 
c o nse q ue nces. E ur J Cell Bi ol 2 0 1 2; 9 1( 6- 7): 5 5 2 -6 6.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 9
1 5.
Gittler J K , S he mer A, S ua rez-Fa ri nas M, F ue ntes- D uc ula n J, et al. Pr o gressi ve 
acti vati o n of T( H) 2/ T( H) 2 2 c yt o ki nes a n d selecti ve e pi der mal pr otei ns c haracterizes 
ac ute a n d c hr o nic at o pic der matitis. J Aller g y  Cli n Im m u n ol 2 0 1 2; 1 3 0( 6): 1 3 4 4 - 5 4.
1 6.
J u ni per E F, O' B yr ne P M, G u y att G H, et al. D e vel o p me nt a n d vali dati o n of a 
q uesti o n naire t o meas ure ast h ma c o ntr ol. E ur Res pir J 1 9 9 9; 1 4: 9 0 2 – 9 0 7.
1 7.
J u ni per E F, B o us q uet J, A betz L, Bate ma n E D. I de ntif yi n g ' well-c o ntr olle d' a n d ' n ot 
well -c o ntr olle d' ast h ma us i n g t he Ast h ma C o ntr ol Q uesti o n naire. Re s pirat or y Me dici ne 
2 0 0 6 ( 1 0 0): 6 1 6 – 6 2 1.
1 8.
P os ner K, O q ue n d o M A, G o ul d M, et al. C ol u m bia Classificati o n Al g orit h m of S uici de 
Assess me nt ( C - C A S A): classificati o n of s uici dal e ve nts i n t he F D A's pe diatric s uici dal 
ris k anal ys is of a nti de pressa nts. A m J Ps ychia tr y 2 0 0 7; 1 6 4( 7): 1 0 3 5 - 4 3.
1 9.
Ra bi n R, G u de x C, Selai C, et al. Fr o m tra nslati o n t o versi o n ma na ge me nt: a hist or y  a n d 
re vie w of met h o ds f or t he c ult ural a da ptati o n of t he E ur o Q ol fi ve-di me nsi o nal 
q uesti o n naire. Val ue i n H ealt h 2 0 1 4; 1 7( 1): 7 0 - 6.  
2 0.
Va n H o ut B, Ja nssen M F, Fe n g Y S, et al. I nteri m sc ori n g f or t he E Q- 5 D-5 L : ma p pi n g 
t he E Q- 5 D-5 L  t o E Q- 5 D-3 L  val ue sets. Val ue i n Healt h 2 0 1 2; 1 5( 5): 7 0 8-1 5.  
2 1.
Ra m os -G o ñi J M, Pi nt o -Pra des J L,  O p pe M, et al. Val uati o n a n d m o deli n g of E Q- 5 D- 5 L  
healt h states u sin g a h y bri d a p pr oac h. Me dical care 2 0 1 7; 5 5( 7):e 5 1 - 8.  
2 2.
Ya n g Y, Brazier J, L o n g w ort h L . E Q-5 D i n s ki n c o n diti o ns: a n assess me nt of vali dit y  
a n d res p o nsi ve ness. E ur J Healt h Ec o n. 2 0 1 5; 1 6( 9): 9 2 7- 9 3 9.
2 3.
Ja nsse n M F, Pic kar d A S, G olic ki D, et al. Meas ure me nt pro p erties of t he E Q - 5 D-5 L  
c o m pare d t o t he E Q - 5 D-3 L  acr oss ei g ht patie nt gr o u ps: a m ulti-c o u ntr y st u d y. Q ualit y 
of L ife Researc h. 2 0 1 3; 2 2( 7): 1 7 1 7- 2 7.  
2 4.
A g b orsa n ga y a C B, La hti ne n M, C o o ke T, J o h ns o n J A. C o m pari n g t he E Q -5 D 3 L a n d 
5 L : meas ure me nt pr o perties a nd ass ociati o n wit h c hr o nic c o n diti o ns a n d m ulti m or bi dit y 
i n t he ge neral p o p ulati o n. Healt h a n d q uality of life o utc o mes 2 0 1 4; 1 2( 1): 7 4.
2 5.
Her d ma n M, G u de x C, Ll o y d A, et al. De vel o p me nt a n d preli mi nar y  testi n g of t he ne w 
fi ve-le vel versio n of E Q -5 D ( E Q - 5 D-5 L ). Q ualit y  of life researc h 2 0 1 1; 2 0( 1 0): 1 7 2 7 - 3 6. 
2 6.
Wille N, Ba dia X, B o nsel G, B urstr o m K, Ca vri ni G, De vli n N, E g mar A C, Grei ner W, 
G usi N, Her d ma n M, Jels ma J  De vel o p me nt of t he E Q - 5 D-Y: a c hil d -frie n dl y versi o n 
of t he E Q -5 D.  Q ual L ife Res 2 0 1 0 A u g; 1 9( 6): 87 5 - 8 8 6. 
2 7.
Ra ve ns- Sie berer U, Wille N, Ba dia X, et al. Feasi bilit y , relia bilit y, a n d vali dit y of t he 
E Q - 5 D-Y: res ults fr o m a m ulti nati o nal st u d y . Q ual Life Res 2 0 1 0; 1 9( 6): 8 8 7- 9 7. 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 0
2 8.
E ur o Q ol Gr o u p. E ur o Q olea ne w facilit y f or t he meas ure m e nt of healt h -relate d q ualit y 
of life . The E ur o Q ol Gr o u p. Healt h P olic y  1 9 9 0; 1 6: 1 9 9- 2 0 8.
2 9.
Si m ps o n E L , Ga d kari A, W or m M, et al. D u pil u ma b t hera p y pr o vi des cli nicall y 
mea ni n gf ul i m pr o ve me nt i n patie nt-re p orte d o utc o mes ( P R Os): A p hase II b, 
ra n d o mize d, place bo - c o ntr olle d, cli nical trial i n a d ult pa tients wit h m o derate t o se vere 
at o pic der matitis ( A D). J A m Aca d Der mat ol. 2 0 1 6; 7 5( 3): 5 0 6- 5 1 5.
3 0.
Si m ps o n E L , Bie ber T, G utt ma n-Yass k y E, et al. T w o P hase 3 trials of d u pil u ma b 
vers us place b o i n at o pic der matitis. N E n g l J Me d. 2 0 1 6; 3 7 5: 2 3 3 5- 23 4 8.
3 1.
P o ole C D , Cha m bers C, Si d h u M K, et al. Healt h -relate d utilit y a m o n g a d ults wit h 
at o pic der matitis treate d wit h 0. 1 % tacr oli m us oi nt me nt as mai nte na nce t hera p y o ver 
t he l o n g ter m: fi n di n gs fr o m t he Pr ot o pic C O N T R O L st u d y. Br J Der mat ol 
2 0 0 9; 1 6 1( 6): 1 3 3 5 - 4 0.
3 2.
Ki m C, P ar k K Y , A h n S, et al. Ec o n o mic i m pact of at o pic der matitis i n K orea n patie nts. 
A n n Der mat ol. 2 0 1 5; 2 7( 3): 2 9 8- 3 0 5. 
3 3.
Fi nla y  A Y, K ha n G K. Der mat ol o g y Life Q ualit y In de x ( D L QI): A si m ple practical 
meas ure f or r o uti ne cli nica l use. Cli nical a n d E xpe ri me ntal Der mat ol o gy 1 9 9 4; 1 9: 
2 1 0 - 2 1 6.
3 4.
Le wis -J o nes M S, Fi nla y A Y. T he C hil dre n's Der mat ol o g y Life Q ualit y In de x ( C D L QI ): 
I nitial vali dati o n a n d practical use. Britis h J o ur nal of Der mat ol o g y 1 9 9 5; 1 3 2: 9 4 2- 4 9. 
3 5.
Ersser SJ, C o w dell F, L atter S, et al. Ps y c h olo g ical a n d e d ucati o nal i nter ve nti o ns f or 
at o pic ecze ma i n c hil dre n. T he C oc hra ne Li brar y . 2 0 1 4;Ja n 1. 
3 6.
Sc h mitt J, La n ga n S, Willia ms H et al. W hat are t he best o utc o me meas ure me nts f or 
at o pic ecze ma? A s yste matic re vie w. J Aller g y Clinical I m m u n ol 2 0 0 7; 1 2 0 ( 6): 1 3 8 9- 9 8. 
3 7.
W hite D , Leac h C, Si ms R, et al. Vali dati o n of t he H os pital A n xiet y a n d De pressi o n 
Scale f or use wit h a d olesce nts. Br J Ps y c hiatr y 1 9 9 9; 1 7 5( 5): 4 5 2- 4.  
3 8.
Ware J, K osi ns ki M, Bj or ner J, et al. Deter mi ni n g i m p orta nt differe n ces i n sc ores. 
User's Ma n ual f or t he S F - 3 6 v2 ® Healt h S ur ve y . Li nc ol n ( RI): Q ualit yMetric 
I nc or p orate d; 2 0 0 7: 1 2 5- 3 3. ( Refere nce a vaila ble u p o n re q uest.).
3 9.
Cella D, Lai J S, C ha n g C H, et al. Fati g ue i n ca ncer patie nts c o m pare d wit h fati g ue i n 
t he ge neral U nited States p o p ula ti o n. Ca ncer 2 0 0 2; 9 4( 2 ): 5 2 8-3 8. 
4 0.
Os ma n A, Ba g ge C L, G utierrez P M, et al. T he S uici dal Be ha vi ors 
Q uesti o n naire -Re vise d ( S B Q - R): vali dati o n wit h cli nical a n d n o ncli nical sa m ples. 
Assess me nt. 2 0 0 1; 8( 4): 4 4 3 - 5 4.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 1
4 1.
Kr oe n ke K., Stri ne, T., S pitzer C ., et al, T he PH Q -8 as a meas ure of c urre nt de pressi o n 
i n t he ge neral p o p ulati o n 2 0 0 9. J Affect Dis or d 2 0 0 9; 1 1 4( 1-3); 1 6 3 – 7 3. 
4 2.
Lai J, Cella D., H ol m S, et al, Meas uri n g Fati g ue f or C hil dre n wit h Ca ncer: 
De vel o p me nt a n d Vali dati o n of t he Pe diatric F u ncti o nal Assess me nt of C hr o nic Ill ness 
T hera p y Fati g ue ( P E D S F A CI T- F). J Pe diatr He mat ol O nc ol 2 0 0 7; 2 9( 7): 4 7 1 - 9.
4 3.
Ha nifi n J M, Raj ka G. Dia g n ostic feat ures of at o pic der matitis. Acta Der m Ve nere ol 
1 9 8 0; 9 2(s u p pl): 4 4- 7.
4 4.
Y osi p o vitc h G, Rea ne y  M, Maste y V, et al. Vali dati o n of t he pea k pr urit us n u merical 
rati n g scale: Res ults fr o m cli nical st u dies of d u pil u ma b i n a d ult patie nts wit h m o derate 
t o se vere at o pic der matitis: 5 0 6 3. J o ur nal of t he A merica n Aca de my of Der mat ol o g y. 
2 0 1 7 J u n 1; 7 6( 6): A B 2 7 8.
4 5.
J u ni per E F, S ve nss o n K, M or k A - C, et al., Meas ureme nt pr o perti es a n d i nter pretati o n of 
t hree s h orte ne d versi o ns of t he ast h ma c o ntr ol q uesti o n naire. Res pirat or y Me dici ne. 
2 0 0 5; 9 9: 5 5 3 - 5 5 8.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 2
A p pe n di x 1. A b bre vi ati o ns 
T his f oll o wi n g is a list of a b bre viati o ns t hat ma y  be use d i n t he pr ot oc ol. 
A b bre vi ati o n
Te r m
A C Q
A st h ma C o ntr ol Q uest i o n naire
A D
at o pic der matitis
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A T P
a de n osi ne tri p h os p hate
A U C
Area u n der t he c ur ve
A U C i nf
Area u n der t he c ur ve fr o m 0 t o i nfi nit y
A U C last
rea u n der t he cur ve fr o m 0 t o last
B C G
Bacille Cal mette G uéri n
BI D
t wice a da y
B P
bl o o d press ure
B S A
b o d y s urface area
C ma x
ma xi m u m c o nce ntrati o n 
C D
Cl uster of differe ntiati o n
C D L QI
C hil dre n’s Der mat ol o g y L ife Q ualit y I n de x
C F B
cha n ge fr o m ba seli ne
CI
c o nfi de nce i nter val
C L/ F
cleara nce/fracti o n of d ose a bs or be d
C O 2
car b o n di o xi de
C K
creati ne ki nase
C R F
case re p ort f or m
C S A
cli nical st u d y a gree me nt
Cs A
c ycl os p ori n A
C S F
cere br os pi nal fl ui d
C S R
cli nical st u d y re p ort
C -S S R S
C ol u m bia S ui ci de Se verit y Rati n g Scale
C T
cli nical trial
C T A
cli nical trial a p plicati o n
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C V
C oefficie nt of variati o n
C Y P
C y t oc hr o me P
D C T
Data C ollecti o n T o ol
DI LI
dr u g -i n duce d li ver i nj ur y
D L Q I
Der m at ol o g y L ife Q ualit y I n de x
D M C
data m o nit ori n g c o m mittee
D N A
de o x yri b o n ucleic aci d
D U
dis pe nsa ble u nit
E A SI
Ecze m a Area a n d Se verit y I n de x
E B V
E pstei n Barr vir us
E C
et hics c o m mittee
E C G
electr ocar di o gra m
E -D M C
e xter nal d ata m o nit ori n g c o m mitt ee
E D P
e x p os ure d uri n g pre g na nc y
E LI S A
E nz y me -Li n ke d I m m u n os or be nt Assa y
E M A
E ur o pea n Me dici nes A ge nc y
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 3
A b bre vi ati o n
Te r m
E O S
e n d of st u d y
E O T
e n d of treat me nt
E P O
er yt hr o p oieti n
e P R O
electr o nic Patie nt Re p orte d O utc o me 
E Q -5 D -5 L
E ur o Q ol Q ualit y of Life 5 -Di me nsi o n 5 -Le vel Scale
E Q -5 D -Y
E ur o Q ol Q ualit y of Life 5 -Di me nsi o n Y o ut h Scale
E T
earl y ter mi nati o n 
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n Cli nical Trials Data base
F A CI T -F
F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y Fati g ue Scale
F A Cs
fl u oresce nce-acti vate d cell s orti n g
F A S
f ull a nal ysis set
F A S -M A R
f ull a nal ysis set – missi n g at ra n d o miz ati o n
F A S -O L
f ull a nal ysis set – o pe n la bel r u n -i n
F A S -R A
f ull a nal ysis set - ra n d o mize d
F A S -R E
f ull a nal ysis set - resc ue
F D A
F o o d a n d Dr u g A d mi nistrati o n 
F E V
F orce d e x pirat or y v o l u me
F S H
f ollicle-sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
G G T
Ga m ma -gl uta m yl tra nsferase
G M -C S F
gra n ul oc yte -macr o p ha ge c ol o n y -sti m ulati n g fact or
H A D S
H os pital A n xiet y a n d De pressi o n Scale
H Bs A b
he patitis B s urface a nti b o d y
H Bs A g
he patitis B s urface a nti ge n
H Bc A b 
he patitis B c ore a nti b o d y
H B V
he patitis B vir us
H B V D N A
he patitis B vir us de o x yri b o n ucleic aci d
H C V
he patitis C vir us
H C V A b 
he patitis C a nti b o d y
H C V R N A
he patitis C viral ri b o n ucleic aci d
H D L
hi g h -de nsit y li p o pr ot ei n 
H E E N T
h ea d, e yes, ears, n ose a n d t hr oat
He p B
he patitis B
HI V
h u ma n i m m u n o deficie nc y vir us
H R Q L
healt h -relate d q ualit y of life
hs C R P
hi g h -se nsiti vit y C-reacti ve pr otei n
H S V
her pes si m ple x vir us
H T A
healt h tec h n ol o gies as sess me nt 
I B
I n vesti gator’s Br oc h ure
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I D
i de ntificati o n
I F N
i nterfer o n
I F N-
i nterfer o n-al p ha
I F N-
i nterfer o n-ga m ma
I G A
I n vesti gat or’s Gl o bal Assess me nt
I g E 
I m m u n o gl o b uli n E
I g G
i m m u n o gl o b uli n G
II V
i nter i n di vi d ual variabi lit y
I L
i nterle u kin
I N D
i n vesti gati o nal ne w dr u g a p plicati o n


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 4
A b bre vi ati o n
Te r m
I N R
i nter nati o nal n or malize d rati o
I P
i n vesti gati o nal pr o d uct
I R B
i nstit uti o nal re vie w b oar d
I R C
i nter nal re vie w c o m mittee
I R T
i nteracti ve res p o nse tec h n ol o g y
I U D
i ntra uteri ne de vice
IW R
i nteracti ve we b re s p o nse
J A K
Ja n us ki nase
J A K 1
Ja n us ki nase 1
J A K 2
Ja n us ki nase 2
J A K 3
Ja n us ki nase 3
K 2E D T A
di p otassi u m et h yle ne dia mi netetraacetic aci d
L D L
l o w-de nsit y li p o pr otei n
L F T
li ver f u ncti o n test
L L Q
l o wer li mit of q ua ntificati o n
L S L V
last s u bject last visit 
L T E
l o n g-ter m e xte nsi o n
M A A
mar keti n g a ut h orisati o n a p plicati o n
M C H
mea n c or p usc ular he m o gl o bi n
M C H C
mea n c or p usc ular he m o gl o bi n c o nce ntrati o n
M C V
mea n c or p usc ular v ol u me
M H P
me ntal healt h pr ofessi o nal
M M R M
mi xe d -effect m o de l wit h re peate d meas u res
M n B
me ni n giti dis ser o gr o u p B
M RI
ma g netic res o na nce i ma gi n g
M T X
met h otre xate
N/ A
n ot a p plica ble
N B -U V B
narr o w ba n d ultra vi olet B li g ht
N K
Nat ural Killer
N R S 
n u merical rati n g scale
O T C
o ver t he c o u nter
P C D
pri mar y c o m pleti o n date
P D
P har mac o d y na mics
P D E -4
P h os p h o diesterase 4
Pe ds -F A CI T -F
Pe diatric F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y Fati g ue Scale
P E E R
Pe diatric Ecze ma Electi ve Re gistr y
P F S
prefille d s yri n ge
P GI C
Patie nt Gl o bal I m press i o n of C ha n ge
P GI S
P a tie nt Gl o bal I mpressi o n of Se verit y
P G x
P har m ac o ge n o mics
P H P
Pri mar y Care P h ysicia n
P H Q 8
Patie nt Healt h Q uesti o n naire - 8 ite ms
PI
pri nci pal i n vesti gat or
P K
P har m ac o ki netics
P O C
pr o of of c o nce pt
P O E M
Patie nt -Orie nte d Ecze ma Mea s ure
P P A S
per -pr ot oc o l a nal ysis set
P P D
p urifie d pr otei n deri vati ve test
P R O
patie nt re p orte d o utc o me
P S A A D
Pr urit us a n d S y m pt o ms Assess me nt f or At o pic Der matitis
P T
pr ot hr o m bi n ti me
Pt G A 
Patie nt Gl o bal Assess me nt


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 5
A b bre vi ati o n
Te r m
Q D
o nce dail y
Q F T - G
Q ua nti F E R O N -T B G ol d
Q T
Q T i nter va l
R ac
acc u m ulati o n rati o 
R B C
re d bl o o d cell
R N A
ri b o n ucleic aci d
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B Q -R
S uici de Be ha vi ors Q uesti o n naire -Re vise d
S C O R A D 
S C O Ri n g At o pic Der matitis
S F -3 6
S h ort F or m -3 6
SI B
suici dal i deati o n a n d b e ha vi or
S O C
sta n dar d of care
S O P
sta n dar d o perati n g pr oce d ure
S R S D
si n gle refere nce safet y d oc u me nt
S T A T
si g nal tra ns d ucers a n d acti vat ors of tra nscri pti o n
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T 1/ 2
Half -life
T m a x
ti me at w hic h C ma x oc c urre d
T A R C
t h y m us a n d acti vati o n re g ulate d c he m o ki ne
T B
t u berc ul osis
T Bili
t otal bilir u bi n
T CI
T o pical calci ne uri n i n hi bit ors
T C S
t o pical c ortic oster oi ds 
T d P
T orsa des de P oi ntes
T H 1
t ype 1 hel per T cell
T H 2
t ype 2 hel per T cell
T ma x
Ti m e t o ma xi m u m c o nce ntra ti o n
T P O
T hr o m b o p oieti n
T Y K 2
t yr osi ne ki nase 2
U L N
u p per li mit of n or mal
U S
U nite d States
U S A
U nite d States of A merica
U V A
ultra vi olet A li g ht
U V B
ultra vi olet B li g ht
V A S
vis ual a nal o g scale
V/ F
v ol u me of distr i b uti o n/fracti o n a bs orbe d
V Z V 
varic ella zoster vir us
W B C
w hite bl o o d cell
W H O
W orl d Healt h Or ga nizati o n
W O N C B P 
w o me n of n o n -c hil d beari n g p ote ntial


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 6
A p pe n di x 2. Di a g n ostic Criteri a f or At o pic Der m atitis
Per I ncl usi o n Criteri o n 3 , a su bject is t o ha ve a cl i nical dia g n osis of at o pic der matitis 
acc or di n g t o t he criteria of Ha nifi n a n d Raj ka. 4 3
H a nifi n a n d R aj k a’s Di a g n ostic Criteri a f or At o pic Der m atitis
M ust h a ve t hree or m ore b asic fe at ures descri be d bel o w:
Pr ur itus
T y pical m or p h ol o g y  a n d distri b uti o n:
Fle x ural lic he nificati o n i n a d ults
Facial a n d e xte ns or er u pti o ns i n i nfa nts a n d c hil dre n
C hr o nic or c hr o nicall y -rela psi n g der matitis
Pers o nal or fa mil y hist or y of at o p y (ast h ma, aller gic r hi nitis, at o pic der matitis)
M ust h a ve t hr ee or m ore f oll o wi n g mi n or fe at ures:
Xer osis
Ic ht h yosis/ pal mar h y perli nearit y , kerat osis pilaris
I m me diate (ty pe 1) s ki n test reacti o n
Ele vate d ser u m I g E
Earl y a ge of o nset
Te n de nc y  t o war d c uta ne o us i nfecti ons (es p. sta p h. a ure us an d her pes si m ple x), i m paire d 
cell-me diate d i m m u nit y
Te n de nc y  t o war d n o n-s pecific ha n d or f o ot der matitis
Ni p ple ecze ma
C heilitis
Rec urre nt c o nj u ncti vitis
De n nie -M or ga n i nfra or bital f ol d
Kerat oc o n us
A nteri or s u bca ps ular catara cts
Or bital dar ke ni n g
Facial pall or , facial er yt he ma
Pit y riasis al ba
A nteri or nec k f ol ds
Itc h w he n s weati n g
I nt olera nce t o w o ol a n d li pi d s ol ve nts
Peri of ollic ular acce nt uati o n
F o o d i nt olera nce
C o urse i nfl ue nce d b y e n vir o n me ntal a n d e m oti o nal fact o rs
W hite der m o gra p his m, dela y e d bla n c h


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 7
A p pe n di x 3. Pr o hi bite d C o nc o mit a nt Me dic ati o ns
Pr o hi bite d c o nc o mita nt me dicati o n liste d bel o w s h o ul d n ot be ta ke n wit h st u d y  dr u g. 
Patie nts re q uiri n g treat me nt wit h a liste d pr o hi bite d c o nc o mita nt me dicati o n s h o ul d be 
disc usse d wit h t he Me dical M o n itor. S uc h s u b jects ma y  still be eli gi ble/c o nti n ue i n t he st u d y 
if t he y d o n ot ha ve t o i nterr u pt d osi n g wit h st u d y dr u g f or m ore t ha n 2 8 c o nsec uti ve da ys.
C Y P 2 C 1 9 I n hi bit ors 
C Y P 2 C 1 9 I n d ucers
Fl uc o naz ole ( Difl uca n)
E nzal uta mi de ( Xta n di)
Fl u v o xa mi ne ( L u v o x)
Rifa m pi n
T icl o pi di ne ( Ticli d)
Es o me praz ole ( Ne xi u m)
Fl u o xeti ne ( Pr ozac)
M ocl o be mi de
O me praz ole ( Pril osec)
V oric o naz ole ( Vfe n d)
C Y P 2 C 9 I n hi bit ors 
C Y P 2 C 9 I n d ucers
Fl uc o naz ole ( Difl uca n)
Car ba maze pi ne ( Te gret ol)
A mi o d ar o ne ( C or dar o ne)
E nza l uta mi de ( Xta n di)
Fl u v o xa mi ne ( L u v o x)
Rifa m pi n
Mic o naz ole
O xa n dr ol o ne ( O xa n dri n)
V oric o naz ole ( Vfe n d)
T he was h o ut peri o d f or all C y t oc hr o me P ( C Y P) 2 C 9 a n d C Y P 2 C 1 9 i n hi bit ors is 1 wee k or 
5 half -li ves, w hic he ver is l o n ger.
T he was h o ut peri o d f or all C Y P 2 C 9 a n d al l C Y P 2 C 1 9 i n d ucers is 5 half -li ves pl us 1 4 da y s
pri or t o t he first d ose of i n vesti gati o nal pr o d uct . F or e xa m ple, t he a vera ge half-life of 
Car ba maze p i ne after re peat d osi n g is i n a vera ge 1 5 h o urs.   T he was h o ut peri o d is calc ulate d 
as t he s u m of 5 half -li ves (a p pr o xi matel y 3 d a y s) a n d a n a d diti o nal 1 4 d a y s f or a t otal of 
1 7 da y s.
T his is n ot a n all-i ncl usi ve list. St u d y  pers o n nel s h o ul d sta y c urre nt a n d c o ns ult wit h t heir 
p har mac y  t o e xcl u de all c o nc o mita nt me dicati o ns that are C Y P 2 C 9 or C Y P 2 C 1 9 i n hi bit ors 
or i n d ucers .  Half -life refers t o half-life of t he pare nt dr u g a n d its meta b olites w hic h are 
i n hi bit ors or i n d ucers. T he l o n g est half-life s h o ul d be use d t o calc ulate t he peri o d necessar y  
t o was h o ut a me dicati o n pri or t o t he first d ose of in vesti gati o nal pr o d uct.  F or e xa m ple, 
fl u o xeti ne a n d its meta b olite n orfl u o xeti ne are b ot h i n hi bot ors of C Y P 2 C 1 9.  T he ter mi nal 
half -life of fl u o xeti ne is u p t o 6 da y s; h o we ver, n orfl u o xeti ne has a l o n ger half-life, u p t o 
1 6 da y s.  T heref ore, t he was h o ut p eri o d s h o ul d be calc ulate d base d o n 5 ti mes t he half- life of 
n orfl u o xeti ne, f or a t otal of a p pr o xi matel y  8 0 da ys pri or t o t he first d ose of in vesti gati o nal 
pr o d u ct.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 8
Use of c o nc o mita nt me dicati o ns t hat pr ol o n g t he Q T/ Q Tc F i nter val were e xcl usi o nar y f or 
e nr oll me nt i n t he st u d y.  After t he c o m pleti o n of e nr oll me nt t he restricti o n o n t hese 
pr o hi bite d me d icati o ns was re m o ve d.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 9
A p pe n di x 4. G ui deli nes f or M o nit ori n g a n d Disc o nti n u ati o n 
M o nit ori n g Criteri a 
T he f oll o wi n g la b orat or y a b n or malities re q uire pr o m pt retesti n g:

Ne utr o p hil c o u nts < 1 0 0 0 ne utr o p hils/ m m 3; c o nfir me d pr o m ptl y b y re peat testi n g, 
i deall y wit hi n 3-5 da y s; 

L y m p h oc y te c o u nt < 5 0 0/ m m3; c o nfir me d pr o m ptl y b y re peat testi n g, wit hi n 4 8 h o urs;

Platelet c o u nts < 7 5, 0 0 0 platelets/ m m 3; c o nfir me d pr o m ptl y  b y re peat testi ng, i deall y  
wit hi n 3 - 5 da y s; 

A n y  si n gle he m o gl o bi n val ue <9. 0 g/ d L or o ne t hat dr o ps 2 g/ d L bel o w baseli ne; 
c o nfir me d pr o m ptl y b y re peat tes ti n g, i deally wit hi n 3 - 5 d a y s; 

A n y  si n gle A S T a n d/ or A LT ele vati o n > 3 ti mes t he u p per li mit of n or mal re gar dless 
o f acc o m pa nyi n g s ym pt o ms or t he t otal Bilir u bi n s h o ul d pr o m pt re peat testi n g.  T his 
s h o ul d als o pr o m pt re vie w of Secti o n 8. 4. 2 ; a d diti o nal i n vesti gati o ns m ust be 
c o n d ucte d.
Te m p or ar y I nterr u pti o n t o D osi n g 
A n i n vesti gat or ca n te m p orarily i nterr u pt d osi n g f or u p t o a ma xi m u m of 2 8 c o nsec uti ve da ys 
f or a s u bject, f or safety reas o ns or w hile m o nit ori n g a b n or mal la b orat or y  tests if t he 
i n vesti gat or j u d ges t hat t his is necessar y. T he i n vesti gat or s h o ul d use t heir j u d ge me nt wit h 
re gar d t o u nsc he d ule d visits/la b orat or y/cli nical assess me nts re q uire d t o m o nit or t he s u bject 
d uri n g t his ti me-f ra me. If wit hi n t his ti mefra me t he i n vesti gat or j u d ges t hat it is safe t o 
restart d osi n g, t he n t he s u bject ma y restart i n vesti gati o nal pr o d uct. If t he i n vesti gat or j u d ges 
t hat it is n ot safe t o restart d osi n g wit hi n t his ti mefra me t he n t he s u bject m ust be per ma ne ntl y 
disc o n ti n ue d fr o m treat me nt, ha ve a n E n d of Treat me nt visit a n d e nter t he 4-wee k f oll o w - u p 
peri o d.  D oses n ot ta ke n f or t he reas o ns me nti o ne d a b o ve d o n ot c o nstit ute pr ot oc ol 
de viati o ns or me dicati o n err ors a n d s h o ul d n ot be c o nsi dere d d osi n g err ors, b ut s h o ul d be 
n ote d i n t he d osi n g l o g wit h t he reas o n f or re d uce d dr u g c o ns u m pti o n c learl y descri be d.
Disc o nti n u ati o n Cri teri a
S u bjects m ust be per ma ne ntl y  disc o nti n ue d fr o m treat me nt if t he y meet a n y of t he f oll o wi n g 
criteria at a n y p oi nt i n t he st u d y:

Mar ke d pr ol o n gati o n of t he Fri dericia -c orrecte d Q T ( Q Tc F) i nter val t o > 5 0 0 ms or 
> 6 0 m s c ha n ge fr o m scree ni ng E C G.

Seri o us i nfecti o n (see defi niti o n f or Seri o us A d verse E ve nts i n Secti o n 8. 2. 3 ).


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 0

A n y  blee di ng e ve nt t h o u g ht t o be ass ociate d wit h a platelet c o u nt re d ucti o n per t he 
j u d ge me nt of t he i n vesti gat or (or, if necessar y / desire d, f oll o wi n g disc ussi o n wit h 
s p o ns or).

Ot her a d vers e e ve nt, per j u d g me nt of t he i n vesti gat or, re q uiri n g disc o nti n uati o n fr o m 
treat me nt ( or, if necessar y/ desire d, f oll o wi n g disc ussi o n wit h s p o ns or).

A n y  a d verse e ve nt or la b or at or y a b n or malit y, t hat per t he i n vesti gat or’s j u d ge me nt 
re q uires te m p orar y i nterr upti o n t o d osi n g of i n vesti gati o nal pr o d uct f or > 2 8 da y s.
N O T E: a n y i nitial la b val ue bel o w m ust be reteste d, wit hi n 4 8 h o urs.

T w o se q ue ntial platelet c o u nts < 5 0, 0 0 0/ m m 3.  If t he s u bject has a platelet c o u nt 
< 2 5, 0 0 0/ m m 3, i n vesti gati o nal pr o d uct s h o ul d be tem p oraril y  wit h hel d pe n di n g t he 
c o nfir mat or y retest.

T w o se q ue ntial ne utr o p hil c o u nts < 5 0 0/ m m 3.

T w o se q ue ntial l y m p h oc y te c o u nts < 5 0 0/ m m3.

T w o se q ue ntia l he m o gl o bi n assess me nts < 8. 0 g/ d L or 3 0 % fr o m baseli ne val ue.
A n y  of t he f oll o wi n g:

T w o se q ue ntial A S T or A L T ele vati o ns > 3 ti mes t he u p per li mit of n or mal wit h at 
least o ne t otal bilir u bi n val ue > 2 ti mes t he u p per li mit of n or mal.

T w o se q ue ntial A S T or A L T ele vati o ns > 3 ti mes t he u p per li mit of n or mal wit h a n 
a b n or mal I N R.

T w o se q ue ntial A S T or A L T ele vati o ns > 3 ti mes t he u p per li mit of n or mal 
acc o m pa nie d b y s y m p t o ms c o nsiste nt wit h he patic i nj ur y .

T w o se q ue ntial A S T or A L T ele vati o ns > 5 ti mes t he u p per li mit of n or mal, re gardless 
of t otal bilir u bi n or acc o m pa n y i n g sy m pt o ms.
N ote: A n y of t he a b o ve fi n di n gs s h o ul d pr o m pt re vie w of “ T he P ote nti al C ases of 
Dr u g -I n d uce d Li ver I nj ur y ”, Secti o n 8. 4. 1 f or w hic h a d diti o n a l i n vesti g ati o ns 
m ust be c o n d ucte d.

T w o se q ue ntial i ncreases i n ser u m creati ni ne t hat are > 5 0 % o ver t he a vera ge of 
scree ni n g an d baseli ne val ues A N D a n a bs ol ute i ncrease i n ser u m creati ni ne 
0. 5 m g/ d L.  At t he ti me of s t u d y c o m pleti o n or disc o nti n uati o n, i f a patie nt s h o ul d 
e x hi bit ele vati o ns i n ser u m creati ni ne 3 3 % a b o ve t he a vera ge of scree ni n g a n d 
baseli ne val ues, t he y  will be re-teste d e ver y 1 t o 2 wee ks u ntil t he ser u m creati ni ne 
ele vati o n is f ull y re verse d t o wit hi n 1 0 % of t he a vera ge of scree ni n g a n d baseli ne 
val ues or has sta bilize d.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 1
A p pe n di x 5. Fitz p atric k S ki n T y pe 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 2
A p pe n di x 6. Pr urit us Se verit y a n d Fre q ue nc y ( Pr urit us N R S)
Se verit y of Pr uri t us
O n a scale of 0 t o 1 0, wit h 0 bei n g “ n o itc h” a n d 1 0 bei n g “ w orst itc h i ma gi na ble”, h o w 
w o ul d y o u rate y o ur itc h at t he w orst m o me nt d uri n g t he pre vi o us 2 4 h o urs?
Fre q ue nc y of Pr urit us
Select t he n u m ber t hat best descri bes fre q ue nc y  of itc hi n g d ue t o At o pic Der matit is o ver t he 
past 2 4 h o urs (c hec k o ne n u m ber o nl y ).
1 0
9
8
7
6
5
4
3
2
1
0
1 0
9
8
7
6
5
4
3
2
1
0
N o 
itc h
W orst 
itc h 
i ma gi na ble
1 0
9
8
7
6
5
4
3
2
1
0
1 0
9
8
7
6
5
4
3
2
1
0
Ne ver / N o 
itc hi n g
Al wa y s/c o nsta nt
itc hi n g


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 3
A p pe n di x 7. P atie nt Gl o b al Asses s me nt ( Pt G A)
Clear 
Al m ost Clear
Mil d
M o derate
Se vere
O verall, h o w w o ul d y o u descri be y o ur At o pic Der matitis ri g ht n o w ?
C h o ose o nl y O N E res p o nse.


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 4
A p pe n di x 8. E ur o pe a n Q u alit y of Li fe 5-Di me nsi o n 5 -Le vel Sc ale ( E Q - 5 D-5 L) a n d 
E ur o pe a n Q u alit y of Life 5- Di me nsi o n Y o ut h Sc ale ( E Q - 5 D-Y i n select c o u ntries)
E Q - 5 D- 5 L
U n der eac h hea di n g, please c hec k t he O N E b o x t hat best descri bes y o ur healt h T O D A Y.
M O BI LI T Y
I ha ve n o pr o ble m s wal ki n g

I ha ve sli g ht pr o ble ms wal ki n g

I ha ve m o derate pr o ble ms wal ki n g

I ha ve se vere pr o ble ms wal ki n g

I a m u na ble t o wal k

S E L F -C A R E
I ha ve n o pr o ble ms was hi n g or dressi n g m yself

I ha ve sli g ht pr o ble ms was hi ng or dressi n g m yself

I ha ve m o derate pr o ble ms was hi n g or dressi n g m yself

I ha ve se vere pr o ble ms was hi n g or dressi n g m yself

I a m u na ble t o was h or dress m y s elf

U S U A L A C TI VI TI E S (e g, w ork, st u dy, h o use w ork, f a mily or leis ure 
activities)
I ha ve n o pr o ble m s d oi n g m y us ual acti vities

I ha ve sli g ht pr o ble ms d oi n g m y us ual acti vities

I ha ve m o derate pr o ble ms d oi n g m y us ual acti vities

I ha ve se vere pro ble ms d oi n g m y us ua l acti vities

I a m u na ble t o d o m y us ual acti vities

P AI N/ DI S C O M F O R T
I ha ve n o pai n or di sc o mf ort

I ha ve sli g ht pai n or disc o mf ort

I ha ve m o derate pai n or disc o mf ort

I ha ve se vere pai n or disc o mf ort

I ha ve e xtre me pai n or disc o mf ort

A N XI E T Y/ D E P R E S SI O N
I a m n ot a n xi o us or de presse d

I a m sli g htl y a n xi o us or de presse d

I a m m o deratel y a n xi o us or de presse d

I a m se verel y a n xi o us or de presse d

I a m e xtre mel y a n xi o us or de presse d



P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 5

We w o ul d li ke t o k n o w h o w g o o d or ba d y o ur 
heal t h is T O D A Y.

T his scale is n u m bere d fr o m 0 t o 1 0 0.

1 0 0 mea ns t he best hea lt h yo u ca n i ma gi ne.

0 mea ns t he w ors t healt h y o u ca n i ma gi ne.

Mar k a n X o n t he scale t o i n dicate h o w y o ur 
healt h is T O D A Y.

N o w, please write t he n u m ber y o u mar ke d o n 
t he scale i n t he b o x bel o w.
Y O U R H E A L T H T O D A Y =
1 0 0
9 5
9 0
8 5
8 0
7 5
7 0
6 5
6 0
5 5
5 0
4 5
4 0
3 5
3 0
2 5
2 0
1 5
1 0
5
0
T h e b e st h e alt h 
y o u c a n i ma gi n e
T h e w o r st h e alt h 
y o u c a n i ma gi n e


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 6
E Q - 5 D- Y
Descri bi n g y o ur he alt h T O D A Y
U n der eac h hea di n g, please c hec k t he O N E b o x t hat best descri bes yo ur healt h T O D A Y.
M o bilit y ( w al ki n g ar o u n d)
I ha ve n o pr o ble m s wal ki n g ar o u n d

I ha ve s ome pr o ble ms wal ki n g ar o u n d

I ha ve a l ot of pr o ble ms wal ki n g ar o u n d

T a ki n g c are of m ysel f
I ha ve n o pr o ble m s ta ki n g a bat h or s h o wer b y m yself or getti n g dresse d b y 
m yself

I ha ve s o me pr o ble ms ta ki n g a bat h or s h o w er b y m yself or getti n g dresse d b y  
m yself

I ha ve a l ot of pr o ble ms ta ki n g a bat h or s h o w er b y m yself or getti n g dresse d 
b y m yself

D oi n g us u al acti vities (f o r e x a mple, g oi n g t o sc h o ol, h o b bies, s p orts, 
pl a yi n g, d oi n g t hi n gs wit h f a mil y or frie n ds)
I ha ve n o pr o ble m s d oi n g m y us ual acti vities

I ha ve s o me pr o ble ms d oi n g m y us ual acti vities

I ha ve a l ot of pr o ble ms d oi n g m y us ual acti vities

H a vi n g p ai n or disc o m f ort
I ha ve n o pai n or disc o mf ort

I ha ve s o me pai n or disc o mf ort

I ha ve a l ot of pai n or disc o mf ort

Feeli n g w orrie d, s a d, or u n h a p p y
I a m n ot w o rrie d, sa d, or u n ha p p y

I a m a little w orrie d, sa d , or u n ha p p y

I a m v er y w orrie d, sa d, or u n ha p p y



P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 7
H o w g o o d is y o ur he alt h T O D A Y 

We w o ul d li ke t o k n o w h o w g o o d or 
ba d y o ur healt h is T O D A Y.

T his li ne is n u m b ere d fr o m 0 t o 1 0 0.

1 0 0 mea ns t he best healt h y o u ca n 
i ma gi ne.

0 mea ns t he w orst healt h y o u c a n 
i ma gi ne.

Please mar k a n X o n t he s cale t o 
i n dicate h o w y o ur healt h is T O D A Y.
1 0 0
9 5
9 0
8 5
8 0
7 5
7 0
6 5
6 0
5 5
5 0
4 5
4 0
3 5
3 0
2 5
2 0
1 5
1 0
5
0
T h e b e st h e alt h 
y o u c a n i ma gi n e
T h e w o r st h e alt h 
y o u c a n i ma gi n e






P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 0


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 1
A p pe n di x 1 0. P atie nt - Orie nte d Ecze m a Me as ure ( P O E M)


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 2
A p pe n di x 1 1. H os pit al A n xiet y a n d De pressi o n Sc ale ( H A D S)


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 3


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 4
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 5
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 6
C CI


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 7


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 8
A p pe n di x 1 3. S h ort F or m -3 6 Versi o n 2 ( S F -3 6 v 2)


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 9


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 0


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 1


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 2


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 3


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 4
A p pe n di x 1 4. F u ncti o n al Assess me nt of C hr o nic Ill ness T her a p y F ati g ue Sc ale 
( F A CI T-F)


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 5


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 6
A p pe n di x 1 5. C ol u m bi a Se verit y S uici d e R ati n g Sc ale ( C-S S R S) f or Scree ni n g a n d 
B aseli ne Visits


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 7


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 8


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 9
A p pe n di x 1 6. C ol u m bi a Se verit y S uici de R ati n g Sc ale ( C- S S R S) Si nce L ast Visit


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 0


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 1
A p pe n di x 1 7. S uici de Be h a vi ors Q uesti o n n aire – Re vise d ( S B Q- R) 


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 2
A p pe n di x 1 8. P atie nt He alt h Q uesti o n n aire – 8 ite ms ( P H Q - 8)


P F- 0 4 9 6 5 8 4 2
B 7 4 5 1 0 1 4
Fi nal P r otoc ol A me n d me nt 5, 2 8 Oct o ber 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 3
A p pe n di x 1 9. Ast h m a C o ntr ol Q uesti o n n aire ( A C Q)

SAP_001.pdf: 
Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
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PROTOCOL B7451014
A PHASE 3 RANDOMIZED WITHDRAWAL, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTI-CENTER STUDY INVESTIGATING THE 
EFFICACY AND SAFETY OF PF-04965842 IN SUBJECTS AGED 12 YEARS AND 
OVER, WITH MODERATE TO SEVERE ATOPIC DERMATITIS WITH THE 
OPTION OF RESCUE TREATMENT IN FLARING SUBJECTS
STATISTICAL ANALYSIS PLAN 
(SAP)
Version:
2
Date:
22-SEP-2020


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoint ....................................................................................................10
3.2. Key Secondary Endpoint.........................................................................................11
3.3. Secondary Endpoints...............................................................................................11
3.3.1. Response Based on the IGA Score.............................................................11
3.3.2. Responses Based on the Total EASI Score ................................................11
3.3.3. Response Based on IGA and EASI-75.......................................................11
3.3.4. Responses Based on the Total SCORAD Score.........................................11
3.3.5. Response Based on the PtGA Score...........................................................11
3.4. Baseline Variables...................................................................................................12
3.5. Safety Endpoints .....................................................................................................12
3.5.1. Adverse Events...........................................................................................12
3.5.2. Laboratory Data..........................................................................................13
3.5.3. Vital Signs, Including Height and Weight..................................................13
3.5.4. Physical Examinations................................................................................13
4. ANALYSIS SETS ...............................................................................................................13
4.1. Full Analysis Set (FAS) ..........................................................................................13
4.2. Per Protocol Analysis Set (PPAS)...........................................................................14
4.3. Safety Analysis Set (SAF).......................................................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................15
5.1. Hypotheses and Decision Rules ..............................................................................15
5.2. General Methods .....................................................................................................16
5.2.1. Analyses for Binary Data............................................................................16


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5.2.2. Analyses for Longitudinal Continuous Data ..............................................17
5.2.3. Analyses for Categorical Data....................................................................17
5.2.4. Analyses for Time to Event Data................................................................17
5.3. Methods to Manage Missing Data ..........................................................................18
5.3.1. Binary Endpoints ........................................................................................18
5.3.2. Continuous Endpoints.................................................................................19
5.3.3. Time to Event Endpoints ............................................................................19
6. ANALYSES AND SUMMARIES ......................................................................................20
6.1. Primary Endpoint ....................................................................................................20
6.1.1. Loss of Response........................................................................................20
6.1.1.1. Primary Analysis.......................................................................20
6.1.1.2. Additional/Supportive Analyses ...............................................20
6.2. Key Secondary Endpoint.........................................................................................21
6.2.1. Loss of Response Based on the IGA Score ................................................21
6.2.1.1. Primary Analysis.......................................................................21
6.2.1.2. Additional/Supportive Analyses ...............................................21
6.3. Secondary Endpoints (Efficacy)..............................................................................21
6.3.1. Response Based on (IGA, EASI-50, EASI-75, EASI-90, EASI-100, 
NRS4 for Severity of Pruritus, SCORAD50 and SCORAD75, IGA + 
EASI-75)..........................................................................................................21
6.3.2. Change from Baseline in (Total EASI Score, SCORAD (VAS) 
Pruritus and Sleep Sub-Scales, PP-NRS for Severity and Percent BSA)........22
6.4. Secondary Endpoints (PRO) ...................................................................................22
6.4.1. Change from Baseline in (HADS, POEM, PSAAD and 
DLQI/CDLQI) .................................................................................................22
6.4.2. Response Based on PtGA...........................................................................23
6.5. Subset Analyses.......................................................................................................23
6.6. Baseline and Other Summaries and Analyses.........................................................24
6.6.1. Baseline Summaries....................................................................................24
6.6.2. Study Conduct and Subject Disposition .....................................................24
6.6.3. Study Treatment Exposure .........................................................................24
6.6.4. Concomitant Medications and Non-Drug Treatments................................24
6.7. Safety Summaries and Analyses .............................................................................25


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6.7.1. Adverse Events...........................................................................................25
6.7.2. Laboratory Data..........................................................................................25
6.7.3. Vital Signs, including Height and Weight..................................................26
6.7.4. Electrocardiogram.......................................................................................26
6.7.4.1. Physical Examination................................................................26
6.7.5. Asthma Control Questionnaire (ACQ).......................................................26
7. INTERIM ANALYSES.......................................................................................................26
8. REFERENCES ....................................................................................................................26
9. APPENDICES .....................................................................................................................27
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Study Objectives and Endpoints.................................................................6
LIST OF FIGURES
Figure 1.
Study Design Schematic.............................................................................9
APPENDICES
Appendix 1. Summary of Clinical Efficacy Analyses.............................................................27
Appendix 2. Definition and Use of Visit Windows in Reporting............................................28
Appendix 3. Investigators Global Assessment ........................................................................30
Appendix 4. Eczema Area and Severity Index (EASI)............................................................31
Appendix 5. Scoring Atopic Dermatitis (SCORAD)...............................................................34
Appendix 6. A Weibull Proportional-Hazards Model for Event Time Data and Tipping 
Point Analysis...........................................................................................35
Appendix 7. Schedule Of Activities ........................................................................................37


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1. VERSION HISTORY
This is the first amendment of the Statistical Analysis Plan (SAP) for study B7451014 and is 
based on Protocol Amendment 5 dated 28OCT2019 and the latest Protocol Administrative 
Change Letter (PACL) dated 07MAY2020.
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
08 May 2018
Original
26 Feb 2018
N/A
N/A
2
22-Sep-2020
Amendment 5
28 Oct 2019
Regulatory (FDA) 
Input; Clarification 
or completion of 
prior version
Added a key secondary endpoint as loss of response 
due to IGA of 2 or more in Table 2 and Section 3.2.1. 
See also, Section 6.2.
Added responder analyses based on HADS, 
DLQI/CDLQI, PtGA and PSAAD as endpoints in 
Sections 3.2.5 through 3.2.9. See also, Section 6.4.2.
Updated the definition of TEAE in Section 3.5.1.
Added a description of the multiple testing procedure 
for the primary and key secondary endpoints in 
Section 5.1.
Added disease severity at Study Baseline as a 
stratification factor in Sections 5.2.1 through 5.2.2.
Additional minor changes to improve clarity and 
alignment with the protocol.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7451014.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
Study objectives and corresponding endpoints are provided in Table 2 below.


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Table 2.
Study Objectives and Endpoints
Primary Objective:
Primary Endpoint:

To evaluate and compare 
the maintenance of effect 
of two doses of 
PF-04965842 (200 mg and 
100 mg once daily (QD)) 
and placebo in subjects 
aged 12 and above with 
moderate to severe atopic 
dermatitis who respond to 
initial open-label run-in 
treatment of 200 mg 
PF-04965842 QD.
1.
Loss of response requiring rescue treatment will be evaluated and 
compared among groups during the blinded treatment period.  
Loss of response is denoted as flare and is defined as a loss of at 
least 50% of the Eczema Area and Severity Index (EASI) response 
at Week 12 and an Investigator’s Global Assessment (IGA) score 
of 2 or higher.
Secondary Objectives:
Secondary Endpoints:

To evaluate and compare 
the effect of PF-04965842 
on additional efficacy 
endpoints and 
patient-reported outcomes 
over time in subjects aged 
12 years and older with 
moderate to severe atopic 
dermatitis;

To assess the efficacy of 
open label rescue treatment 
consisting of 200 mg 
PF-04965842 in 
combination with topical 
therapy per standard of 
care in cases of flare (per 
protocol definition). 
Key Secondary Endpoint
1.
Loss of response during the blinded treatment period based on an 
IGA score of 2 or higher.
Clinical Efficacy Assessments:

Response based on the IGA at all scheduled time points. 

Response based on EASI total score at all scheduled time points.

Response based on achieving ≥4-point improvement in the severity 
of pruritus Numerical Rating Scale (NRS) from baseline at all 
scheduled time points.

Percent change from baseline in percent Body Surface Area (BSA) 
at all scheduled time points.

Percent change from baseline in SCORing Atopic Dermatitis 
(SCORAD) subjective assessments of itch and sleep loss at all 
scheduled time points. 

Response based on achieving a 50% and 75% improvement in 
SCORAD (SCORAD-50, SCORAD-75) from baseline at all 
scheduled time points.
Clinical Efficacy Assessments in Subjects Requiring Rescue 
Treatment:

Response based on the IGA at the end of rescue therapy. 

Response based on the EASI total score at the end of rescue 
therapy. 


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
Response based on achieving ≥4-point improvement in the severity 
of pruritus Numerical Rating Scale (NRS) at the end of rescue 
therapy relative to the start of rescue therapy baseline value.

Percent change in percent Body Surface Area (BSA) at the end of 
rescue therapy relative to the start of rescue therapy baseline value.

Percent change in SCORAD subjective assessments of itch and 
sleep loss at the end of rescue therapy relative to the start of rescue 
therapy baseline value.

Response based on achieving a 50% and 75% improvement in 
SCORAD (SCORAD-50, SCORAD-75) at the end of rescue 
therapy relative to the start of rescue therapy baseline value.
Patient-Reported Outcomes in All Subjects:
1.
Response based on achieving Patient Global Assessment (PtGA) 
score of clear (0) or almost clear (1); and a reduction from baseline 
of 2 points at all scheduled time points (among subjects with a 
score 2 at baseline).
2.
Change from baseline in Dermatology Life Quality Index (DLQI) 
or Children’s DLQI (CDLQI) at all scheduled time points.
3.
Change from baseline in Hospital Anxiety Depression Scale 
(HADS) at all scheduled time points.
4.
Change from baseline in Patient Oriented Eczema Measure 
(POEM) at all scheduled time points.
5.
Change from baseline in the Pruritus and Symptoms Assessment in 
Atopic Dermatitis (PSAAD) at all scheduled time points.
Safety Objective:
Safety Endpoints:

To assess the safety and 
tolerability of 
PF-04965842 during open 
label and double blind 
treatment in subjects aged 
12 and over with moderate 
to severe AD.

Incidence of treatment emergent adverse events.

Incidence of Serious Adverse Events (SAE)s and Adverse Events 
(AE)s leading to discontinuation.

The incidence of clinical abnormalities and change from baseline 
in clinical laboratory values, electrocardiogram (ECG) 
measurements, and vital signs.
Pharmacokinetic Objective:
Pharmacokinetic Endpoint:

To evaluate the PK of 
PF-04965842 in subjects 
aged 12 years and older 
with moderate to severe 
atopic dermatitis following 
1.
Population PK characterization in subjects aged 12 years old and 
above with moderate to severe atopic dermatitis.


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12 weeks of maintenance
treatment.
 
 
 
 
 
 
 
AD = Atopic dermatitis; AE = Adverse Event; BSA = Body Surface Area; CDLQI = Children’s Dermatology Life 
Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = 
Electrocardiogram; EQ-5D-5L =  EuroQol; Quality of Life measure; 5-Dimension 5-Level Scale; EQ-5D-Y = 
EuroQol Quality of Life 5-Dimension Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy 
Fatigue Scale; Peds-FACIT-F = Pediatric FACIT-F; HADS = Hospital Anxiety and Depression Scale; IGA = 
Investigator’s Global Assessment; NRS = pruritus numerical rating scale; PK = pharmacokinetics; SCORAD = 
Scoring Atopic Dermatitis; POEM = Patient-Oriented Eczema Measure; PtGA = Patient Global Assessment; PSAAD 
= Pruritus and Symptoms Assessment for Atopic Dermatitis; QD = Once Daily; SF-36 = Short Form-36; SAE = 
Serious Adverse Event.
2.2. Study Design
This is a randomized, responder-enriched, double-blind, placebo-controlled, Phase 3 
withdrawal trial to evaluate the efficacy and safety of PF-04965842 monotherapy in subjects 
aged 12 years and older with chronic moderate to severe AD as defined per the inclusion 
criteria and a body weight ≥40 kg.
The trial consists of an open-label run-in period to determine responder status to an initial 
induction treatment with 200 mg PF-04965842 QD, a randomized, placebo-controlled, 
double-blinded PF-04965842 maintenance treatment period, and a 4-week untreated 
follow-up safety period. A study design schematic is presented in Figure 1.
CCI
CCI
CCI


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Figure 1.
Study Design Schematic
Note: Flare is defined as a loss of response associated with a decrease of at least 50% of the EASI response 
compared to randomization and an IGA score of 2.
Responder criteria are defined as a) achieving an IGA of clear (0) or almost clear (1) (on a 
5-point scale), b) a reduction from IGA baseline of 2 points, and c) reaching an EASI-75 
response (at least 75% improvement). Subjects not meeting criteria are declared as
non-responders and are not eligible for randomization in this study. They may choose to 
enroll into the PF-04965842 Long Term Extension (LTE) study B7451015 providing they 
remain eligible; otherwise, they are permanently discontinued from treatment and enter the 
4-week untreated follow-up period in this study.
Responders at the end of the 12-week open-label run-in period enter the 40 week, 
double-blind, maintenance treatment period in which they are randomized 1:1:1 into either 
PF-04965842 200 mg QD, PF-04965842 100 mg QD or placebo. Randomization is stratified 
by age category, ie, <18 years and 18 years.
Following completion of the 40-weeks of blinded treatment, all subjects are to be assessed 
for eligibility to enter study B7451015. If a subject discontinues prematurely or is not 
eligible/willing to participate in B7451015, then the subject enters the 4-week untreated 
follow-up period.
During the blinded treatment period, subjects meeting the protocol definition of flare enter an 
open-label rescue period during which they receive another 12-week course of PF-04965842 
200 mg QD with topical therapy per local standard of care (SOC).  In this study, flare 


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requiring rescue treatment will be defined as a loss of at least 50% of the EASI response at 
Week 12 and an IGA score of 2 or higher.  
After completing the 12-week rescue period, eligible subjects may enter study B7451015. 
Subjects discontinuing early from treatment, or who are otherwise ineligible for the LTE 
study will undergo a 4 week follow-up period in B7451014.
The total study duration if a subject does not flare is 52 weeks (12 weeks open-label 
treatment + 40 weeks blinded treatment).  The maximum study duration is up to 64 weeks. 
This would only be achieved if a subject flared on the last day of the maintenance treatment 
period (52 weeks +12 weeks rescue).  If subjects do not intend to enroll in the LTE study, the 
above durations are extended by +4 weeks of an untreated follow-up period.  
A full schedule of activities for the study is provided in Appendix 7.
Sample Size Determination
A total of 600 subjects with 200 receiving PF-04965842 200 mg QD, 200 receiving 
PF-04965842 100 mg QD, and 200 receiving placebo (1:1:1 randomization) will provide 
94% power to detect a ratio of median time to flare of at least 1.5 times between either dose 
of PF-04965842 (200 mg or 100 mg) and placebo.  The Type I error rate is set at 
5% (2-sided).  Assuming that about 44% of subjects would meet the protocol-defined criteria 
to be a responder at Week 12, (based on prior data), approximately 1370 subjects would need 
to enter the open label run-in period of the study to ensure that 600 subjects are available for 
randomization.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
Loss of response requiring rescue treatment will be evaluated in each group during the 
blinded treatment period.  Loss of response is denoted as a flare and is defined as a loss of at 
least 50% of the Eczema Area and Severity Index (EASI) response at Week 12 and an 
Investigator’s Global Assessment (IGA) score of 2 or higher.
Detailed descriptions of how the IGA and the EASI scores are derived are provided in 
Appendix 3 and Appendix 4 respectively.
Calculation for determining flare:
If ݔ଴is the EASI score at baseline and ݔோis the EASI score at Week 12 (randomization), the 
EASI response at Week 12 (randomization) is defined as ݔோെݔ଴. During the randomized, 
double-blind period, a subject would have met the definition of a flare if their EASI score is 
greater than or equal to ݔோ൅0.5 ൈ|ݔோെݔ଴| and their IGA score is greater than or equal to 
2.


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For example, if a subject has a total EASI score of 40 at baseline and a score of 10 at Week 
12 (achieving EASI-75 to be a responder at randomization), the EASI response is -30.  To 
meet the definition of flare, the total EASI score for this subject would have to go up by at 
least 15 (50% of -30) from Week 12, which computes to a total EASI score of at least 25, and
in addition have an IGA score of 2.
3.2. Key Secondary Endpoint
As the key secondary endpoint, loss of response is defined as being no longer able to 
maintain an IGA score of 0 or 1 (as at randomization) and having an IGA score of 2 during 
the randomized, double-blind period. 
3.3. Secondary Endpoints
A list of all the secondary and other endpoints is already provided alongside the study 
objectives in Table 2. Here we describe definitions for some of the clinical efficacy 
endpoints.
3.3.1. Response Based on the IGA Score 
A successful response at a visit (eg, Week 12) is defined as an IGA score of 0 (clear) or 
1 (almost clear) and a drop of 2 points in the IGA score from baseline (see Section 3.4 for 
definitions of baseline).
3.3.2. Responses Based on the Total EASI Score
A successful response on the EASI-50 at a visit (eg, Week 12) is defined as a 50% 
improvement in the total EASI score from baseline. Successful responses on the EASI-75,
EASI-90 and EASI-100 are defined similarly (with a 75%, 90% and 100% improvement, 
respectively).
3.3.3. Response Based on IGA and EASI-75 
A successful response (at a given visit) based on both IGA and EASI-75 (IGA + EASI-75) is 
defined as being a responder on both the IGA (see Section 3.3.1) and the EASI-75 (see 
Section 3.3.2).
3.3.4. Responses Based on the Total SCORAD Score
A detailed description of the derivation of the SCORAD score is provided in Appendix 5. A 
successful response on the SCORAD-50 at a visit (eg, Week 12) is defined as a 50% 
improvment in the total SCORAD score from baseline. A successful response on the 
SCORAD-75 is defined similarly (with a 75% improvement).
3.3.5. Response Based on the PtGA Score
A successful response at a visit (eg, Week 12) is defined as a PtGA score of 0 (clear) or 
1 (almost clear) and a drop of 2 points in the PtGA score from baseline.


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3.4. Baseline Variables
Baseline values for demographics, medical history, primary diagnosis and prior drug 
treatments for atopic dermatitis will be based on measures collected at Visit 1/Screening visit 
or Day 1 visit. For analysis purposes, randomization strata information will be taken from 
the Case Report Form (CRF).
For all other analyses (including change from baseline), there are three possible choices for 
baseline in this study as,
Study Baseline: This baseline value will be defined as the last observation collected on or 
prior to Day 1 (first dose day) of study treatment. If a value is missing on Day 1, then the 
last available observation before Day 1 will be used. For the PSAAD score, baseline will be 
defined as a simple average of all values recorded between Day -6 and Day 1. 
Randomization Baseline: This baseline value will be defined as the last observation 
collected between last dose of run-in treatment and Day 1 (first dose day) of randomized 
treatment. For the PSAAD score, randomization baseline will be defined as a simple average 
of all values recorded between last dose of run-in treatment and Day 1 of randomized 
treatment.
Rescue Baseline: This baseline value will be defined as the last observation collected 
between last dose of blinded treatment and Day 1 (first dose day) of rescue treatment. For 
the PSAAD score, rescue baseline will be defined as a simple average of all values recorded 
between last dose of blinded treatment and Day 1 of rescue treatment.
3.5. Safety Endpoints
Safety will be assessed by the spontaneous reporting of AEs, physical examinations, and 
clinical laboratory results in all subjects who receive at least one dose of the investigational 
product.  Unscheduled safety assessments may be performed at any time during the study to 
assess any perceived safety concerns. Endpoints will be assessed as,

Treatment-emergent adverse events.

Treatment-emergent SAEs and AEs leading to discontinuation.

Clinical abnormalities and change from baseline in selected clinical laboratory values, 
ECG measurements, and vital signs.
The safety endpoints will be defined in accordance with Clinical Data Interchange Standards 
Consortium (CDISC) and Pfizer Standards (CaPS).
3.5.1. Adverse Events
An adverse event is considered TEAE to a given treatment if the event started during the 
effective duration of treatment. All events that start on or after the first dosing day, but 
before or on the last dosing day plus the lag time (28 days) will be flagged as TEAEs. The 
algorithm will not consider any events that started prior to the first dose date.


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3.5.2. Laboratory Data
Below is a list of hematology and serum chemistry test parameters.

Hematology: hemoglobin, hematocrit, red blood cell count, reticulocyte count, 
platelet count, white blood cell count with differential, total neutrophils, eosinophils, 
monocytes, basophils, lymphocytes, lymphocyte subsets (markers), coagulation 
panel.

Serum chemistry: blood urea nitrogen, creatinine, creatine phosphokinase, glucose, 
sodium, potassium, chloride, calcium, total bicarbonate, aspartate aminotransferase, 
alanine aminotransferase, gamma-glutamyl transferase, bilirubin, alkaline 
phosphatase, lactate dehydrogenase, uric acid, albumin, total protein, total 
cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), 
triglycerides.
3.5.3. Vital Signs, Including Height and Weight
Vital sign measurements are oral or tympanic temperature, respiratory rate, pulse rate, and 
blood pressures.
Weight is collected at pre- and post-treatment. Height is not required at the baseline visit. 
Only adolescents (12 to <18 years old) require repeated height measurement at Screening, 
Week 12 and End of Treatment (EOT) visits during the double-blind phase. Adults require 
one height measurement at the Screening visit. See Appendix 7 for further details.
3.5.4. Physical Examinations
Complete physical examinations consist of assessments of general appearance; skin; head, 
eyes, ears, nose and throat; mouth, heart; lungs; breast (optional); abdomen; external 
genitalia (optional); extremities; neurologic function; and lymph nodes.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Full Analysis Set (FAS)
The following groups of FAS will be defined for this study:
FAS-OL: This is the set of all subjects who received at least one dose of study treatment 
during the open label run-in phase. For all analyses, Study Baseline will be used (see
Section 3.4).
FAS-RA: This is the set of all subjects who have been randomized at Week 12 and have 
received at least one dose of study treatment within the double-blind phase. By study design, 
this will be a subset of FAS-OL. Subjects are assigned to the randomized treatment group 
regardless of actual treatment received. All analyses will be reported by treatment 


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regimen/sequence (eg, OL 200 mg DB 200 mg or OL 200 mg DB 100 mg or
OL 200 mg DB Placebo). For analysis purposes, either the Study Baseline or the 
Randomization Baseline will be used, depending on the endpoint and/or the analysis (see
Sections 3.4 and 6).
FAS-RE: This is the set of all subjects who have met the protocol definition of a flare (see
Section 2.2) during the double-blind phase and have received at least one dose of rescue 
treatment. By study design, this will be a subset of FAS-RA. In general, for efficacy 
analyses, Rescue Baseline will be used (see Section 3.4).
In general, change from baseline analyses based on any of the above FAS groups will require 
at least one post-baseline observation recorded.  Analyses for endpoints that are defined 
based on a threshold of change from baseline (eg, NRS4) will also require the baseline value 
to meet that threshold (eg, for NRS4, the baseline value needs to be ≥4).
4.2. Per Protocol Analysis Set (PPAS)
The PPAS will be a subset of the FAS-RA consisting of subjects who had no major protocol 
violations. Subjects excluded from the PPAS will be determined and documented before the 
study is un-blinded. This set will include subjects who:

Met key inclusion criteria (ie, IGA ≥3, EASI ≥16 at Study Baseline, had documented 
prior qualifying treatment for AD).

Met protocol-defined criteria for randomization (ie, responder for both IGA and 
EASI-75 at Week 12).

Did not take a protocol-prohibited therapy for the primary diagnosis (ie, high potency 
or systemic medication or phototherapy) during the initial run-in period and during 
the randomized withdrawal period.

Did not take a protocol prohibited (CYP2C19/CYP2C9 inhibitor and/or inducer drug) 
concomitant medication.

Had an overall compliance of ≥80% but 120% with randomized study treatment.

(if not flared), completed the study.

Had no other major protocol violations that is likely to affect materially the clinical 
observations, or the outcomes of the subject determined by the clinical team.


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4.3. Safety Analysis Set (SAF)
In accordance with the FAS, the following groups of SAF will be defined: 
SAF-OL: This is the set of all subjects who received at least one dose of study treatment 
during the open label run-in phase and is the same as FAS-OL. Note that this includes all 
subjects from the entire study who have received at least one dose of study treatment. For all 
analyses, Study Baseline will be used (see Section 3.4).
SAF-RA: This is the set of all subjects who have been randomized at Week 12 and have 
received at least one dose of study treatment within the double-blind phase. By study design, 
this will be a subset of SAF-OL. Subjects are classified according to actual study treatment 
received. I n general, for analysis purposes, Study Baseline will be used (see Section 3.4).
SAF-RE: This is the set of all subjects who have met the protocol definition of a flare (see
Section 2.2) during the double-blind phase and have received at least one dose of rescue 
treatment. In general, for analysis purposes, Rescue Baseline will be used (see Section 3.4).
The safety analysis set is the primary population for treatment administration/compliance and 
safety. 
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis and reporting of results will be performed after the completion of the study 
and the database is locked.
5.1. Hypotheses and Decision Rules
The statistical objective of the study is to characterize the loss of response within each 
randomized group after achieving response at Week 12 following open-label treatment with 
200 mg QD PF-04965842.
There are six key hypotheses to be tested for each pairwise comparison between two 
PF-04965842 doses (200 mg QD and 100 mg QD) and placebo, for the primary and key 
secondary endpoints.  For these hypotheses, the familywise Type-I error rate will be strongly 
controlled at 5% using a sequential, gatekeeping procedure. 
The procedure will first test the hypothesis of no difference for the primary endpoint between 
200 mg QD and placebo at 5% level of significance.  If this hypothesis is rejected, statistical 
significance will be assessed for the hypothesis of no difference for the key secondary 
endpoint between 200 mg QD and placebo at 5% level of significance.  If rejected, the 
procedure will continue with the hypothesis of no difference for the primary endpoint 
between 100 mg QD and placebo and if rejected, continuing with the hypothesis of no 
difference between 100 mg QD and placebo for the key secondary endpoint.  Finally, if all 
the above hypotheses are rejected, the procedure will continue with the hypothesis of no 
difference between 200 mg QD and 100 mg QD for the primary endpoint and if rejected, 
continuing with the hypothesis of no difference between 200 mg QD and 100 mg QD for the 
key secondary endpoint.  All tests will be conducted at 5% level of significance.  Formal 
statistical significance for any subsequent tests specified in this test hierarchy will not be 
claimed if the previous hypothesis in the sequence has not been rejected.


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Hypotheses for all other endpoints not described here are to be tested at the nominal 5% 
level, without making adjustments for multiple comparisons.
5.2. General Methods 
In general, for descriptive analyses, number and percent will be presented for binary 
endpoints.  Number, median, Q1 and Q3 will be presented for descriptive analyses of 
continuous efficacy endpoints.
For each of the analysis methods below, treatment comparisons will only be displayed for the 
FAS-RA analysis set where it is relevant. Pairwise comparisons will be reported among the 
treatment groups. No treatment comparisons are relevant for the FAS-OL and FAS-RE 
analysis sets.
5.2.1. Analyses for Binary Data
For analyses where treatment comparisons are relevant, binary data at each scheduled visit 
will be analyzed by two approaches: (1) the test of hypothesis (and the p-value) between two 
pairwise treatment groups will be conducted by the Cochran-Mantel-Haenszel (CMH) 
statistic adjusting for the effect of randomization strata and disease severity (moderate 
[IGA=3] or severe [IGA=4]) at Study Baseline; p-values will be calculated from the CMH 
statistic; and (2) the proportion of responders in each treatment group will be summarized 
along with pairwise differences and their 95% confidence intervals obtained by normal 
approximation. The difference in proportions will be calculated within each stratum. The 
final estimate of the difference in proportions will be a weighted average of these 
stratum-specific estimates using CMH weights. The CMH weight ݓ௞for stratum ݇ሺ݇ൌ
1, 2, … , ܭሻis given by,
ݓ௞ൌ
݊௜௞݊௖௞
݊௜௞൅݊௖௞
∑
݊௜௝݊௖௝
݊௜௝൅݊௖௝
௄
௝ୀଵ
where ݊refers to sample size, the subscript ܿrefers to a comparator group and the subscript ݅
refers to a test group. The difference is estimated as ݀መൌ∑
ݓ௞ሺ݌̂௜௞െ݌̂௖௞ሻ
௄
௞ୀଵ
, where ݌̂ refers 
to the estimated relative frequency (or proportion of responders).
Two-sided 95% confidence intervals for the difference (based on a normal approximation)
are formed by:
݀መേ1.96ඩ෍ݓ௞
ଶ
௄
௞ୀଵ
൬݌̂௜௞ሺ1 െ݌̂௜௞ሻ
݊௜௞
൅݌̂௖௞ሺ1 െ݌̂௖௞ሻ
݊௖௞
൰
In the above formula for the variance of ݀መ(under the square-root sign), when the number of 
responders is zero ሺݔൌ0ሻ, then ݌̂ will be replaced by 0.5/ሺ݊൅1ሻ. This change will be 
made only for calculating the variance of ݀መand not anywhere else. Estimates of the 


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difference in proportions along with the two-sided 95% confidence interval will also be 
provided for the PF-04965842 200 mg QD group versus the PF-04965842 100 mg QD group. 
No hypotheses will be tested. In analyses of responders, 95% confidence intervals will be 
calculated for the estimated proportion of response.  The confidence interval is based on the 
normal approximation (or the Clopper-Pearson exact method when there are no or 100% 
responders).
For analyses where treatment comparisons are not relevant, only the proportion of responders 
will be reported along with its 95% confidence interval based on normal approximation (or 
the Clopper-Pearson exact method when there are no or 100% responders).
5.2.2. Analyses for Longitudinal Continuous Data
Mixed-effect, repeated measures (MMRM) models will be used. Fixed effects for visit, 
treatment group, treatment-by-visit interaction (where treatment comparisons are relevant), 
disease severity at Study Baseline and randomization stratification factor will be included in 
the model. Visit will be modeled as a categorical covariate. Unstructured covariance matrix 
will be assumed for the model errors. Compound symmetry covariance matrix will be used if 
the model with unstructured covariance doesn’t converge.
When modeling the change from baseline values, the variable for visit will start with the first 
post-baseline visit, and the actual baseline value will be included as a covariate. At each 
visit, estimates of least square mean (LSM) values and the pairwise LSM differences 
between the treatment groups will be derived from the model. The corresponding p-values 
and 95% confidence intervals will also be derived from the model.
For analyses where treatment comparisons are not relevant, the MMRM model will not have 
treatment as a factor and only estimates of the LSM values along with their 95% confidence 
intervals by visit will be reported.
5.2.3. Analyses for Categorical Data
The frequency and percentage for each category will be presented.
5.2.4. Analyses for Time to Event Data
For all time to event analyses, an origin and an accrual period will be defined (see table 
below), depending on the analysis populations. For a subject who experiences the event, the 
time to event will be the study day (relative to the origin being used for the analysis) 
corresponding to the actual date of the event or the earliest visit date at which the subject has 
already experienced the event. For all subjects who have not experienced the event and 
reached the end of the accrual period, their time to event will be right censored at the end of 
the accrual period. For subjects who permanently discontinue before the end of the accrual 
period without experiencing the event, their time to event will be considered missing data 
(see Section 5.3.3 for handling of missing data in analysis).


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Origin
End of the Accrual Period
FAS-OL 
Study Baseline
Last dose of open-label, run-in treatment
FAS-RA
First dose of randomized 
treatment
Last dose of randomized treatment
FAS-RE
Rescue Baseline
Last dose of rescue treatment
Time-to-event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically.  Graphs will describe the number of patients at 
risk over time.  The median, quartiles and probabilities of not having an event at particular 
points in time will be estimated by the Kaplan-Meier method and their 95% CIs will also be 
provided when the data allows for their calculation. For some analyses, treatment differences 
between the probabilities of not having the event may be reported. Wald-type CIs for such 
differences will be reported using standard errors for the probabilities based on Greenwood’s 
formula.
The log-rank test (stratified using age group [adults and adolescents] and disease severity
[moderate and severe] at Study Baseline) p-value will be used for comparing time to event 
data between treatment groups.
For some analyses, a Cox regression model will be fit with treatment, age group and disease 
severity at Study Baseline as covariates. The estimated hazard ratio for the three pairwise 
treatment comparisons and its 95% CI will be reported from this model. For subgroup 
analyses, we will only have fixed effect of treatment in the model. 
5.3. Methods to Manage Missing Data
In general, for analyses using descriptive statistics, missing values will not be imputed. In 
addition, for safety endpoints, missing values will not be imputed. Other methods for 
handling missing values are discussed below.
5.3.1. Binary Endpoints
In the context of analyses based on the FAS-RA analysis set, some subjects may enter the 
rescue phase of the study. This intercurrent event (receiving rescue treatment after 
randomization) may be considered a dropout from randomized treatment with regard to the 
effect of the treatment difference for various efficacy measurements as compared among the 
three different randomized treatments during the double-blind period. This implies that 
outcome values after this intercurrent event will be considered missing data.
One way to handle the missing observations is to define responses for all subjects who 
dropout for any reason, including a protocol-defined flare, to be “non-responsive” at all 
subsequent visits from first rescue dosing date (for subjects who get rescue treatment) or 
dropout date (for subjects whose last recorded observation is before dropout) or after the last 
recorded observation (for subjects whose last recorded observation is on or after dropout), so 
there is no missing data in these cases. Any observations missing intermittently (not due to 
the subject dropping out) will be considered missing completely at random (MCAR) and will 
remain missing with this approach. 


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For analyses using the FAS-RE analysis sets and for binary endpoints analyzed at each 
scheduled visit separately, where subjects may dropout for any reason, missing responses for 
such subjects will also be defined as “non-responsive” at all subsequent visits after the last 
recorded observation. Any observations missing intermittently (before the last recorded 
observation) will be considered missing completely at random (MCAR) and will remain 
missing with this approach.
For analyses using the FAS-OL analysis sets and for binary endpoints analyzed at each 
scheduled visit separately, where subjects may dropout for any reason except for being a 
protocol-defined non-responder at Week 12, missing responses for such subjects will also be 
defined as “non-responsive” at all subsequent visits after the last recorded observation. Any 
observations missing intermittently (before the last recorded observation) will be considered 
missing completely at random (MCAR) and will remain missing with this approach.
5.3.2. Continuous Endpoints
For longitudinal continuous endpoints based on the FAS-OL or FAS-RE analysis sets, 
assuming that the missing data mechanism is missing at random (MAR), the data will be 
analyzed based on the full likelihood using a linear mixed-effect model with repeated 
measures for these continuous variables (see Section 5.2.2). This model will yield unbiased 
estimates and valid inferences in the presence of a missing data mechanism that is MAR.
In the context of analyses based on the FAS-RA analysis set, subjects requiring to enter the 
rescue phase of the study are considered dropouts from randomized treatment along with 
discontinuation from study during double blind period due to any reason. This implies that 
outcome values after this intercurrent event will be considered missing data. The 
determination of a protocol-defined flare event (or dropout) is based on past and current 
values for the total EASI score and the IGA score prior to dropout and not influenced by 
future (unobserved) values of these assessments beyond dropout. So the mechanism for such 
a dropout, conditional on the past and current values for total EASI score and IGA score, 
may be considered MAR. Therefore, the data may be analyzed based on the full likelihood 
using a linear mixed-effect model with repeated measures for these continuous variables (see
Section 5.2.2). This model will yield unbiased estimates and valid inferences in the presence 
of a missing data mechanism that is MAR.
In general, for non-PRO continuous endpoints measured longitudinally, missing values 
post-baseline will not be imputed explicitly. For the continuous PRO variables such as 
pruritus NRS, DLQI/CDLQI, POEM, PSAAD and HADS, rules (if any) suggested by the 
developers of these instruments will be followed in calculating the outcome value in the 
presence of missing data. If these rules are not enough for imputing a value, then the missing 
values will be handled in the same way as other non-PRO variables.
5.3.3. Time to Event Endpoints
Subjects who reach the end of their accrual period without experiencing the event of interest 
will have their event times right censored at the end of their accrual period (ie, administrative 
censoring). Subjects who permanently discontinue before the end of their accrual period
without experiencing the event of interest will have their event times considered missing.


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For the primary analysis, these missing event times will be considered as right censored 
(censored at random) on their last date of dosing. As sensitivity analyses, tipping point 
analyses will be performed where these missing event times will be multiply imputed under 
an assumption of censoring not at random as proposed in Atkinson et al. (2019)1 (see 
Appendix 6).
6. ANALYSES AND SUMMARIES
Treatment comparisons will only be displayed for the FAS-RA analysis set where it is 
relevant. Pairwise comparisons will be reported among the treatment groups. No treatment 
comparisons are relevant for the FAS-OL and FAS-RE analysis sets. Similarly, safety data 
displays will be by treatment group only for SAF-RA and not for SAF-OL or SAF-RE.
A summary of analyses for clinical efficacy endpoints is provided in Appendix 1.  Visit 
windows to be used for all efficacy analyses and some relevant safety analyses are detailed in
Appendix 2.
Efficacy and PRO data collected at the Week 16/Week 56 follow-up visits or at the Rescue 
Visit Week 16 follow-up visit will be displayed in listings only, and will not be part of any 
analyses, unless specifically noted otherwise.
6.1. Primary Endpoint
6.1.1. Loss of Response 
6.1.1.1. Primary Analysis

Summary: Time to loss of response (or protocol-defined flare) as measured from date 
of first dose of randomized treatment until the date of protocol-defined flare as 
recorded on the CRF.

Population: FAS-RA.

Statistical Method: Analyses for Time to Event Data in Section 5.2.4. Probabilities of 
not having had the event will be reported at Week 52. Pairwise differences in these 
probabilities between treatments and their 95% CIs will also be reported. Hazard 
ratios and their 95% CIs will also be reported.

Missing Data: See Section 5.3.3.
6.1.1.2. Additional/Supportive Analyses 
Additional analysis of the loss of response would be as:

The time to loss of response will be analyzed using the methods in Section 5.2.4 for 
the PPAS population.

Missing time to loss of response will be multiply imputed under censoring not at 
random under a tipping point analysis framework using the methods in Section 5.2.4
and Appendix 6 for the FAS-RA population.


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6.2. Key Secondary Endpoint
6.2.1. Loss of Response Based on the IGA Score
6.2.1.1. Primary Analysis

Summary: Time to loss of response based on achieving IGA 2 (for the first time) as 
measured from date of first dose of randomized treatment until the last dose of
randomized treatment (if not entered rescue) or first day of rescue treatment (if 
entered rescue).

Population: FAS-RA.

Statistical Method: Analyses for Time to Event Data in Section 5.2.4. Probabilities of 
not having had the event will be reported at Week 52.

Missing Data: See Section 5.3.3.
6.2.1.2. Additional/Supportive Analyses 
Additional analysis of the loss of response based on the IGA score would be as:

The time to loss of response based on the IGA score will be analyzed using the 
methods in Section 5.2.4 for the PPAS population.
6.3. Secondary Endpoints (Efficacy)
6.3.1. Response Based on (IGA, EASI-50, EASI-75, EASI-90, EASI-100, NRS4 for 
Severity of Pruritus, SCORAD50 and SCORAD75, IGA + EASI-75)
All Randomized 
Subjects 
Randomized Subjects 
Requiring Rescue 
Treatment
Pre- Randomization 
Subjects
Summary
Proportion of subjects
achieving a response
at Weeks 12, 16, 28, 
40 and 52 
Proportion of subjects
achieving a response at 
Rescue Weeks 2, 4, 8 
and 12 
Proportion of subjects
achieving a response
at Weeks 2, 4, 8 and 
12
Population
FAS-RA
FAS-RE
FAS-OL
Baseline
Study (see
Section 3.4)
Rescue (see
Section 3.4)
Study (see
Section 3.4)
Statistical 
Method
CMH and normal 
approximation as in
Section 5.2.1. 
Normal approximation 
as in Section 5.2.1. 
Normal 
approximation as in
Section 5.2.1. 
Missing Data
Missing values after 
dropout are defined as 
“non-response” (see
Section 5.3.1)
Missing values after 
dropout are defined as 
“non-response” (see
Section 5.3.1)
Missing values after 
dropout are defined as 
“non-response” (see
Section 5.3.1)


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6.3.2. Change from Baseline in (Total EASI Score, SCORAD (VAS) Pruritus and Sleep
Sub-Scales, PP-NRS for Severity and Percent BSA)
All Randomized Subjects 
Randomized Subjects Requiring 
Rescue Treatment
Summary
Change from baseline at Weeks 
12, 16, 28, 40 and 52
Percent change/Change from 
baseline at Rescue Weeks 2, 4, 8 and 
12 
Population
FAS-RA
FAS-RE
Baseline
Study (for Week 12); 
Randomization (for visits after 
Week 12) (see Section 3.4)
Rescue (see Section 3.4)
Statistical 
Method
MMRM as in Section 5.2.2
MMRM as in Section 5.2.2
Missing Data
Use observed data (see Section 5.3.2)
Change from Study Baseline at Week 12 and its 95% CI will be estimated for each randomized 
treatment group using an MMRM analysis using data from Weeks 2, 4, 8 and 12. For PP-NRS, 
data will be included from Days 2 – 15, Weeks 4, 8 and 12.
6.4. Secondary Endpoints (PRO)
6.4.1. Change from Baseline in (HADS, POEM, PSAAD and DLQI/CDLQI)
Summary
Change from baseline at Weeks 12, 16, 28, 40 and 52
Population
FAS-RA
Baseline
Study (for Week 12); Randomization (for visits after Week 12) (see
Section 3.4)
Statistical 
Method
MMRM as in Section 5.2.2
Missing Data
Rules, if any, suggested by the developers of these instruments will be 
followed in calculating the outcome value in the presence of missing 
data. If these rules are not enough for defining an outcome value, then 
the missing values will be handled in the same way as other continuous 
variables. (see Section 5.3.2)
Change from Study Baseline at Week 12 and its 95% CI will be estimated for each randomized 
treatment group using an MMRM analysis using data from Weeks 2, 4, 8 and 12. For PSAAD, 
weekly data will be included from Weeks 1 – 12. 


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6.4.2. Response Based on PtGA
Summary
Proportion of subjects achieving a response at Weeks 12, 16, 28, 40 and 
52
Population*
FAS-RA
Baseline
Study (see Section 3.4)
Statistical 
Method
CMH and normal approximation as in Section 5.2.1
Missing Data
Missing values after dropout are defined as “non-response” (see
Section 5.3.1)
* For endpoints that are defined based on meeting a threshold for a visit value or change from 
baseline, only subjects with a baseline value above that threshold will be included (see
Section 3.3).
6.5. Subset Analyses 
Summary statistics for the primary endpoint will be presented by subgroups as below:

Age (years) group (<18, ≥18; <40, ≥40; <65, ≥65);

Sex (Male, Female);

Race (White, Black or African American, Asian, Other1);

Weight (kg) group (<70, 70-100, >100);

Responder based on IGA + EASI-75 (before Week 8, at Week 8, after Week 8);

Region of enrollment (US/Canada, Eastern Europe, Western Europe, Asia, Latin 
America);

AD Duration (years) group (<26, ≥26);

Study Baseline disease severity based on IGA score (moderate, severe);

Randomization Baseline IGA score;

Study Baseline EASI group (16-25, >25);
                                                
1 For purposes of analysis, Other will comprise the categories of American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multi-Racial and any other category reported on the CRF.


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
Study Baseline % BSA group (10-30, >30-50, >50);

Prior (to Study Baseline) use of systemic immunosuppressant for AD (Yes, No).
Pairwise treatment comparisons using the hazard ratio and its 95% confidence interval will 
be presented for each defined category of each subgroup. No p-values will be presented. 
The primary purpose of the subgroup analyses is to check for consistency of results across 
subgroups, to make sure overall results are not being driven by some subset of subjects.
There is no intention to have any specific inference within subgroups.
6.6. Baseline and Other Summaries and Analyses
6.6.1. Baseline Summaries
Demographics, medical history, primary diagnosis and prior treatments for atopic dermatitis
collected during Visit 1/Screening will be summarized according to CaPS. Baseline disease 
severity based on IGA, baseline EASI score and baseline BSA will also be summarized by 
gender and by age group (adults and adolescents). Summaries will be displayed for each of 
the FAS analysis sets (see Sections 4.1 and 4.3) only.
6.6.2. Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized according to CaPS.
Summaries will also be displayed for each of the SAF analysis sets (see Sections 4.1 and 
4.3). A listing of all subjects whose study participation was impacted by COVID-19 and 
subject discontinuations due to COVID-19 will be displayed.
6.6.3. Study Treatment Exposure
A summary of compliance by study period will be provided.
The exposure to study drug will be summarized by the total number of days of dosing, and 
number and percentage of subjects who were not compliant (<80% or >120%) with the 
dosing schedule.
Summaries will be displayed for each of the SAF analysis sets (see Section 4.3).
6.6.4. Concomitant Medications and Non-Drug Treatments
Prior drug and non-drug treatment, general concomitant drug and non-drug treatment will be 
summarized according to CaPS.
For SAF-OL, only summaries of prior drug treatments for primary diagnosis and non-drug 
treatments will be displayed. For SAF-RA and SAF-RE, only summaries of general 
concomitant drug treatments will be displayed. Concomitant drug treatments for primary 
diagnosis and non-drug treatments will be displayed for each of the SAF analysis sets.


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6.7. Safety Summaries and Analyses
Safety analysis will be based on the SAF analysis sets (see Section 4.3). The SAF-OL 
analysis set will be used to summarize the safety experience for all subjects during the first 
12 weeks of open label treatment with PF-04965842 200 mg QD using the Study Baseline 
(see Section 3.4). The SAF-RA analysis set will be used to summarize the safety experience 
for all randomized subjects using the Randomization Baseline. Subjects who report a 
protocol-defined flare and get rescue treatment will be censored at the day before the first 
day of rescue in this analysis. All subjects will be classified according to the actual treatment 
regimen they received. The SAF-RE analysis set will be used to summarize the safety 
experience for the subjects who receive rescue treatment using the Rescue Baseline. Study 
Baseline will be used for all displays of results meeting lab abnormality criteria, throughout 
the subject’s study experience.
All clinical AEs, SAEs, treatment-emergent signs and symptoms (TEAEs), withdrawal due to 
AEs, ECGs, vital signs and safety laboratory data will be summarized to evaluate the safety 
of subjects.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. All safety endpoints will be listed and summarized in 
accordance with Pfizer Standards. Categorical outcomes (eg, AEs) will be summarized by 
subject counts and percentage. Continuous outcome (eg, blood pressure, pulse rate, etc.) will 
be summarized using N, mean, median, standard deviation, etc. Change from baseline in 
laboratory data, ECGs and vital signs will also be summarized.  Subject listings will be 
produced for these safety endpoints accordingly. Separate summaries will be displayed for 
adjudicated data on cardiovascular (CV), malignancy, opportunistic infection, 
histopathologic and hepatic events.
6.7.1. Adverse Events
The safety data will be summarized in accordance with Pfizer Data Standards.  All safety 
data will be summarized descriptively through appropriate data tabulations, descriptive 
statistics and categorical summaries.  Safety endpoints for the study include:

Treatment-emergent AEs and SAEs;

Withdrawals from active treatment due to AEs;

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
hospitalization or parenteral antimicrobials.
6.7.2. Laboratory Data
Laboratory data will be listed and summarized in accordance with the Pfizer reporting 
standards. Change from baseline analyses using the SAF-RA analysis set will describe the 
movement of laboratory assessments from Study Baseline to Week 12, randomization 
baseline and then again from Week 16 to the end of randomized treatment for all the three 
regimens. Similarly, change from baseline analyses using the SAF-RE analysis set will 


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describe the movement of laboratory assessments from Rescue Baseline to the end of the 
rescue period. Results from analyses of absolute values as well as of change from baseline 
will be displayed using both tabular and graphical formats.
6.7.3. Vital Signs, including Height and Weight
Vital signs will be summarized at all scheduled visits. Height and weight will be 
summarized at all visits where they are assessed.
6.7.4. Electrocardiogram
ECG parameters, if applicable, will be summarized at all assessment visits.
6.7.4.1. Physical Examination
Physical examinations will be summarized at all assessment visits.
6.7.5. Asthma Control Questionnaire (ACQ)
The questions on the ACQ are equally weighted and the ACQ score (or the response) for 
each subject is the mean of the 5 questions and therefore between 0 (totally controlled) and 
6 (severely uncontrolled). Categorical summary of the responses to the individual questions
will be summarized using methods in Section 5.2.3.
7. INTERIM ANALYSES
This study uses an External Data Monitoring Committee (E-DMC). The E-DMC will be 
responsible for ongoing monitoring of the efficacy, safety and PKs of subjects in the study 
according to the charter. Any recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision. Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate. Composition of the E-DMC 
and processes under which the E-DMC operates will be documented in the E-DMC charter.   
8. REFERENCES 
1.
Atkinson A, Kenward MG, Clayton T and Carpenter JR. Reference-based sensitivity 
analysis for time-to-event data. Pharmaceutical Statistics, 2019, 645-658.


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9. APPENDICES
Appendix 1. Summary of Clinical Efficacy Analyses
Clinical Efficacy Endpoints
Analysis 
Set
Baseline
Analysis Method
Missing
Data 
Imputation
Primary
Analysis for
Primary
Endpoint
Loss of Response
FAS-RA
Randomization Date
Time to Event
CAR
Yes
Loss of Response
PPAS
Randomization Date
Time to Event
CAR
No
Loss of Response
FAS-RA
Randomization Date
Time to Event
CNAR
No
Loss of Response based on the IGA score
FAS-RA
Randomization Date
Time to Event
CAR
Loss of Response based on the IGA score
PPAS
Randomization Date
Time to Event
CAR
Weeks 2, 4, 8 and 12 IGA Response
FAS-OL
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 IGA Response
FAS-RA
Study
CMH and Normal approx.
NR
Rescue Weeks 2, 4, 8 and 12 IGA Response
FAS-RE
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 EASI-50 Response
FAS-RA
Study
CMH and Normal approx.
NR
Weeks 2, 4, 8 and 12 EASI-75 Response
FAS-OL
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 EASI-75 Response
FAS-RA
Study
CMH and Normal approx.
NR
Rescue Weeks 2, 4, 8 and 12 EASI-75 Response
FAS-RE
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 EASI-90 Response
FAS-RA
Study
CMH and Normal approx.
NR
Weeks 2, 4, 8 and 12 NRS4 Severity Response
FAS-OL
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 NRS4 Severity Response
FAS-RA
Study
CMH and Normal approx.
NR
Rescue Weeks 2, 4, 8 and 12 NRS4 Severity Response
FAS-RE
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 SCORAD50 Response
FAS-RA
Study
CMH and Normal approx.
NR
Rescue Weeks 2, 4, 8 and 12 SCORAD50 Response
FAS-RE
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 SCORAD75 Response
FAS-RA
Study
CMH and Normal approx.
NR
Rescue Weeks 2, 4, 8 and 12 SCORAD75 Response
FAS-RE
Study
Normal approx.
NR
Weeks 12, 16, 28, 40 and 52 CFBL in Total EASI Score
FAS-RA
Randomization
MMRM
OD
Rescue Weeks 2, 4, 8 and 12 PCFBL in Total EASI Score
FAS-RE
Rescue
MMRM
OD
Weeks 12, 16, 28, 40 and 52 CFBL in Total SCORAD Score
FAS-RA
Randomization
MMRM
OD
Rescue Weeks 2, 4, 8 and 12 PCFBL in Total SCORAD Score
FAS-RE
Rescue
MMRM
OD
Weeks 12, 16, 28, 40 and 52 CFBL in NRS Score for Severity
FAS-RA
Randomization
MMRM
OD
Rescue Weeks 2, 4, 8 and 12 CFBL in NRS Score for Severity
FAS-RE
Rescue
MMRM
OD
Weeks 12, 16, 28, 40 and 52 CFBL in Percent BSA
FAS-RA
Randomization
MMRM
OD
Rescue Weeks 2, 4, 8 and 12 PCFBL in Percent BSA
FAS-RE
Rescue
MMRM
OD
CFBL=Change from baseline; PCFBL=Percent change from baseline; CMH=Cochran-Mantel-Haenszel; MMRM=Mixed-effect Model Repeated Measures; 
NR=Non-Responder; OD=Observed Data; CAR=Censoring at Random; CNAR=Censoring not at Random


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Appendix 2. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy variables, and for any safety lab data that display or 
summarize by study visit.  For other endpoints (eg, ECG, vital signs), visit windows will be 
applied for summary statistics by study visits if required.
Visit Windows Applicable for Run-In and Blinded Phases
Visit Label
Target Day
Definition [Day window]
Screening
Days -28 to Day -1
Study Baseline
Day 1 (Day of first 
dose)
Last observation prior to and 
including day of first dose
Week 2
15
Days 2 to 22
Week 4
29
Days 23 to 43
Week 8
57
Days 44 to 71
Week 12
85
Days 72 to 99 but not beyond 
first randomized dosing date
Week 16
113
Days 100 to 155 but after first 
randomized date
Week 28
197
Days 156 to 239
Week 40
281
Days 240 to 323
Week 52
365
Days 324 to 379
Week 56
-
Days 380 to -
For the lab values, if the calculated study day for the labelled baseline visit is not study Day 1 
but falls within 28 days before the start of the study dosing, then that data should be used for 
the baseline instead of leaving baseline missing.
For the other values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls before the start of the study dosing, then that data should be used for the 
baseline instead of leaving baseline missing.
Visit Windows Applicable for Rescue Therapy Phase
Rescue Visit Label
Target Day*
Definition [Day window*]
Rescue Baseline
Day 1 (Day of first 
rescue dose)
Last dose of blinded treatment 
until Day 1
Rescue Week 2
15
Days 2 to 22
Rescue Week 4
29
Days 23 to 43
Rescue Week 8
57
Days 44 to 71
Rescue Week 12
85
Days 72 to 99
Rescue Week 16
-
Days 100 to -

* Days are relative to Day 1 being the first day of rescue therapy.


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If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used.
If there are more than one observations collected on the same day, the one with the latest 
time should be used.
Safety analysis may follow CaPS standards.


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Appendix 3. Investigators Global Assessment
The clinical evaluator of atopic dermatitis will perform an assessment of the overall severity 
of atopic dermatitis and assign an IGA score and category as described in the table below.  
The assessment will be a static evaluation without regard to the score at a previous visit.
IGA Score
Score
Category
Description
0
Clear
Atopic dermatitis is cleared, except for any residual discoloration 
(post-inflammatory hyperpigmentation and/or hypopigmentation).
1
Almost 
Clear
Overall, the atopic dermatitis is not entirely cleared and remaining lesions 
are light pink (not including post inflammatory hyperpigmentation) 
and/or; have barely palpable hard thickened skin and/or papules and/or; 
have barely perceptible lichenification; excoriation and oozing/crusting 
are absent.
2
Mild
Overall, the atopic dermatitis consists of lesions that are light red; with 
slight, but definite hard thickened skin and/or papules; with slight, but 
definite linear or picked scratch marks or penetrating surface injury; with 
slight, but definite thickened skin, fine skin markings, and lichenoid scale; 
oozing/crusting is absent.
3
Moderate
Overall, the atopic dermatitis consists of lesions that are red; with easily 
palpable moderate hard thickened skin and/or papules; with moderate 
linear or picked scratch marks or penetrating surface injury; with 
moderate thickened skin, coarse skin markings, and coarse lichenoid 
scale; with slight oozing/crusting.
4
Severe
Overall, the atopic dermatitis consists of lesions that are deep, dark red; 
with severe hard thickened skin and/or papules; with severe linear or 
picked scratch marks or penetrating surface injury; with severe thickened 
skin with very coarse skin markings and lichenoid scale; with moderate to 
severe oozing/crusting.
The IGA will exclude scalp, palms, and soles from the assessment/scoring.


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Appendix 4. Eczema Area and Severity Index (EASI)
The EASI quantifies the severity of a subject’s atopic dermatitis based on both severity of 
lesion clinical signs and the percent of BSA affected.  EASI is a composite scoring by the 
atopic dermatitis clinical evaluator of the degree of erythema, induration/papulation, 
excoriation, and lichenification (each scored separately) for each of four body regions, with 
adjustment for the percent of BSA involved for each body region and for the proportion of 
the body region to the whole body.
Lesion Severity by Clinical Signs: The basic characteristics of atopic dermatitis 
lesions-erythema, induration/papulation, excoriation, and lichenification-provide a means for 
assessing the severity of lesions.  Assessment of these four main clinical signs is performed 
separately for four body regions: head and neck, upper limbs, trunk (including axillae and 
groin) and lower limbs (including buttocks).  Average erythema, induration/papulation, 
excoriation, and lichenification are scored for each body region according to a 4-point scale: 
0=absent; 1=mild; 2=moderate; 3=severe.  Morphologic descriptors for each clinical sign 
severity score are shown in the table below.
Clinical Sign Severity Scoring Criteria for the EASI
Score
Description*
Erythema (E)
0
Absent
None; may have residual discoloration (post-inflammatory 
hyperpigmentation and/or hypopigmentation).
1
Mild
Light pink to light red
2
Moderate
Red
3
Severe
Deep, dark red
Induration/Papulation (I)
0
Absent
None
1
Mild
Barely palpable to slight, but definite hard thickened skin and/or papules
2
Moderate
Easily palpable moderate hard thickened skin and/or papules
3
Severe
Severe hard thickened skin and/or papules
Excoriation (Ex)
0
Absent
None
1
Mild
Slight, but definite linear or picked scratch marks or penetrating surface 
injury
2
Moderate
Moderate linear or picked scratch marks or penetrating surface injury
3
Severe
Severe linear or picked scratch marks or penetrating surface injury
Lichenification (L)
0
Absent
None
1
Mild
Barely perceptible to slight, but definite thickened skin, fine skin markings, 
and lichenoid scale
2
Moderate
Moderate thickened skin, coarse skin markings, and coarse lichenoid scale
3
Severe
Severe thickened skin with very coarse skin markings and lichenoid scale
The EASI will exclude scalp, palms, and soles from the assessment/scoring.


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%BSA with Atopic Dermatitis: The number of handprints of skin afflicted with atopic 
dermatitis in a body region can be used to determine the extent (%) to which a body region is 
involved with atopic dermatitis (see table below).  When measuring, the handprint unit refers 
to the size of each individual subject’s hand with fingers in a closed position.
Handprint Determination of %BSA
Body Region
Total Number of 
Handprints in Body 
Region*
Surface Area of Body 
Region Equivalent of 
One Handprint*
Head and Neck
10
10%
Upper Limbs
20
5%
Trunk (including axillae and 
groin/genitals)
30
3.33%
Lower Limbs (including 
buttocks)
40
2.5%
Handprint refers to the hand size of each individual subject.
* The number of handprints will be for the entire body region; these values will not be 
adjusted for exclusion of scalp, palms, and soles from the BSA assessment.
EASI Area Score Criteria
Percent BSA with Atopic Dermatitis in a Body Region
Area Score
0%
0
>0 - <10%
1
10 - <30%
2
30 - <50%
3
50 - <70%
4
70 - <90%
5
90 - 100%
6
Body Region Weighting: Each body region is weighted according to its approximate 
percentage of the whole body (see table below).
EASI Body Region Weighting
Body Region
Body Region Weighting
Head and Neck
0.1
Upper Limbs
0.2
Trunk (including axillae and 
groin/genitals)
0.3
Lower Limbs (including buttocks)
0.4
* No adjustment for body regions excluded for assessment


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In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score and by 
the Body Region Weighting to provide a body region value, which is then summed across all 
four body regions resulting in an EASI score as described in Equation below.
EASI = 0.1Ah(Eh+Ih+Exh+Lh) + 0.2Au(Eu+Iu+ExU+Lu) + 0.3At(Et+It+Ext+Lt) + 
0.4Al(El+Il+Exl+Ll)
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; 
L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs
The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores 
representing greater severity of atopic dermatitis.


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Appendix 5. Scoring Atopic Dermatitis (SCORAD)
SCORAD is a validated scoring index for atopic dermatitis, which combines extent (0-100), 
severity (0-18), and subjective symptoms (0-20) based on pruritus and sleep loss, each scored 
(0-10).
Extent (A, maximum of 100%): To determine extent of AD, rule of 9 is used to calculate 
body surface area affected by AD as a percentage of the whole body surface area.  Body 
surface area as percentage of total body surface area for each body region is as follows:

Head and neck 9%;

Upper limbs 9% each;

Lower limbs 18% each;

Anterior trunk 18%;

Back 18%;

1% for genitals.
The score for each body region is added up to determine the BSA affected by AD (A), which 
has a possible maximum of 100%.
Severity (B, maximum of 18): A representative area of AD is selected.  In this area, the 
severity of each of the following signs is assessed as none (0), mild (1), moderate (2) or 
severe (3).

Erythema (reddening);

Edema (swelling);

Oozing/crusting;

Excoriation (scratch marks);

Skin thickening (lichenification);

Xerosis (dryness) (this is assessed in an area where there is no inflammation).
The severity scores are added together to give 'B' (maximum of 18).
Subjective Symptoms (C, maximum of 20): Subjective symptoms, ie., itch and sleep loss, 
are each scored by the subject or caregiver using a visual analog scale (VAS) where “0” is no 
itch (or no sleep loss) and “10” is the worst imaginable itch (or sleep loss).  The value for 
each should reflect the average on a 10-point scale for the last 3 days/nights.  These scores 
are added to give 'C' (maximum score of 20).
SCORAD Total Score: The SCORAD for an individual is calculated by the formula: A/5 + 
7B/2 + C (can range from 0 to 103).


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Appendix 6. A Weibull Proportional-Hazards Model for Event Time Data and Tipping 
Point Analysis
A Weibull Proportional-Hazards (WPH) Model
Let ܶ௜be the time to event (observed or unobserved) and ܥ௜the censoring time for subject ݅
ሺ݅ൌ1, 2, … , ܰሻ. We model the hazard function as,
݄ሺݐ|ݔ௜, ߚሻൌ݄଴ሺݐሻ݁ఉ೅௫೔, ݐ൐0
ሺ1ሻ
Here, ߚis a vector of unknown parameters corresponding to the vector of fixed effects ݔ௜.
There are three treatment groups, so the model term ߚ்ݔ௜when written out looks like,
ߚଵݔ௜ଵ൅ߚଶݔ௜ଶ
Here, ݔ௜ଵൌ1, ݔ௜ଶൌ0 if subject ݅is randomized to PF-04965842 100 mg QD, ݔ௜ଵൌ0, ݔ௜ଶൌ
1 if subject ݅is randomized to PF-04965842 200 mg QD and ݔ௜ଵൌ0, ݔ௜ଶൌ0 if subject ݅is 
randomized to placebo. 
For further convenience, we also assume that ݄଴ሺݐሻcorresponds to the hazard function from 
the Weibull distribution with shape parameter ݇൐0 and scale parameter ߠ൐0. So the 
survivor function ܵሺݐ; ߚ்ݔ௜ሻamounts to,
logሺെlog ܵሺݐ; ߚ்ݔ௜ሻሻൌߚ்ݔ௜൅݇log ݐെ݇log ߠ
In other words, this can be fit as a parametric regression model as,
log ݐ௜ൌlog ߠെ1
݇ߚ்ݔ௜൅1
݇logሺെlog ܵሺݐ௜; ߚ்ݔ௜ሻሻ
ൌߚ଴൅൬െߚଵ
݇൰ݔ௜ଵ൅൬െߚଶ
݇൰ݔ௜ଶ൅ߝ௜
with an intercept term as ߚ଴ൌlog ߠ. Maximum likelihood estimates (MLE) for ߚൌ
ሺߚ଴, ߚଵ, ߚଶሻand ݇can be obtained using standard statistical software.
Tipping Point Analysis
Under censoring at random (CAR), ݄ሺݐ|ݔ௜, ߚሻwill be the same for all values of ݐ൐0. If 
censoring is not at random (CNAR), then the post-censoring hazard ݄∗ሺݐ|ݔ௜, ߚሻ, ݐ൐ܥ௜, will 
be different from ݄∗ሺݐ|ݔ௜, ߚሻ, ݐ൑ܥ௜. We propose,
݄∗ሺݐ|ݔ௜, ߚሻൌ݄଴ሺݐሻexpሼߚଵݔ௜ଵ൅ߚଶݔ௜ଶሽ, ݐ൑ܥ௜
ൌ݄଴ሺݐሻexpሼߚଵሺ1 െߜଵሻݔ௜ଵ൅ߚଶሺ1 െߜଶሻݔ௜ଶሽ, ݐ൐ܥ௜


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When ߜଵൌߜଶൌ0, we are in the CAR situation. For any other values of ሺߜଵ, ߜଶሻ, we have 
CNAR. In particular, when ߜଵൌߜଶൌ1, we have a jump to reference situation where we 
assume that post-censoring, the hazard rate is no different from that in the placebo 
(reference) arm. We note also that this formulation assumes CAR for the placebo arm.
The corresponding survivor function ܵ∗ሺݐ; ߚ்ݔ௜ሻis,
logሺെlog ܵ∗ሺݐ; ߚ்ݔ௜ሻሻൌߚଵݔ௜ଵ൅ߚଶݔ௜ଶ൅݇log ݐെ݇log ߠ,
ݐ൑ܥ௜
ൌߚଵሺ1 െߜଵሻݔ௜ଵ൅ߚଶሺ1 െߜଶሻݔ௜ଶ൅݇log ݐെ݇log ߠ,
ݐ൐ܥ௜
The WPH model, as described in equation (1) above, will be used as the imputation model.
Estimation of the model parameters will be performed under the Bayesian framework using 
Markov Chain Monte Carlo (MCMC) methods.  We assign a non-informative prior for each 
component of ߚൌሺߚ଴, ߚଵ, ߚଶሻto be independent and identically distributed as ~ܰሺ0, 10଺ሻ  
and assign a weakly informative prior for the Weibull shape parameter ݇൐0 as an 
Inverse-Gamma distribution with shape=10ସand scale=10ସ. 
Let ሼߚ௕ൌሺߚ଴
௕, ߚଵ
௕, ߚଶ
௕ሻ, ݇௕: ܾൌ1, 2, … , ܤሽbe a sample (seed = 1848654157) from the 
posterior distribution. A single imputation ܶప௕
෪of the unobserved (or censored) ܶ௜is based on 
the posterior predictive distribution of the event times estimated from the WPH model.  For 
example, if subject ݅is censored at ܥ௜, ܶప௕
෪must be sampled from the conditional distribution 
of ܶప௕
෪|ܶప௕
෪൐ܥ௜. This can be easily done by equating the conditional survivor function 
ܵ∗ሺݐ|ݐ൐ܥ௜, ߚ௕೅ݔ௜ሻto a uniform random variable and solving for ݐ. Under our Weibull 
model, we draw ݑ௜~ ܷሾ0, 1ሿand solve,
ܵ∗ሺݐ௜|ݐ௜൐ܥ௜, ߚ௕೅ݔ௜ሻൌܵ∗ሺݐ௜; ߚ௕೅ݔ௜ሻ
ܵ∗ሺܥ௜; ߚ௕೅ݔ௜ሻൌݑ௜,
which has a simple closed form solution as,
݇௕ሺlog ݐ௜െߚ଴
௕ሻ
ൌexpሺߚଵ
௕ߜଵݔ௜ଵ൅ߚଶ
௕ߜଶݔ௜ଶሻlog ൜െexp൫െߚଵ
௕ݔ௜ଵെߚଶ
௕ݔ௜ଶ൯log ݑ௜൅ሺܥ௜
݁ఉబ
್ሻ௞್ൠ
Analysis of an imputed data set will produce an estimate as well as standard error of the 
hazard ratios using a Cox model as described in Section 5.2.4.  For given values of CNAR 
parameters ሺߜଵ, ߜଶሻ, this is repeated for B (typically, B=500) times to generate B complete 
imputed data sets and these B sets of estimates are combined using the Rubin’s Method 
(Rubin, 1987).  This can then be repeated for different values of MNAR parameters ሺߜଵ, ߜଶሻ
to evaluate the impact of missing data. Note that ሺߜଵ, ߜଶሻൌሺ0, 0ሻcorresponds to an MAR 
analysis and ሺߜଵ, ߜଶሻൌሺ1, 1ሻcorresponds to an analysis commonly known as 
Jump-To-Reference (JTR).


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Appendix 7. Schedule Of Activities
SCHEDULE OF ACTIVITIES FOR RUN-IN AND BLINDED TREATMENTS
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Visit Identifier
Day -28a
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
Week 12 
Randomize
Responders
Day 113b
Week 16
Day 
197b
Week 
28
Day 281b
Week 40
Day 365b
Week 52 
EOT/ET
EOS, 
Follow-up
Week 56/
4 Weeks 
post ET
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit Window
None
None
1 Day 1 Day 2 Days 3 Days 3 Days
3 Days
3 Days 7 Days 7 Days
3 Days
3 Days
Enrollment Procedure
Informed consentc
X
Register subject using IRT 
system
X
Inclusion/Exclusion Criteria
X
X
X
C-SSRSd
X
X
X
X
X
X
X
X
X
SBQ-Rd
X
PHQ-8d
X
Demographics, Medical 
History, Tobacco and Alcohol 
History, Atopic Dermatitis 
Disease Historye
X
Review Prior/Concomitant 
Medications & Treatments
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense e-Diary and instruct 
subjects on use
X
Provide Patient Emergency 
Contact Card
X


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 38
Visit Identifier
Day -28a
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
Week 12 
Randomize
Responders
Day 113b
Week 16
Day 
197b
Week 
28
Day 281b
Week 40
Day 365b
Week 52 
EOT/ET
EOS, 
Follow-up
Week 56/
4 Weeks 
post ET
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit Window
None
None
±1 Day ±1 Day ±2 Days ±3 Days ±3 Days
±3 Days
±3 Days ±7 Days ±7 Days
±3 Days
±3 Days
Medical Procedures
Complete Physical Examf
X
X
X
X
Targeted Physical Examf
X
X
X
X
X
X
X
Vital Signsg
X
X
X
X
X
X
X
X
X
X
X
Weight/Heightdd
X
X
X
X
ECG (12-lead)kk
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessmentsh
Hematologyi
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panelj
X
X
X
X
X
X
X
X
X
X
X
Serum chemistryk
X
X
X
X
X
X
X
X
X
X
X
Urinalysisl
X
X
X
X
X
X
X
X
X
X
X
Lipid Panelm
X
X
X
X
X
Serum FSH (post-menopausal) 
or Pregnancy Testn
X
Urine Pregnancy Test 
(conducted at study site)o
X
X
X
X
X
X
X
X
X
X
HIV Testingq
X
Hepatitis B Surface Antigen 
(HBsAg), Hepatitis B 
Surface Antibody (HBsAb), 
Hepatitis B Core Antibody 
(HBcAb), Hepatitis C 
Antibody (HCV Ab), 
Hepatitis C Viral RNA (HCV 
RNA)r
X
CCI


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 39
Visit Identifier
Day -28a
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
Week 12 
Randomize
Responders
Day 113b
Week 16
Day 
197b
Week 
28
Day 281b
Week 40
Day 365b
Week 52 
EOT/ET
EOS, 
Follow-up
Week 56/
4 Weeks 
post ET
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit Window
None
None
1 Day 1 Day 2 Days 3 Days 3 Days
3 Days
3 Days 7 Days 7 Days
3 Days
3 Days
HBV DNA testing for China 
and Taiwanjj
X
X
X
X
X
Varicella Zoster Virus (VZV 
IgG Ab) (adolescents only, if 
applicable)s
X
Tuberculosis Testt
X
Xii
Chest X-rayhh
X
Xii
Pharmacokinetic 
Pharmacokinetic Blood 
Sampling (Post-dose)u
X
Trial Treatment 
Randomization 
X
Drug Dispensing
X
X
X
X
X
X
X
Investigational Product 
Accountability 
X
X
X
X
X
X
X
X
Investigational Treatment 
Administrationv
X--------------------------------------------------------------------------------------------------------------------------X
Review eDiary to assess 
completion
X
X
X
X
X
X
X
X
X
X
Assess eligibility for 
B7451015w
X
X
Clinical Assessments 
Fitzpatrick Skin Type 
Assessment
X
Investigator’s Global 
Assessment (IGA) 
X
X
X
X
X
X
X
X
X
X
X
SCORing Atopic Dermatitis 
(SCORAD)
X
X
X
X
X
X
X
X
X
X
X
Eczema Area and Severity 
Index (EASI)
X
X
X
X
X
X
X
X
X
X
X
Total Body Surface Area 
(BSA from EASI) 
X
X
X
X
X
X
X
X
X
X
X


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 40
Visit Identifier
Day -28a
Screening
Day 1
Week 0
Baseline
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
Week 12 
Randomize
Responders
Day 113b
Week 16
Day 
197b
Week 
28
Day 281b
Week 40
Day 365b
Week 52 
EOT/ET
EOS, 
Follow-up
Week 56/
4 Weeks 
post ET
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8  
Visit 9
Visit 10
Visit 11
Visit 12
Visit 13
Visit Window
None
None
1 Day 1 Day 2 Days 3 Days 3 Days
3 Days
3 Days 7 Days 7 Days
3 Days
3 Days
Patient-reported Outcome 
Pruritus Numerical Rating 
Scale -eDiary (NRS)x
X---------X
X---------------------X
X
X
X
X
X
X
X
X
Patient Global Assessment 
(PtGA)
X
X
X
X
X
X
X
X
X
X
Dermatology Life Quality 
Index (DLQI or CDLQI)y
X
X
X
X
X
X
X
X
X
X
Patient-Oriented Eczema 
Measure (POEM)
X
X
X
X
X
X
X
X
X
X
Hospital Anxiety and 
Depression Scale (HADS)
X
X
X
X
X
X
X
X
X
X
Pruritus and Symptoms 
Assessment for Atopic 
Dermatitis - eDiary (PSAAD)z
X---------X
X----------------------------------------------------------------------------------------------------------------------------------------X
EQ-5D-5L (adults) or 
EQ-5D-Y (ages 12-17 years)aa
X
X
X
X
X
X
X
X
X
X
SF-36v2, Acutebb (adults)
X
X
X
X
FACIT-F (adults) or 
Peds-FACIT-F (ages 12-17 
years)cc
X
X
X
X
Asthma Control Questionnaire 
(ACQ) for all subjects with a 
prior diagnosis of asthma 
X
X
X
X
Safety
Serious and non-serious 
adverse event monitoring
X 











X
Assess for presence of flareee
X
X
X
X
Contraception Checkff
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Sample for Baseline 
Viral Screengg
X


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 41
Abbreviations: ACQ = Asthma Control Questionnaire; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; C-SSRS = Columbia 
Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; EOS=End of 
Study; EOT = End of Treatment; ET= early termination; EQ-5D-5L = EuroQol Quality of Life 5-Dimension 5-Level Scale; EQ-5D-Y = EuroQol Quality of Life 
5-Dimension, Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy Fatigue Scale; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyl transferase; HADS= Hospital Anxiety and Depression Scale; HBsAg = hepatitis B surface antigen; HBsAb = hepatitis B surface 
antibody; HBcAb = hepatitis B core antibody; HBV DNA = hepatitis B virus deoxyribonucleic acid; HCVAb = hepatitis C antibody; HCV RNA = Hepatitis C 
Viral RNA; Hep B = Hepatitis B; HIV = human immunodeficiency virus; HSV-1 = herpes simplex virus type 1; HSV2 = herpes simplex virus type 2; 
IGA = Investigator’s Global Assessment; IgE = Immunoglobulin E; IRT = Interactive Response System; LDH = Lactate dehydrogenase; LLQ = lower limit of 
quantification; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; NK = Natural 
Killer; NRS = numerical rating scale; Peds-FACIT-F = Pediatric Functional Assessment of Chronic Illness Therapy Fatigue Scale; PHQ-8 = Patient Health 
Questionnaire 8 items; POEM= Patient-Oriented Eczema Measure; PSAAD=Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global 
Assessment; RBC = Red blood cell; RNA = Ribonucleic acid; SBQ-R = Suicide Behaviors Questionnaire-Revised; SCORAD = SCORing Atopic Dermatitis; 
SF-36v2 = Short Form-36 Health Survey Version 2;VZV = varicella zoster virus; VZV IgG Ab = varicella zoster virus immunoglobulin G antibody.
a.
Day relative to start of study treatment (Day 1).
b.
From Day 86 through Day 365, if the subject flares as defined by protocol, begin rescue treatment period.  See Schedule of Activities for Rescue Treatment. 
c.
Obtain written informed consent; for subjects aged under the legal age of majority (legal adulthood) in the subject’s country, obtain written informed consent 
from legally acceptable representative/parent(s) orlegal guardian, and informed assent from the patient (if age appropriate according to local regulations).
d.
Site staff is to administer the C-SSRS, SBQ-R and PHQ-8 to all subjects at screening and score immediately.  Subjects who have recent or active suicidal 
ideation or behavior or clinically significant depression will be excluded from the study or discontinued from the study per Section 4.2, Section 7.5.1, 
Section 7.5.2 and Section 7.5.3.  Subjects meeting exclusionary results on the C-SSRS, SBQ-R and PHQ-8 should be excluded from participation; it is 
recommended the subject’s primary care physician (PCP) should be informed, and the subject referred to a mental health professional, either by the PCP or 
the investigator according to their usual practice.  Post-screening, if there are “yes” answers on items 4, 5 or on any behavioral question of the Since Last 
Visit C-SSRS a risk assessment by a qualified mental health professional (MHP) should be done to determine whether it is safe for the subject to continue to 
participate in the trial.
e.
Atopic Dermatitis Disease History includes collection of details of AD: AD diagnosis and duration, the use of topical treatments, systemic treatments and 
other treatments for AD. 
f.
Complete physical examinations must be performed by the investigator, sub investigator or a qualified health professional per local guidelines.  Complete 
physical examinations consist of assessments of general appearance; skin; head, eyes, ears, nose and throat (HEENT); mouth, heart; lungs; breast (optional); 
abdomen; external genitalia (optional); extremities; neurologic function; and lymph nodes.  Targeted physical examinations must be performed by the 
investigator, sub-investigator or a qualified health professional per local guidelines and should include skin, heart, lungs, and abdomen and examination of 
body systems where there are symptom complaints by the subject.
g.
Vital Signs include sitting blood pressure, pulse, respiratory rate, and temperature measured after at least 5 minutes of rest. 
h.
Laboratory tests with abnormal results (per Section 6.1 and Section 7.6.2) may be repeated once during the screening period; the last value will be used to 
determine eligibility.


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 42
i.
Hematology includes: Hemoglobin, hematocrit, red blood cell count and indices (MCH, MCHC, MCV, RBC Morphology), white blood cells, neutrophils 
(%, absolute), lymphocytes (%, absolute), monocytes (%, absolute), eosinophils (%, absolute), basophils (%, absolute), platelets, reticulocyte count, 
lymphocyte subsets and markers (Total T cells [CD3+], CD4+ T cells [CD3+CD4+], CD8+ T cells [CD3+CD8+], NK cells [CD3- CD16+CD56+], 
B cells [CD3-CD19 +). 
j.
Coagulation panel includes: Activated Partial Thromboplastin Time (APTT), Prothrombin Time/International Normalized Ratio (PT/INR).
k.
Serum chemistry includes: blood urea nitrogen (BUN), serum creatinine, creatine phosphokinase, glucose, Ca++, Na+, K+, Cl-, total CO2, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total, indirect and direct bilirubin, alkaline phosphatase, 
lactate dehydrogenase, uric acid, albumin and total protein.
l.
Urinalysis includes: pH, Glucose (qualitative), Protein (qualitative), Blood (qualitative), Ketones, Nitrites, Leukocyte esterase, Microscopy and/or culture 
(performed as appropriate). 
m. Lipid Panel includes: total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides.  A minimum of 8-hour fasting is 
required for lipid profile evaluation at Day 1, Week 4, Week 12, Week 52 and EOS visits.
n.
Serum pregnancy testing at screening is required for women of childbearing potential including adolescents aged 12 years and older regardless of whether 
they have experienced menarche.  Follicle stimulating hormone (FSH) test to be performed at Screening to confirm postmenopausal status in female subjects 
who have been amenorrheic for at least 12 consecutive months.
o.
Urine pregnancy test must be performed at every site visit prior to dosing with the investigational product for female subjects of childbearing potential 
including adolescents aged 12 years and older regardless of whether they have experienced menarche.
 
 
q.
Subjects testing positive for HIV will be screen-failed. 
r.
HBsAb reflex testing will be performed only if HBsAg negative but HBcAb positive.  Subjects who are positive for HCVAb and HCV RNA will be 
screen-failed. 
s.
VZV IgG antibody testing is required to confirm eligibility in adolescent subjects who have not received at least one dose of a varicella vaccine.
t.
A documented TB test performed within 12 weeks prior to Day 1 is acceptable.  Subjects with a history of tuberculosis may not require TB testing as per the 
protocol exclusion criteria in Section 4.2.  Perform TB test procedure using the QuantiFERON®-TB Gold In Tube Test (or Purified Protein Derivative).  A 
negative PPD test can be substituted for the QuantiFERON®-TB Gold In-Tube test only if the central laboratory is unable to perform the 
QuantiFERON®-TB Gold In-Tube test or cannot determine the results to be positive or negative and the Pfizer Medical Monitor approves it on a 
case-by-case basis.  In addition to protocol required TB testing, sites should follow their local standards for TB status determination, which may include 
chest X-ray.  See Section 7.3.4. 
u.
A PK blood sample will be collected at 2.0 hours (±30 min) postdose of open-label study drug (200 mg) at the Week 12 visit.  For Early Termination (ET) 
visits, if the subject discontinues before Week 4, do not collect a PK sample.  If the ET visit occurs at or after Week 4 and before Week 12, collect a PK 
sample only if the subject takes the investigational product at the site visit.
CCI


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 43
v.
Subjects should take the medication from study Days 1 to 365.  Subjects will be encouraged to take the medication in the morning whenever possible; 
however, at study visit days, subjects are to be instructed to refrain from dosing at home and are to take the dose in the clinic.  Instruct subjects regarding 
proper storage conditions for investigational product on Day 1. 
w.
Subjects who are non responders but complete the 12 week run-in treatment and subjects who are reponders at EOT will be assessed for eligibility for 
participation in long-term extension study B7451015 as noted in Section 6.3.5. 
x.
Pruritus Numerical Rating Scale (NRS) will be assessed using an eDiary daily during the screening period and from Study Day 1 to 15.  After Day 15, the 
Pruritus NRS will be completed only on study visit days in the eDiary.  At the Screening visit, site staff will dispense the electronic tablet (ePRO device) and 
review instructions for completion of the subject eDiary for the NRS.  At every visit, the study coordinator will review the eDiary for completeness and 
counsel the subject on how to complete the items in the daily eDiary, if needed. 
y.
DLQI will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the CDLQI instead.
z.
Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) will be conducted (only in selected countries) to assess the severity and frequency of 
pruritus, symptoms and sleep collected daily in a subject e-diary during the screening period and from Day 1 through the End of Study visit (See 
Section 7.8.7).  At the Screening visit, site staff will dispense the ePRO device and review instructions for completion of the subject eDiary for the PSAAD 
questionnaire.  Subjects will be asked to record their assessment in their eDiary once a day before taking the investigational product.  At every visit, the 
study coordinator will review the eDiary for completeness and counsel the subject on how to complete the items in the daily eDiary, if needed.
aa. The EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) will be completed by adult subjects only.  Adolescents 12-17 years of age will 
complete the EuroQol Quality of Life 5-Dimension, Youth Scale (EQ-5D-Y) in select countries.
bb. SF-36v2 will be completed by adult subjects only.  Adolescents 12-17 years of age will not complete this assessment.
cc. FACIT-F will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the Peds-FACIT-F instead.
dd. Height is not required at the baseline visit.  Only adolescents (12 to <18 years old) require repeated height measurement at screening, Week 12, and EOT/ET 
visits.  Adults require one height measurement at the screening visit.
ee. Assess for the emergence of flare defined as a loss of at least 50% of the EASI response at Week 12 and an IGA of 2 or higher.
ff.
The contraception check is an opportunity to confirm that contraception, if assigned, is used consistently and correctly.  It also facilitates continual 
reassessment of child-bearing potential in women.  This allows for implementing necessary changes to contraception; for example, investigators may need to 
ensure alternative contraceptive methods if new concomitant disease contraindicates a selected method of contraception, or if a subject is demonstrably no 
longer of child-bearing status (as per protocol) then they will no longer require contraception.  Continual reassessment of contraceptive needs is imperative.
gg. A serum sample will be collected at baseline but analyzed only if the subject has suspected varicella or herpes zoster.  In that event, the sample would be 
analyzed for HSV-1, HSV-2 and VZV.
hh. Chest X-ray or other appropriate diagnostic image (ie, CT or MRI) may be performed up to 12 weeks prior to Study Day 1.  Chest X-rays (posterior-anterior 
and lateral views) are required for adults and recommended for adolescents as per local guidelines and standard of care.  Official reading must be located and 
available in the source documentation.
ii.
Following one year of total exposure to study drug since the last TB test, all subjects in regions which are above a low-risk for Tuberculosis 
(ie, >10/100,000 prevalence) will undergo tuberculosis (TB) testing.  A chest X-ray will be performed to aid in TB status determination for all adults and 
recommended for adolescents according to local guidelines and standard of care in countries with a high incidence rate of TB.


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 44
jj.
In China and Taiwan only: Subjects who are HBsAg negative, HBcAb positive, and HBsAb positive at Screening will have reflex testing for Hepatitis B 
Virus (HBV) DNA.  Subjects who have HBV DNA above the lower limit of quantification (LLQ) will be excluded.  Subjects who are HBV DNA negative 
or below LLQ may enroll but will have HBV DNA testing repeated at Weeks 12, 28, 40, 52, and early termination from study during any treatment period.  
A single positive HBV DNA test result above the LLQ for a subject requires immediate and permanent discontinuation from treatment.  Refer to 
Section 7.6.2.1.
kk. A single 12-Lead ECG will be performed at screening and at all other planned on-site visits and interpreted by a central reader.  Clinically significant or 
exclusionary ECG findings at the screening or baseline visits will require screen failure.


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 45
SCHEDULE OF ACTIVITIES FOR RESCUE TREATMENT ̢ FLARE AT SCHEDULED OR UNSCHEDULED VISIT
Visit Identifier
Day 1
Week 0
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
EOT/ET
Week 12
EOS, Follow-up
Week 16/
4 Weeks post ET
Rescue
Visit 1
Rescue
Visit 2
Rescue
Visit 3
Rescue
Visit 4
Rescue
Visit 5
Rescue
Visit 6
Rescue
Visit 7
Rescue
Visit 8
Visit Window
±3 Days
±1 Day
±1 Day
±2 Days
±3 Days
±3 Days
±3 Days
±3 Days
Enrollment Procedure
Review Prior/Concomitant 
Medications & Treatments
X
X
X
X
X
X
X
X
Medical Procedures
Targeted Physical Exama
X
X
X
X
X
Complete Physical Exama
X
Vital Signsb
X
X
X
X
X
X
Weight/Heightq
X
X
ECG (12-lead)
X
X
X
X
X
X
Tuberculosis Testr
X
Laboratory Assessments 
Hematologyc
X
X
X
X
X
X
Coagulation Paneld
X
X
X
X
X
X
Serum chemistrye
X
X
X
X
X
X
Urinalysisf
X
X
X
X
X
X
Banked Biospecimen Sample 
Prep B1.5g
X
X
Urine Pregnancy Test 
(conducted at study site)i
X
X
X
X
X
X
HBV DNA testing for China 
and Taiwans
X
Trial Treatment 
Drug Dispensing
X
X
X
Investigational Product 
Accountability 
X
X
X
X
X
Investigational Treatment 
Administrationj
X----------------------------------------------------------------------------------------------------------------------X
CCI


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 46
Visit Identifier
Day 1
Week 0
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
EOT/ET
Week 12
EOS, Follow-up
Week 16/
4 Weeks post ET
Rescue
Visit 1
Rescue
Visit 2
Rescue
Visit 3
Rescue
Visit 4
Rescue
Visit 5
Rescue
Visit 6
Rescue
Visit 7
Rescue
Visit 8
Visit Window
3 Days
1 Day
1 Day
2 Days
3 Days
3 Days
3 Days
3 Days
Review eDiary to assess 
completion
X
X
X
X
X
X
X
X
Assess eligibility for 
B7451015k
X
Clinical Assessments
Investigator’s Global 
Assessment (IGA) 
X
X
X
X
X
X
SCORing Atopic Dermatitis 
(SCORAD)
X
X
X
X
X
X
Eczema Area and Severity 
Index (EASI)
X
X
X
X
X
X
Total Body Surface Area (BSA 
from EASI) 
X
X
X
X
X
X
Patient-reported Outcome 
Pruritus Numerical Rating 
Scale -eDiary (NRS)l
X--------------------------------------X
X
X
X
X
Patient Global Assessment 
(PtGA)
X
X
X
X
X
X
Dermatology Life Quality 
Index (DLQI or CDLQI)m
X
X
X
X
X
X
Patient-Oriented Eczema 
Measure (POEM)
X
X
X
X
X
X
Hospital Anxiety and 
Depression Scale (HADS)
X
X
X
X
X
X
Pruritus and Symptoms 
Assessment for Atopic 
Dermatitis - eDiary (PSAAD)
X----------------------------------------------------------------------------------------------------------------------------------------------X
EQ-5D-5L (adults) or 
EQ-5D-Y (ages 12-17 years)n
X
X
X
X
X
X
SF-36v2, Acuteo (adults)
X
X
X
FACIT-F (adults) or 
Peds-FACIT-Fp (ages 12-17 
years only)
X
X
X


Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 47
Visit Identifier
Day 1
Week 0
Day 8
Week 1
Call
Day 15
Week 2
Day 29
Week 4
Day 43
Week 6
Call
Day 57
Week 8
Day 85
EOT/ET
Week 12
EOS, Follow-up
Week 16/
4 Weeks post ET
Rescue
Visit 1
Rescue
Visit 2
Rescue
Visit 3
Rescue
Visit 4
Rescue
Visit 5
Rescue
Visit 6
Rescue
Visit 7
Rescue
Visit 8
Visit Window
±3 Days
±1 Day
±1 Day
±2 Days
±3 Days
±3 Days
±3 Days
±3 Days
Asthma Control Questionnaire 
(ACQ) for all subjects with a 
prior diagnosis of asthma
X
X
X
Safety
C-SSRSt
X
X
X
X
Serious and non-serious 
adverse event monitoring
X→
→
→
→
→
→
→
→X
Contraception Check
X
X
X
X
X
X
X
X
a.
Complete physical examinations must be performed by the investigator, sub investigator or a qualified health professional per local guidelines.  Complete physical 
examinations consist of assessments of general appearance; skin; head, eyes, ears, nose and throat (HEENT); mouth, heart; lungs; breast (optional); abdomen; external 
genitalia (optional); extremities; neurologic function; and lymph nodes.  Targeted physical examinations must be performed by the investigator, sub-investigator or a qualified 
health professional per local guidelines and should include skin, heart, lungs, and abdomen and examination of body systems where there are symptom complaints by the 
subject.
b.
Vital Signs include sitting blood pressure, pulse, respiratory rate, and temperature measured after at least 5 minutes of rest.
c.
Hematology includes: Hemoglobin, hematocrit, red blood cells, white blood cells, neutrophils (%, absolute), lymphocytes (%, absolute), monocytes (%, absolute), eosinophils 
(%, absolute), basophils (%, absolute), platelets, reticulocyte count, RBC Indices (MCH, MCHC, MCV, RBC Morphology), lymphocyte subsets and markers (Total 
T cells [CD3+], CD4+ T cells [CD3+CD4+], CD8+ T cells [CD3+CD8+], NK cells [CD3-CD16+CD56+], B cells [CD3-CD19 +).
d.
Coagulation panel includes: Activated Partial Thromboplastin Time (APTT), Prothrombin Time/International Normalized Ratio (PT/INR).
e.
Serum chemistry includes: blood urea nitrogen (BUN), serum creatinine, creatine phosphokinase, glucose, Ca++, Na+, K+, Cl-, total CO2, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total, indirect and direct bilirubin, alkaline phosphatase, lactate dehydrogenase, uric acid, albumin and 
total protein.
f.
Urinalysis includes: pH, Glucose (qualitative), Protein (qualitative), Blood (qualitative), Ketones, Nitrites, Leukocyte esterase, Microscopy and/or culture (performed as 
appropriate).
 
 
h.
Lipid Panel includes: total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides.  A minimum of 8-hour fasting is required for lipid 
profile evaluation at the following Rescue Visits: Day 1, Week 4, Week 12 and EOS visits.
i.
Urine pregnancy test must be performed at every site visit prior to dosing with the investigational product for female subjects of childbearing potential including adolescents 
aged 12 years and older regardless of whether they have experienced menarche.
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Protocol B7451014 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
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j.
Subjects should take the medication from study Days 1 to 85 of the rescue treatment.  Subjects will be encouraged to take the medication in the morning whenever possible; 
however, at study visit days, subjects are to be instructed to refrain from dosing at home and are to take the dose in the clinic.
k.
Subjects who complete EOT will be assessed for eligibility for participation in long-term extension study B7451015 as noted in Section 6.5.7. 
l.
Pruritus Numerical Rating Scale (NRS) will be assessed using an eDiary, and will be collected daily in the eDiary from Study Days 1-15 during the rescue treatment and then 
only on study visit days at the investigative site thereafter.  PSAAD will be completed daily (in selected countries) in the eDiary from Day 1 through the End of Study (EOS) 
visit during rescue treatment.  At every visit, the study coordinator will review the eDiary for completeness and counsel the subject on how to complete the items in the daily 
eDiary, if needed.
m.
DLQI will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the CDLQI instead.
n.
The EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the EuroQol 
Quality of Life 5-Dimension, Youth Scale (EQ-5D-Y) in select countries.
o.
SF-36v2 will be completed by adult subjects only.  Adolescents 12-17 years of age will not complete this assessment.
p.
FACIT-F will be completed by adult subjects only.  Adolescents 12-17 years of age will complete the Peds-FACIT-F instead.
q.
Collect weight for all subjects and height for adolescents only (12 to <18 years old).
r.
Following one year of total exposure to study drug since the last TB test, all subjects in regions which are above a low-risk for Tuberculosis (ie, >10/100,000 prevalence) will 
undergo tuberculosis (TB) testing.  A chest X-ray will be performed to aid in TB status determination for all adults, and recommended for adolescents according to local 
guidelines and standard of care in countries with a high incidence rate of TB. 
s.
In China and Taiwan only: For subjects who had HBV DNA testing at Screening, HBV DNA testing is repeated at Rescue Week 12 or at an early termination visit.  A single 
positive HBV DNA test result above the LLQ for a subject requires immediate and permanent discontinuation from treatment.  Refer to Section 7.6.2.1.
t.
Post-screening, if there are “yes” answers on items 4, 5 or on any behavioral question of the Since Last Visit C-SSRS a risk assessment by a qualified mental health 
professional (MHP) should be done to determine whether it is safe for the subject to continue to participate in the trial.