Conditions: Nonalcoholic Fatty Liver Disease Nonalcoholic Steatohepatitis With Liver Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 256
Healthy volunteers: no

Brief summary:
The study aims to evaluate two, orally administered, investigational agents - PF-06865571 (DGAT2 inhibitor) and the coadministration of PF-06865571 with PF-05221304 (ACC inhibitor). This study is specifically designed to evaluate the effect of a range of doses of DGAT2i alone, and DGAT2i + ACCi, on resolution of NASH or improvement in liver fibrosis, as assessed histologically (via liver biopsy).

Detailed description:

Arms:
arm 1: participants will receive medication for 48 weeks arm 2: participants will receive medication for 48 weeks arm 3: participants will receive medication for 48 weeks arm 4: participants will receive medication for 48 weeks arm 5: participants will receive medication for 48 weeks arm 6: participants will receive medication for 48 weeks arm 7: participants will receive medication for 48 weeks

Interventions: intervention 1: Placebo intervention 2: PF-06865571 intervention 3: PF-05221304
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Tablet

Protocol document:
Prot_000.pdf: 
P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1
A P H A S E 2, R A N D O MI Z E D, D O U B L E - BLI N D, D O U B L E -D U M M Y, 
P L A C E B O -C O N T R O L L E D , D O S E-R A N GI N G, D O S E - FI N DI N G, P A R A L L E L 
G R O U P S T U D Y T O A S S E S S E F FI C A C Y A N D S A F E T Y O F  P F -0 6 8 6 5 5 7 1 ( D G A T 2I )
A L O N E A N D W H E N C O A D MI NI S T E R E D WI T H P F - 0 5 2 2 1 3 0 4 (A C CI ) I N A D U L T 
P A R TI CI P A N T S WI T H BI O P S Y -C O N FI R M E D N O N A L C O H O LI C 
S T E A T O H E P A TI TI S A N D FI B R O SI S S T A G E 2 O R 3
St u d y I nter ve nti o n N u m ber:
P F - 0 6 8 6 5 5 7 1 ( D G A T 2i);
P F -0 5 2 2 1 3 0 4 ( A C Ci)
St u d y I nter ve nti o n N a me:
N/ A
U S I N D N u m ber:
1 3 3 3 2 2 ( D G A T 2i)
E u dr a C T N u m ber:
2 0 1 9 - 0 0 4 7 7 5- 3 9
Cli nic al T rials. g o v I D:
N C T 0 4 3 2 1 0 3 1
Pr ot oc ol N u m ber:
C 2 5 4 1 0 1 3
P h ase:
2
S h ort Title: M et a b olic Inter ve nti o ns t o R es ol ve N A S H w it h Fi br osis (MI R N A)
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.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
D oc u me nt
Versi o n D ate
A me n d me nt 1
3 0 A u g ust 2 0 2 1
Ori gi nal pr ot oc ol
2 2 Ja n uar y 2 0 2 0
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 re visi o ns ma de at t he re q uest of 
c o u ntr y healt h a ut h orities a n d IR Bs/ E Cs a n d a n y  pr ot oc ol a d mi nistrati ve clarificati o n letters.
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
A m e n d me nt 1 3 0 A u g ust 2 0 2 1
O ver all R ati o n ale f or t he A me n d me nt : T his s u bsta ntial a me n d me nt is a res ult of a strate gic 
decisi o n t o re pri oritize t he n u m ber of scie ntific q uesti o ns bei n g a d dresse d b y  t his st u d y after 
acc o u nti n g f or t he t otalit y of data ge nerate d acr oss m ulti ple st u dies. Via t his pr ot oc ol 
a me n d me nt , t his st u d y will f oc us o n a n e val uati o n of d ose-ra ng i n g, d osi n g-fi n di n g, efficac y, 
a n d safet y, of BI D d osi n g re gi me ns of D G A T 2i al o ne, or w he n c oa d mi n istere d wit h A C Ci.
T his a me n d me nt was dee me d necessar y i n li g ht of t he o perati o nal c halle n ges d uri n g t he 
o n g oi n g , gl o bal C O VI D- 1 9 pa n de mic . T his c ha n ge is n ot pr o m pte d b y e mer gi n g safety data 
i n t his or ot her o n g oi n g st u dies i n t he pr o gra m. Data fr o m all ra n d o mize d partici pa nts will be 
use d t o ascertai n efficac y a n d safet y of D G A T 2i al o ne, a n d D G A T 2i + A C Ci.
Secti o n # , Title
Descri pti o n of C h a n ge 
Brief R ati o n ale 
Key C h a n ges 
S y n o psis; 
Secti o n 2. 3. 2, Be nefit 
Assess me nt; Secti o n 4. 3, 
J ustificati o n of D ose; 
Secti o n 6. 1, St u d y 
I nter ve nti o n(s) 
A d mi nistere d – Ta ble 3 ; 
Secti o n 6. 3. 1, All ocati o n 
of S t u d y Inter ve nti o n; 
Secti o n 9. 2, Sa m ple Size 
Deter mi nati o n

E val uati o n of 2 ar ms wit h 
a d mi nistrati o n of D G A T 2i al o ne 
( 1 5 0 m g Q D a n d 3 0 0 m g Q D) is 
n o l o n ger bei n g p urs ue d

T h ose pre vi o usl y 
ra n d o mize d t o t hese 2 ar ms 
will be s witc he d i n a bli n de d 
ma n ner t o recei ve t he 
c orres p o n di n g BI D re gi me n 
t hat mai ntai n s t he sa me t otal 
dail y d ose

Rati o of t h ose o n i n vesti gati o nal 
a ge nt(s) decrease d sli g htl y –

O ri gi nal pr ot oc ol wa s 8 9 % 
( 8 of 9) 

Pr ot oc ol A me n d m e nt 1 will 
be 8 6 % ( 6 of 7)
Strate gic decisi o n t o re pri oritize t he 
n u m ber of scie ntific q uesti o ns bei n g 
a d dresse d b y t his st u d y
Secti o n 9. 1, Esti ma n ds 
a n d Statistical 
H y p ot heses; Secti o n 9. 2, 
Sa m ple Size 

Clarificati o ns offere d f or eac h 
esti ma n d a n d pla n ne d a nal yses 
acr oss t he treat me nt ar ms 
O utli ne i nte nt t o use data fr o m t h ose 
ra n d o mize d t o t he 2 ar ms n ot bei n g 
p urs ue d t o war ds t he o verall assess me nt 
of efficac y a n d safet y
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3
Secti o n # , Title
Descri pti o n of C h a n ge 
Brief R ati o n ale 
Deter mi nati o n ; Secti o n 
9. 3, A nal ysis Sets; 
Secti o n 9. 4, Statistical 
A nal yses
Secti o n 9. 5, I nteri m 
A nal ysis 
N u m ber ra n d o mize d t o tri g ger 1 st
safet y re view b y E -D M C retai ne d b ut 
pr o p orti o n u p date d (fr o m 
a p pr o xi matel y 2 5 %, ~ 1 1 2 
partici pa nts t o 3 3 %, ~ 1 1 5
partici pa nts) 
E ns ure ti mel y E- D M C re vie w a n d 
o versi g ht of partici pa nts safet y
Secti o n 1. 2, Sc he ma; 
S o A -Ta ble A 1, A 2;
Secti o n  
 
 Secti o n 4. 1, 
O verall Desi g n; Secti o n 
4. 2, Scie ntific Rati o nale 
f or St u d y Desi g n; Secti o n 
4. 2. 3, Partici pa nt I n p ut 
I nt o St u d y Desi g n; 
Secti o n 6. 5, C o nc o mita nt 
T hera p y
U p date t o ca pt ure circ u msta nces t hat 
per mit R u n -I n/ Visit 3 t o be 
c o n d ucte d as a tele p h o ne c o ntact vs 
o n -site visit w hile mai ntai ni n g a 
sta bilizati o n peri o d of at le ast 4 -
wee ks bef ore Ba seli ne/ Visit 4 – as 
o utli ne d i n st u d y-le vel P A C L iss ue d 
J u ne 2 0 2 1
Per m its ti me bet wee n c o n d uct of 
S C R 2 bi o ps y a n d w he n S C R 2 res ults 
are re p orte d b y s p o ns or -i de ntifie d 
ce ntral la b orat or y t o be use d as part 
of t he pr ot oc ol -ma n date d mi ni m u m 4 
wee k of sta bilizati o n peri o d pri or t o 
Baseli ne/ Visit 4
T he re visi o ns here will mi ni mize o ut-
of -wi n d o w ra n d o mizati o n (ie, mi n or 
pr ot oc ol de viati o ns of Pre Q t o Da y 1 
i n greater t ha n 1 6 w ee ks) u ni q uel y 
attri b ute d t o dela ys i n re p orti n g of 
S C R 2 bi o ps y res ults b y t he s p o ns or-
i de ntifie d ce ntral la b orat or y a n d 
offers a bilit y t o ma na ge t his p ote ntial 
dela y w hile retai ni n g t he scie ntific 
i nte grit y of t he st u d y desi g n
Secti o n 4. 2, S cie ntific 
R ati o nale f or S t u d y 
D esi g n; Secti o n 5. 1, 
I ncl usi o n criteria ( # 3, # 4)
Be y o n d F A S T T M sc ore, per mit use of 
o nly Fi br o Sca n ® deri ve d para meters , 
C A P T M a n d V C T E T M
E x pa nsi o n be y o n d use of F A S T T M
sc ore t o n o ni n vasi vel y i de ntif y 
p o p ulati o n wit h pres u me d N A S H b ut
a d di n g t he vi g or of re q uiri n g t he s a me 
criteri a t o be met at b ot h Pre Q a n d 
S C R 1
Se cti o n 4. 2, S cie ntific 
R ati o nale f or S t u d y 
D esi g n; Secti o n 5. 1, 
I ncl usi o n criteria ( #6)
Re visi o n t o u p per li mit of B MI fr o m 
4 0 k g/ m 2 t o 4 5 k g/ m 2
Tar get patie nt p o p ulati o n is 
o ver w ei g ht a n d o bese
I nte grit y of c o n d uct retai ne d wit h 
re q uire me nt f or ev al u a ble
Fi br o Sca n ® data a n d p er m itti n g 
c o n d uct of c o mp ute d t o m o gra p h y
g ui de d (i n a d diti o n t o ultras o u n d 
g ui de d) perc uta ne o us li ver bi o ps y
Secti o n 5. 5, S cree n 
F ail ures
Pr o visi o ns a d de d w hic h per mit re -
scree ni n g of t h ose w h o were e xcl u de d 
u n der O ri gi nal P r ot oc ol b ut w o ul d 
q ualif y a gai nst re vise d eli gi bilit y 
criterio n # 3, # 4 , a n d / or # 6
T h ose dee me d eli gi ble per P r ot oc ol 
A me n d me nt 1 offere d a n o p p ort u nit y t o 
j oi n t his st u d y
A d mi nistr ative c h a n ges 
O bjecti ves, Esti ma n ds, 
E n d p oi nts 
Clarificati o ns a d de d t o m o re 
acc uratel y reflect t he esti ma n d 
defi niti o n a n d pla n ne d a nal ysis 
Re visi o ns t o ai de clarit y/ tra ns pare nc y 
Secti o n 2. 2. 2, Cli nical 
O ver vie w 
U p dates ma de t o reflect D G A T 2i I B 
date d Fe b r uar y 2 0 2 1
Ali g n c o nte nt t o m ost rece nt S R S D
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4
Secti o n # , Title
Descri pti o n of C h a n ge 
Brief R ati o n ale 
Secti o n 5. 2, E xcl usi o n 
criteria ( # 1 3); Secti o n 8. 2, 
Safet y Assess me nt 
G ui da nce offere d re gar di n g C O VI D -
1 9 vacci nati o n, a n d ma na ge me nt of 
t h ose w h o test p ositi ve a n d/ or are 
s y m pt o matic – reflecte d i n st u d y-
le vel P A C L iss ue d Ja n uar y 2 0 2 1
A d diti o ns ma de g i ven o n g oi n g 
C O VI D -1 9 pa n de mic i nt o t his 
a me n d me nt 
Secti o n 6. 5, C o nc o mita nt 
T hera p y
A d diti o nal e xa m ples of a ge nts 
per mitte d, pr o hi bite d – a d de d 
I nc or p orate clarif yi n g q ueries re gar di n g 
pr ot oc ol la n g ua ge recei ve d fr o m sites 
si nce i nitiati o n of st u d y e ns uri n g 
u nif or m e xec uti o n of st u d y acr oss all 
re gi o ns
Secti o n 8. 1. 2. 2, 
Assess me nt of Li ver Fat 
usi n g M RI -P D F F
(I ma gi n g S u bst u d y)
Clarificati o n a d de d o utli ni n g t he 1 
re gi o n i ncl u de d i n I ma gi n g S u bst u d y; 
all ot her re gi o ns are e xcl u de d 
Offer tra ns pare nc y t o Healt h 
A ut h orit ies, I R Bs, E Cs re gar di n g t he 
li mite d sc o pe of t his s u bst u d y
Secti o n 8, St u d y 
A ssess me nts a n d 
P r oce d ures 
Bl o o d v ol u me c ollecte d offere d f or
t he f ull ra n ge bei n g c ollecte d acr oss 
all 1 1 c o u ntries i n t his st u d y 
C o nte nt c o nsiste ntl y ca pt uri n g v ol u me 
i n c o u ntr y- a n d site- le vel I C Ds
A p pe n di x 1 0 , G ui da nce t o 
I n vesti gat ors
C ollecti o n of bl o o d t o per mit 
assess me nt of F P G ± H b A 1 C a d de d, 
i n partici pa nts i n w h o m metf or mi n 
d ose is a dj uste d at R u n -I n/ Visit 3
N ee d f or a d diti o nal vi gila nce wit h 
assess me nt of  gl yce mia p ost 
ra n d o mizati o n rei nf orce d 
Secti o n 8. 1. 2. 2 , 
Assess me nt of Li ver Fat 
usi n g M RI -P D F F 
(I ma gi n g S u bst u d y); 
Secti o n 9. 4, Statistical 
A nal yses 
Clarificati o ns a d de d t o t he 
descri pti o ns of a nal yses as well as 
a d diti o nal detail a d de d re gar di n g 
e x pl orat or y M RI -deri ve d e n d p oi nts 
(
)
Ali g n wit h t he details alrea d y i ncl u de d 
i n t he S A P
A p pe n di x 1 0. 4. 1 ,
Male Partici pa nt 
Re pr o d ucti ve I ncl usi o n 
Criteria 
C o u ntr y -S pecific (
o nl y )
req uire me nt f or c o ntrace pti o n i n 
males reflecte d i n P A C L iss ue d A pril 
2 0 2 0
A d diti o ns ma de acc or di n g t o 
re q uire me nts fr o m t he Re g ulat or y 
a ut h orit y i n 
Secti o n 6. 5. 4, ot her 
acce pta ble c o nc o mita nt 
me dicati o ns; A p pe n di x 
 
i n hi bit ors a n d i n d ucers 
C o u ntr y -S pecific ( 
 o nl y )
re q uire me nt f or c o nc o mita nt use of 
her bal pre parati o ns offere d via P A C L 
iss ue d Fe b r uar y 2 0 2 1
I n res p o nse t o t he u ni q uel y 
dis pr o p orti o nate use of her bal 
pre parati o ns, i n t he p o p ulati o n bei n g 
e nr olle d i n t his st u d y, g ui da nce offere d 
t o I n vesti gat ors 
A p pe n di x 2, Cli nical 
La b orat or y Tests 
C o u ntr y -S pecific (
o nl y )
re q uire me nts a d dresse d; P A C L 
iss ue d Ja nuar y 2 0 2 1 i nc or p orate d 
I na bilit y t o e x p ort sa m ples fr o m  
, 
f or a nal ysis of 3 u ni q ue a nal ytes 
( Pr o C 3, Pr o C 6, direct V L D L) 
necessitate d r e mo val of bl o o d
c ollecti o ns f or t hese para meters i n all 
partici pa nts c o nse nte d a n d ra n d o mize d
i n  
 i n t his st u d y 
A p pe n di x 5, Ge netics 
C o u ntr y -S pecific ( 
 o nl y )
re q uire me nts a d dresse d; P A C L 
iss ue d Ma y-2 0 2 0 a n d A u g ust 2 0 2 0 
i nc or p orate d
Sc o pe of e x pl orat or y ge netic a nal yses 
li mite d, per l ocal re q uire me nts
T hr o u g h o ut d oc u me nt 
Clarificati o n s offere d t o ai de i n a 
c o m m o n u n dersta n di n g o f t he 
pr ot oc ol acr oss all sites a n d all 
c o u ntries 
I nc or p orate clarif yi n g q ueries re gar di n g 
pr ot oc ol la n g ua ge recei ve d fr o m sites 
si nce i nitiati o n of st u d y ens ur i n g
u nif or m e xec uti o n of st u d y 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5
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 0
LI S T O F FI G U R E S ................................................................................................................. 1 0
1. P R O T O C O L  S U M M A R Y................................................................................................... 1 1
1. 1. S y n o psis .................................................................................................................. 1 1
1. 2. Sc he ma .................................................................................................................... 1 4
1. 3. Sc he d ule of Acti vities ............................................................................................. 1 4
2. I N T R O D U C TI O N ............................................................................................................... 1 9
2. 1. St u d y  Rati o nale....................................................................................................... 2 0
2. 2. Bac k gr o u n d ............................................................................................................. 2 0
2. 2. 1. N o ncli nical O ver vie w ................................................................................. 2 1
2. 2. 2. Cli nical O ver vie w ....................................................................................... 2 2
2. 3. Be nefit/ Ris k Assess me nt......................................................................................... 2 3
......................................................................................... 2 3
2. 3. 2. Be nefit Assess me nt ..................................................................................... 2 6
2. 3. 3. O verall Be nefit/ Ris k C o ncl usi o n ................................................................ 2 7
3. O BJ E C TI V E S, E S TI M A N D S, A N D E N D P OI N T S........................................................... 2 7
4. S T U D Y D E SI G N ................................................................................................................. 2 8
4. 1. O verall Desi g n ......................................................................................................... 2 8
4. 2. Scie ntific Rati o nale f or St u d y  Desi g n..................................................................... 3 0
4. 2. 1. Partici pa nts of c hil d -beari n g p ote ntial ........................................................ 3 4
......................................... 3 4
4. 2. 3. Partici pa nt I n p ut I nt o St u d y  Desi g n ........................................................... 3 5
4. 3. J ustificati o n f or D ose ..............................................................................................3 6
4. 4. E n d of St u d y  Defi niti o n .......................................................................................... 3 8
5. S T U D Y P O P U L A T I ON ...................................................................................................... 3 9
5. 1. I ncl usi o n Criteria ..................................................................................................... 3 9
5. 2. E xcl usi o n Criteria .................................................................................................... 4 1
5. 3. Ra n d o mizati o n Criteria ........................................................................................... 4 5
5. 4. L ifest yle C o nsi derati o ns.......................................................................................... 4 6
5. 4. 1. C o ntrace pti o n ..............................................................................................4 7
5. 4. 2. Meals a n d Dietar y Restricti o ns...................................................................4 7
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6
5. 4. 3. Alc o h ol, Caffei ne, a n d T o bacc o .................................................................4 8
5. 4. 4. Acti vit y .......................................................................................................4 8
5. 4. 5. O ut patie nt Visits t o Site ..............................................................................4 8
5. 4. 6. O ut patie nt Visits t o I ma gi n g/ Ra di ol o g y  Facilit y........................................4 9
5. 5. Scree n Fail ures ........................................................................................................4 9
6. S T U D Y I N T E R V E N TI O N................................ ..................................................................5 0
6. 1. St u d y  Inter ve nti o n(s) A d mi nistere d ........................................................................5 0
6. 1. 1. A d mi nistrati o n ............................................................................................5 1
6. 2. Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ........................................................5 1
6. 2. 1. Pre parati o n a n d Dis pe nsi n g ........................................................................5 2
6. 3. Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g .....................................5 2
6. 3. 1. All ocati o n t o St u d y I nter ve nti o n ................................................................5 2
6. 3. 2. Brea ki n g t he Bli n d ......................................................................................5 3
6. 4. St u d y  Inter ve nti o n C o m plia nce ...............................................................................5 3
6. 5. C o nc o mita nt T hera p y ..............................................................................................5 4
6. 5. 1. Me dicati o n f or Gl yce mic C o ntr ol ...............................................................5 4
6. 5. 2. Li pi d -m o dif y i n g Me dicati o ns.....................................................................5 5
6. 5. 3. Me dicati o ns f or C o ntr olli n g Bl o o d Press ure.............................................. 5 6
6. 5. 4. Ot her Acce pta ble C o nc o mita nt Me dicati o ns ..............................................5 6
6. 5. 5. Pr o hi bite d Me dicati o ns............................................................................... 5 8
6. 5. 6. Resc ue Me dici ne .........................................................................................5 9
6. 6. D ose M o dificati o n ...................................................................................................5 9
6. 7. I nter ve nti o n After t h e E n d of t he St u d y ..................................................................5 9
7. DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ...........................................................................5 9
7. 1. Disc o nti n uati o n of St u d y  Inter ve nti o n ....................................................................5 9
7. 2. Partici pa nt Disc o nti n uati o n/ Wit h dra wal Fr o m t he St u d y .......................................6 0
7. 2. 1. Wit h dra wal of C o nse nt ...............................................................................6 1
7. 3. L ost t o F oll o w - u p....................................................................................................6 1
8. S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ...............................................................6 2
8. 1. Efficac y  Assess me nts..............................................................................................6 2
8. 1. 1. C o n d uct of Ultras o u n d -g ui de d, Perc uta ne o us L i ver Bi o ps y......................6 2
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7
8. 1. 2. L i ver I ma gi n g Assess me nts........................................................................6 4
8. 1. 2. 1. Assess me nt of L i ver Fat a n d Stiff ness – usi n g Fi br o Sca n ® ......6 4
8. 1. 2. 2. Assess me nt of L i ver Fat Usi n g M RI-P D F F (I ma gi n g 
S u bst u d y )...........................................................................................6 4
8. 1. 3. Patie nt- Re p orte d O utc o m es ........................................................................6 6
8. 1. 3. 1. N A S H- C H E C K .........................................................................6 7
8. 1. 3. 2. N A S H S y m pt o m Diar y .............................................................6 7
8. 1. 3. 3. N A S H Patie nt’s Gl o bal I m pressi o n of Se verit y  ( P GI-S) ..........6 7
8. 1. 3. 4. N A S H Patie nt’s Gl o bal I m pressi o n of C ha n ge ( P GI -C) ...........6 8
8. 1. 3. 5. P R O MI S Fati g ue C ust o m 9 -Ite m Versi o n ................................6 8
8. 2. Safet y Assess me nts .................................................................................................6 8
8. 2. 1. P h y sical E xa mi nati o ns ................................................................................6 9
8. 2. 1. 1. Meas ure me nt of Waist Circ u mfere nce ......................................7 0
8. 2. 2. B o d y Wei g ht ...............................................................................................7 0
8. 2. 3. Electr ocar di o gra ms..................................................................................... 7 1
8. 2. 4. Vital Si g ns ..................................................................................................7 1
8. 2. 5. Cli nica l Safet y La b orat or y Assess me nts....................................................7 2
8. 2. 6. Pre g na nc y  Testi n g ......................................................................................7 2
8. 2. 7. Alc o h ol I nta ke Assess me nt .........................................................................7 2
8. 2. 8. Tri g gere d re q uire me nts a n d I n di vi d ual Partici pa nt st o p pi n g r ules .............7 3
8. 2. 8. 1. P ote ntial Cases of H y pertri gl yc eri de mia ...................................7 3
8. 2. 8. 2. P ote ntial Cases of T hr o m b oc y t o pe nia.......................................7 3
8. 3. A d verse E ve nts a n d Seri o us A d verse E ve nts................................ ..........................7 3
8. 3. 1. Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E a n d S A E I nf or mati o n.......7 4
8. 3. 1. 1. Re p orti n g S A Es t o Pfizer Safet y ...............................................7 4
8. 3. 1. 2. Rec or di n g N o nseri o us A Es a n d S A Es o n t he C R F ...................7 5
8. 3. 2. Met h o d of Detecti n g A Es a n d S A Es ..........................................................7 5
8. 3. 3. F oll o w -u p of A Es a n d S A Es .......................................................................7 5
8. 3. 4. Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...........................................7 5
8. 3. 5. E x p os ure 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 ..........................................................................................................7 6
8. 3. 5. 1. E x p os ure D uri n g Pre g na nc y ......................................................7 6
8. 3. 5. 2. E x p os ure D uri n g Breastfee di n g ................................................7 7
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8
8. 3. 5. 3. Occ u pati o nal E x p os ure ............................................................. 7 8
............................................................. 7 8
8. 3. 7. Me dicati o n Err ors ....................................................................................... 7 8
8. 4. Treat me nt of O ver d ose ............................................................................................ 7 9
8. 5. P har mac o ki netics .................................................................................................... 8 0
8. 6. P har mac o d y na mics .................................................................................................. 8 0
................................................................................................................... 8 1
...................................................................................... 8 1
............................................................ 8 1
8. 8. Bi o mar kers .............................................................................................................. 8 2
.................................................................. 8 2
....................................................... 8 3
................................................................................. 8 3
8. 1 0. Healt h Ec o n o mics ................................................................................................. 8 3
9. S T A TI S TI C A L C O N SI D E R A TI O N S ................................................................................ 8 3
9. 1. Esti ma n ds a n d Statistical H y p ot heses ..................................................................... 8 3
9. 1. 1. Esti ma n ds .................................................................................................... 8 3
9. 1. 2. H y p ot hesis Tests ......................................................................................... 8 5
9. 2. Sa m pl e Size Deter mi nati o n ..................................................................................... 8 5
9. 3. A nal y sis Sets ........................................................................................................... 8 6
9. 4. Statistical A nal y ses ................................................................................................. 8 7
9. 4. 1. Ge neral C o nsi derati o ns ............................................................................... 8 7
9. 4. 2. Pri mar y  E n d p oi nt(s).................................................................................... 8 7
9. 4. 3. Sec o n dar y  E n d p oi nt(s)................................................................................ 8 9
9. 4. 4. Tertiar y / E x pl orat or y E n d p oi nt(s) ...............................................................9 0
9. 4. 5. P har mac o ki netic A nal y sis .......................................................................... 9 0
9. 4. 6. Ot her Safet y A nal yses ................................................................................ 9 0
9. 4. 6. 1. Vital Si g ns A nal y ses ................................................................. 9 1
9. 4. 6. 2. Electr ocar di o gra m A nal y ses...................................................... 9 1
9. 4. 7. Ot her A nal ys e(s) ......................................................................................... 9 1
9. 5. I nteri m A nalys es ..................................................................................................... 9 4
9. 6. Data M o nit ori n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee .............9 4
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9
1 0. S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S................................ ..........................................................................9 6
1 0. 1. A p pe n di x 1: Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsi derati o ns............... 9 6
1 0. 1. 1. Re g ulat or y a n d Et hical C o nsi derati o ns .................................................... 9 6
1 0. 1. 1. 1. Re p orti n g of Safet y  Iss ues a n d Seri o us Breac hes of t he 
Pr ot oc ol or I C H G C P ......................................................................... 9 6
1 0. 1. 2. Fi na ncial Discl os ure ................................................................................. 9 7
1 0. 1. 3. I nf or me d C o nse nt Pr ocess ........................................................................ 9 7
1 0. 1. 4. Data Pr otecti o n ......................................................................................... 9 8
1 0. 1. 5. Disse mi nati o n of Cli nical St u d y  Data ...................................................... 9 8
1 0. 1. 6. Data Q ualit y Ass ura nce ............................................................................ 9 9
1 0. 1. 7. S o urce D oc u me nts .................................................................................. 1 0 1
1 0. 1. 8. St u d y a n d Site Start a n d Cl os ure ............................................................ 1 0 1
1 0. 1. 9. P u blicati o n P olic y ................................................................................... 1 0 2
1 0. 1. 1 0. S p o ns or’s Q ualifie d Me dical Pers o n nel ............................................... 1 0 2
1 0. 2. A p pe n di x 2: Cli nical La b orat or y  Tests...............................................................1 0 4
1 0. 3. A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g .................................................................... 1 0 6
1 0. 3. 1. Defi niti o n of A E ..................................................................................... 1 0 6
1 0. 3. 2. Defi niti o n of S A E................................................................................... 1 0 7
1 0. 3. 3. Rec or di n g/ Re p orti n g a n d F oll o w -u p of A Es a n d/ or S A Es ..................... 1 0 9
1 0. 3. 4. Re p orti n g of S A Es .................................................................................. 1 1 2
1 0. 4. A p pe n di x 4: C o ntrace pti ve G ui da nce .................................................................1 1 3
1 0. 4. 1. Male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria.................................. 1 1 3
1 0. 4. 2. Fe male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria ............................... 1 1 3
1 0. 4. 3. W o ma n of C hil d beari n g P ote ntial .......................................................... 1 1 4
1 0. 4. 4. C o ntrace pti o n Met h o ds ........................................................................... 1 1 5
1 0. 5. A p pe n di x 5: 
.......................................................................................... 1 1 7
1 0. 6. A p pe n di x 6: L i ver Safet y: S u g geste d Acti o ns a n d F oll o w-u p Assess me nts ...... 1 1 9
1 0. 7. A p pe n di x 7: E C G Fi n di n gs of P ote ntial Cli nical C o ncer n .................................1 2 1
1 0. 8. A p pe n di x 
 I n hi bit ors a n d I n d ucers ........................................... 1 2 3
1 0. 9. A p pe n di x 9: Patie nt -Re p orte d O utc o mes ............................................................ 1 2 5
1 0. 9. 1. N A S H C H E C K ....................................................................................... 1 2 5
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0
1 0. 9. 2. N A S H S y m pt o m Diar y ........................................................................... 1 2 9
1 0. 9. 3. N A S H P GI -S .......................................................................................... 1 3 1
1 0. 9. 4. N A S H P GI -C.......................................................................................... 1 3 2
1 0. 9. 5. P R O MI S F A T I GU E C ust o m 9 -Ite m Versi o n ......................................... 1 3 3
1 0. 1 0. A p pe n di x 1 0: G ui da nce t o I n vesti gat ors – Ma na ge me nt of I n di vi d ual 
Partici pa nts Gl y ce mic C o ntr ol – i ncl u di n g Metf or mi n D ose St arti n g at R u n-
I n/ Visit 3 .................................................................................................................. 1 3 4
1 0. 1 1. A p pe n di x 1 1: G ui da nce t o I n vesti gat ors – Ma na ge me nt of I n di vi d ual 
Partici pa nts Wit h Ele vati o n i n Fasti n g Ser u m Tri gl y ceri des .................................. 1 3 5
1 0. 1 2. A p pe n di x 1 2: G ui da nce t o I n vesti gat ors – Ma na ge me nt of I n di vi d ual 
Partici pa nts Wit h Decrease i n Platelet C o u nt.......................................................... 1 3 6
1 0. 1 3. A p pe n di x 1 3: A b bre viati o ns ............................................................................. 1 3 7
1 1. R E F E R E N C E S ................................................................................................................ 1 4 2
LI S T O F T A B L E S
Ta ble 1.
Partici pa nt I n p ut i nt o C 2 5 4 1 0 1 3 St u d y  Desi g n........................................ 3 5
Ta ble 2.
................................................ 3 7
Ta ble 3.
D o u ble- bli n d, D o u ble -d u m m y  Re gi me ns i n St u d y C 2 5 4 1 0 1 3................. 5 0
Ta ble 4.
Patie nt -Re p orte d O utc o me Meas ures Pla n ne d i n St u d y  C 2 5 4 1 0 1 3 ......... 6 6
Ta ble 5.
Safet y -Relate d Assess me nt of Q T a n d Q Tc F I nter val ............................. 9 1
Ta ble 6.
A d diti o nal Tertiar y / E x pl orat or y O bjecti ves a n d E n d p oi nts..................... 9 2
Ta ble 7.
Pr ot oc ol -Re q uire d Safet y- Relate d La b orat or y  Assess me nts a n d 
E x pl orat or y  Bi o mar kers i n St u d y C 2 5 4 1 0 1 3......................................... 1 0 4
LI S T O F FI G U R E S
Fi g ure 1.
O verall St u d y  Desi g n................................................................................ 3 0
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1
1. P R O T O C O L S U M M A R Y 
1. 1. S y n o psis 
S h ort Title: M eta b olic Inter ve nti o ns t o R es ol ve N A S H wit h Fi br osis ( MI R N A)
R ati o n ale : T he c urre nt st u d y ai ms t o e val uate t w o, orall y a d mi nistere d, i n vesti gati o nal 
a ge nts - P F - 0 6 8 6 5 5 7 1, a s mall m olec ule t hat selecti vel y i n hi bits D G A T 2 a n d t he 
c oa d mi nistrati o n of P F- 0 6 8 6 5 5 7 1 wit h P F -0 5 2 2 1 3 0 4, a selecti ve, re versi ble, i n hi bit or of 
A C C, f or t he treat me nt of N A S H wit h li ver fi br osis. T his is t he first cli nical st u d y
s pecifically desi g ne d t o e va l uate t he effect of a ra n ge of d oses of D G A T 2i al o ne, 
a d mi nistere d BI D, a n d D G A T 2i + A C Ci a d mi nistere d BI D, o n res ol uti o n of N A S H or 
i m pr o ve me nt i n li ver fi br osis, as assesse d hist ol o gicall y ( via li ver bi o psy). A d diti o nall y , 
e x pl orat or y assess me nt of n o n-in vasi ve i ma gi n g -base d a n d bl o o d - base d c ollecti o ns are 
pla n ne d t o e na ble p ote ntial i de ntificati o n of n o n -i n vasi ve mar kers of disease a n d/ or treat me nt
res p o nse – i n t he tar get a d ult p o p ulati o n.
O bjecti ves, Esti m a n ds, a n d E n d p oi nts : T he pri mar y, sec o n dar y , an d ke y  tertiar y e n d p oi nts 
of f oc us i n t his st u d y  i ncl u de –
O bjecti ves
Esti m a n ds
E n d p oi nts
Pri m ar y: 
T o e val uate t he effect of a ra n ge 
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, i n p artici p a nts 
wit h bi o psy c o nfir me d N A S H 
a n d fi br osis, o n res ol uti o n of 
N A S H wit h o ut w orse ni n g of 
fi br osis or i m pr ove me nt i n 
fi br osis by ≥1 st a ge wit h o ut 
w orse ni n g of N A S H, or b ot h
Usi n g a c o m p osite esti ma n d strate g y i n 
partici pa nts wit h bi o ps y -c o nfir me d N A S H a n d 
fi br osis, esti mate t he treat me nt effect of D G A T 2i 
d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o 
D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of 
‘cli nical res p o n ders’, defi ne d as partici pa nts 
ac hie vi n g ce ntrall y a dj u dica te d: res ol uti o n of 
N A S H wit h o ut w orse ni n g of fi br osis or 
i m pr o ve me nt i n fi br osis b y ≥1 sta ge wit h o ut 
w orse ni n g of N A S H, or b ot h, at Wee k 4 8 a n d 
treati n g all cases of wit h dra wal fr o m treat me nt 
f or lac k of efficac y or t olerati o n as n o n -
res p o n ders
All treat me nt effect c o ntrasts will be o btai ne d 
t hr o u g h fitti n g t he Ba yesia n d ose-res p o nse 
a n d/ or e x p os ure -res p o nse m o dels wit h a l o git 
tra nsf or mati o n, or l o gistic re gressi o n m o dels
Pr o p orti o n of partici pa nts ac hie vi n g 
res ol uti o n of N A S H wit h o ut 
w orse ni n g of f i br osis or
i m pr o ve me nt i n fi br osis b y ≥1 sta ge 
wit h o ut w orse ni n g of N A S H or
b ot h, base d o n assess me nt b y 
s p o ns or-i de ntifie d ce ntral 
pat h ol o gist(s), at Wee k 4 8
Sec o n d ar y: 
T o e val uate t he effect of a ra n ge
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, o n liver f at
Usi n g a h y p ot hetical esti ma n d strate g y, i n 
partici pa nts wit h bi o ps y -c o nfir me d N A S H a n d 
fi br osis, esti mate t he treat me nt effect of D G A T 2i 
d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o 
D G A T 2i al o ne, i n ter ms of t he p o p ulati o n le vel 
a vera ge perce nt a ge c ha n ge fr o m baseli ne i n li ver 
fat (assesse d via M RI-P D F F) at Wee k 4 8 , 
ass u mi n g all partici pa nts ha d re mai ne d i n t he trial 
a n d recei ve d treat me nt as pla n ne d wit h o ut 
wit h dra wal u p t o 4 8 W ee ks. E n d p oi nt data 
Perce nt c ha n ge i n li ver fat (assesse d 
via M RI -P D F F i n s u bst u d y 
p o p ulati o n), at Wee k 4 8
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2
O bjecti ves
Esti m a n ds
E n d p oi nts
c ollecte d after treat me nt wit h dra wal will be 
cens ore d. 
All treat me nt effect c o ntrasts will be o btai ne d 
t hr o u g h fitti n g t he Ba yesia n d ose-res p o nse 
a n d/ or e x p os ure -res p o nse m o dels, or 
A N C O V A m o dels
T o e val uate t he effect of a ra n ge 
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, i n p artici p a nts 
ac hievi n g i m pr ove me nt i n 
differe nt res p o n der defi niti o ns
Usi n g a c o m p osite esti ma n d strate g y i n 
partici pa nts wit h bi o ps y -c o nfir me d N A S H a n d 
fi br osis, esti mate t he treat me nt effect of D G A T 2i 
d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, r elati ve t o 
D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of 
‘cli nical res p o n ders’, defi ne d as partici pa nts 
ac hie vi n g ce ntrall y a dj u dicate d res ol uti o n of 
N A S H wit h o ut w orse ni n g of fi br osis at Wee k 4 8 
a n d treati n g all cases of wit h dra wal fr o m 
treat me nt f or lac k of efficac y or t olerati o n as n o n-
res p o n ders
All treat me nt effect c o ntrasts will be o btai ne d 
t hr o u g h fitti n g t he Ba yesia n d ose-res p o nse 
a n d/ or e x p os ure -res p o nse m o dels wit h a l o git 
tra nsf or mati o n, or l o gistic re gressi o n m o dels
Si milar esti ma n ds will be asses se d f or:
I m pr o ve me nt i n fi br osis b y ≥1 sta ge, 
wit h o ut w orse ni n g of N A S H
I m pr o ve me nt i n fi br osis b y ≥2 sta ges, 
wit h o ut w orse ni n g of N A S H
I m pr o ve me nt of ≥2 p oi nts i n T otal N A F L D 
Acti vit y Sc ore ( N A S)
Pr o p orti o n of partici pa nts ac hie vi n g 
i m pr o ve me nt i n different res p o n der 
defi niti o ns base d o n assess me nt b y 
s p o ns or-i de ntifie d ce ntral 
pat h ol o gist(s) at Wee k 4 8 –

Res ol uti o n of N A S H, wit h o ut 
w orse ni n g of fi br osis

I m pr o ve me nt i n fi br osis b y ≥1
sta ge, wit h o ut w orse ni n g of 
N A S H

I m pr o ve me nt i n fi br osis b y ≥2
sta ges, wit h o ut w orse ni n g of 
N A S H

I m pr o ve me nt of ≥2 p oi nts i n 
T otal N A S
T o assess t he s afety a n d 
t oler a bility wit h a ra n ge of 
D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci re lati ve t o 
D G A T 2i al o ne
Assess me nt of T E A Es, safet y-
relate d cli nical la b orat or y tests, vital 
si g ns, a n d 1 2-lea d E C Gs, o ver ti me 
u p t o Wee k 4 8
Terti ar y/ E x pl or at or y: 
T o e val uate t he effect of a ra n ge 
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, i n partici pa nts 
wit h w orse ni n g of bi o ps y 
e n d p oi nt c o m p o ne n ts
Pr o p orti o n of partici pa nts wit h 
w orse ni n g i n li ver bi o ps y e n d p oi nt 
c o m p o ne nts base d o n assess me nt b y 
s p o ns or-i de ntifie d ce ntral
pat h ol o gist(s) at Wee k 4 8 –

Pr o gressi o n of fi br osis b y 
≥1 sta ge

W orse ni n g
of ≥2 p oi nts i n T otal 
N A S
F or all e n d p oi nts, baseli ne is defi ne d as t he e val ua ble res ult cl osest pri or t o d osi n g o n Da y 1/ Visit 5
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
O ver all Desi g n : T his is a m ultice nter, m ulti nati o nal, ra n d o mize d, d o u ble -bli n d, d o u ble -
d u m m y , place b o-c o ntr olle d, d ose ra n gi n g/fi n di n g, u p t o 9 -ar ms, parallel- gr o u p, e val uati o n of
D G A T 2i al o ne, a n d D G A T 2i + A C Ci – refer t o Sc he ma offere d i n Secti o n 1. 2 , bel o w. 
N u m ber of P artici p a nts : A p pr o xi matel y  3 5 0 partici pa nts ( 5 0 per ar m) wit h bi o ps y  
c o nfir me d N A S H wit h F 2 -F 3 fi br osis, as assesse d b y s p o ns or-i de ntifie d ce ntral 
pat h ol o gist(s), will b e ra n d o ml y assi g ne d t o t he st u d y i nter ve nti o n t o e ns ure a p pr o xi matel y 
2 8 0 e val ua ble partici pa nts ( 4 0 per ar m) offer e val ua ble data f or t he pri mar y  o bjecti ve. F or 
partici pa nts ra n d o mize d bef ore Pr ot oc ol A me n d me nt 1 is e nacte d th ose ra n d o mize d t o eit her 
o f t he 2 Q D d osi n g re gi me ns of D G A T 2i al o ne will re mai n i n t he st u d y b ut will be s witc he d 
t o t he c orres p o n di n g BI D d osi n g re gi me n of D G A T 2i al o ne, mai ntai ni n g t he assi g ne d t otal 
dail y  d ose a n d t he d o u ble-bli n d , d o u ble-d u m m y  desi g n.
I nter ve nti o n Gr o u ps a n d D ur ati o n : Partici pa nts will be ra n d o mize d i n a bala nce d rati o , 
usi n g a c o m p uter-ge nerate d ra n d o mizati o n c o de , t o recei ve eit her d o u ble-bli n d, d o u ble -
d u m m y  place b o, 1 of 4 d oses/ d osi n g re gi me ns of D G A T 2i al o ne, or 1 of 2 d ose -le vels of
D G A T 2i + A C Ci f or a treat me nt d urati o n of u p t o 4 8 wee ks. A c o m p uter-ge nerate d 
ra n d o mizati o n c o de usi n g t he met h o d of ra n d o m per m ute d bl oc ks will be utilize d t o assi g n 
partici pa nts t o 1 of t he 9 ( Ori gi nal P r ot oc ol) or 7 ( Pr ot oc ol A me n d me nt 1 ) st u d y 
i nter ve nti o ns o n Da y 1/ Visit 5. Partici pa nts ra n d o mize d u n der t he O ri gi nal P r ot oc ol will 
re mai n ra n d o mize d u n der Pr ot oc ol A me n d me nt 1 – r efer t o Ta ble 3 f or details o n 
ma na ge me nt of t he d o u ble- bli n de d treat me nt assi g n me nt bet wee n Ori gi nal a n d 
A me n d me nt 1 of t his pr ot oc ol.
D at a M o nit ori n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee: T hree 
differe nt C o m mittees are e n visi o ne d – ( 1) i n de pe n de nt u n bli n de d E-D M C; ( 2) i n de pe n de nt 
bli n de d A dj u dicati o n C o m mittee; a n d ( 3) bli n de d Steeri n g C o m mittee. 
St atistic al Met h o ds : T he esti mate d sa m ple size is dri ve n b y t he c haracterizati o n of d ose 
res p o nse a n d treat me nt effect usi n g a Ba yesia n E ma x st u d y desi g n a n d m o delli n g a ppr oac h, 
w hic h will utilize wea kl y i nf or mati ve pri ors f or m o del para meters a n d will pr o vi de t he 
a bilit y t o ma ke m ore precise c o m paris o ns bet wee n treat me nt ar ms. It is esti mate d t hat a t otal 
sa m ple size of 3 5 0 partici pa nts will gi ve acce pta ble pr o ba bilities t o ma ke decisi o ns a b o ut t he 
d ose res p o nse i n t he p o p ulati o n bei n g st u die d base d o n si m ulati o n st u dies. At t he t he oretical 
E ma x of 0. 6 (ie, a 6 0 % res p o n der rate), t here w o ul d be e n o u g h precisi o n t o s h o w a greater 
t ha n 2 4 % differe nce i n t he pri mar y e n d p oi nt res p o n der rate bet wee n place b o a n d t he sec o n d 
hi g hest BI D d ose of D G A T 2i (ie, 1 5 0 m g BI D) wit h a pr o ba bilit y  of at least 8 9 %. I n 
a d diti o n, t his sa m ple size will pr o vi de a de q uate precisi o n t o assess w het her D G A T 2i + A C Ci
pr o vi des a hi g her res p o n der rate t ha n D G A T 2i m o n ot hera p y wit h a pr o ba bilit y  of 8 2 % if t he 
tr ue effect size is at least 6 %.
T he pla n ne d statistical a nal y ses f or t he pri mar y, a n d ke y sec o n dar y e n d p oi nts are o utli ne d 
a b o ve wit hi n t he descri pti o n of t he esti m a n ds. 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
1. 2. Sc he m a
T he detaile d set -u p of t he st u d y is s u m marize d bel o w –
1. 3. Sc he d ule of Acti vities
T he t w o S o A ta ble s pr o vi de a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures. Refer t o 
Secti o n 8 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 i n t he S o A 
ta bles, 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 partici pa nt.
Pr e- Q u alifi c ati o n
(1 st n o n-i n v a si v e a s s e s s m e nt s)
S cr e e n 2
( Ultr a s o u n d- g ui d e d li v er B x)
R u n-I n a
(      or o n sit e)
B a s eli n e 
[ Si n gl e- Bli n d Pl a c e b o ( BI D)]
R a n d o mi z ati o n / D a y 1
W e e k 4 8
( Ultr a s o u n d- g ui d e d li v er B x)
F/ U # 1
F/ U # 2
W e e k 2
S cr e e n 1
(2 n d n o n-i n v a si v e a s s e s s m e nt s)
W e e k 4
W e e k 6
W e e k 8
W e e k 1 2
W e e k 1 6
W e e k 2 4
W e e k 3 2
W e e k 4 0
S cr e e ni n g P h a s e 
Tr e at m e nt P h a s e 
F oll o w -u p
a.
R u n -I n/ Vi sit 3 r e q uir e d t o b e o n sit e if c h a n g e s t o b a c k gr o u n d m e di c ati o n s ( pr ot o c ol m a n d at e d or c h a n g e s t o i m pr o v e di s e a s e m a n a g e m e nt) ar e b ei n g m a d e; 
ot h er wi s e, t hi s vi sit p er mitt e d a s a t el e p h o n e c o nt a ct o n t h e s a m e d a y, or u p t o 4 d a y s, p o st c o n d u ct of S C R 2 li v er bi o p s y
b.
St a bili z ati o n p eri o d d efi n e d a s i nt er v al of ti m e fr o m R u n -I n/ Vi sit 3 ( o n-sit e or t el e p h o n e c o nt a ct) t o D a y 1/ Vi sit 5
1 0 - t o 1 6- w e e k s
At l e a st 6 w e e k s b
1 4 ± 4 d a y s
4 8 w e e k s ± 4 d a y s
~ 5 2 w e e k s
M RI -P D F F i n ~ 5 0 % 
of r a n d o mi z e d 
[I m a gi n g S u b- st u d y]
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5
S o A -T a ble A 1: Pr oce d ures i n St u dy C 2 5 4 1 0 1 3
Visit I de ntifier
Pre Q
S C R 1
S C R 2
R u n-I n
B aseli ne
Tre at m e nt P h ase
[All p r oce d ures e xce pt Fi br o Sca n ® , M RI -P D F F a n d li ver bi o ps y bef ore
m or ni n g d ose of  st u d y i nter ve nti o n ±c o n me ds , w he n a p plic a ble ]
F oll o w
- u p
I P D/ C o r St u d y D/C c
Wee ks
a Rel ati ve t o D osi n g o n D a y 1
- 6
- 2
0
2
4
6
8
1 2 1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 0
5 2 b
Visit #
0
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
O n -site ( x) [wit h Tele p h o ne ( T )b ] visits
x 
x 
x
x or T
x 
x 
x 
x 
x 
x 
x 
x
T
x
T
x
T
x
T
x 
x
T
x
I nf or me d c o nse nt & de m o gra p h y
x 
x
( U p date) Me dical & Me dicati o n hist or y
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
Ultras o u n d -g ui de d li ver bi o ps y d
x
x e
x f
Li ver fat a n d stiff ness ( via Fi br o Sca n ® )d
x 
x
x e
x 
x
x 
x 
x 
x e
x g
Li ver M RI -P D F F (I ma gi n g Su bst u d y o nly )d
x e
x
x
x e
x g
P h ysical E xa m h
x 
x
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
Assess alc o h ol i nta ke ( A U DI T q uesti o n naire)
x 
x
x
x
x
Assess c orrect use of c o ntrace pti o n, w here a p plic a ble
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
C o u nseli n g o n diet/e xercise g ui deli nes
x 
x
O pe n -e n de d i n q uir y f or a d verse e ve nts 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
Si n gle s u pi ne 1 2 -lea d E C G 
x 
x
x 
x
x
x 
x 
x
Si n gle seate d vitals ( B P & p ulse rate) a n d b o d y wei g ht
x 
x
x 
x 
x 
x 
x
x 
x 
x 
x 
x 
x
Re gistrati o n of visit i n st u d y ( via I R T)
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
St u d y i nter ve nti o n (I P) ta ke n wit h m or ni n g meal
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
Dis pe nsati o n i ( via I R T) of st u d y i nter ve nti o n (I P)
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
Wit nesse d o n site d osi n g of st u d y i nter ve nti o n
(I P)
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
C o m plia nc e c hec k j of ret ur ne d st u d y i nter ve nti o n (I P)
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
x
C o nti n ue d a d mi nistrati o n of st u d y i nter ve nti o n (I P)i
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
N A S H -C hec k
x
x
x
N A S H S y m pt o m s, P G I- S, P G I- C, P R O MI S Fati g ue k
x
x
x
x
x
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6
S o A -T a ble A 1: Pr oce d ures i n St u dy C 2 5 4 1 0 1 3
Visit I de ntifier
Pre Q
S C R 1
S C R 2
R u n-I n
B aseli ne
Tre at m e nt P h ase
[All p r oce d ures e xce pt Fi br o Sca n ® , M RI -P D F F a n d li ver bi o ps y bef ore
m or ni n g d ose of  st u d y i nter ve nti o n ±c o n me ds , w he n a p plic a ble ]
F oll o w
- u p
I P D/ C o r St u d y D/ Cc
Wee ks
a Rel ati ve t o D osi n g o n D a y 1
- 6
- 2
0
2
4
6
8
1 2 1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 0
5 2 b
Visit #
0
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
a.
Defi ne d rel ati ve t o D a y 1 wit h per mitte d ± 4 -da y wi n d o w f or eac h visit starti n g at Visit 4/ Baseli ne; f or e xa m ple: Wee k -2 = 1 4 ( ± 4) da ys bef ore Da y 1; Wee k 4 = 2 8 ( ± 4) 
da ys p ost Da y 1
b.
R u n -I n Visit re q uire d t o be o n site if c ha n ges t o bac k gr o u n d me dicati o ns are bei n g ma de – ot her wise, R u n -I n Visit per mitte d as a tele p h o ne c o ntact o n t he sa me d a y , or u p t o 
4 da ys , p ost c o n d uct of S C R 2 li ver bi o ps y; p ost r a n d o miz ati o n , tele p h o ne c o ntact visits ca n be s witc he d t o o n -site visits f or f oll o w- u p of T E A Es a n d/ or a b n or mal 
la b orat or y tests; Wee k 5 2 visit at ≥2 8 - a n d ≤3 5 - da ys p ost last d ose of st u d y i nter ve nti o n
c.
Pr oce d ures t o be perf or me d as s o o n as practicall y p ossi ble after decisi o n t o st o p st u d y i nter ve nti o n b ut sta y i n st u d y wit h c o nti n uati o n of sc he d ule d visits or per ma ne ntl y 
wit h dra w fr o m st u d y 
d.
Pr oce d ure perf or me d f oll o wi n g ≥4 h o ur fast, as part of site visit or se parate visit(s) t o I ma gi n g/ Ra di ol o g y facilit y; atte m pts t o be ma de t o perf or m pr oce d ures at t he sa me 
ti me of da y ± 2- h o urs
e.
Baseli ne assess me nt perf or me d bet wee n Visit 4/ Baseli ne a n d Da y 1; e n d -of -st u d y assess me nt perf or me d u p t o 2 da ys p ost last d ose of st u d y i nter ve nti o n
f.
Pr oce d ure perf or me d eit her at ti me of decisi o n t o st o p st u d y i nter ve nti o n if ≥2 4 wee ks p ost Da y 1 or at Wee k 4 8 w hile off st u d y i nter ve nti o n b ut c o nti n ui n g sc he d ule d visits 
g.
Pr oce d ures perf or me d o nl y if decisi o n t o st o p st u d y i nter ve nti o n b ut sta y i n st u d y wit h c o nti n uati o n of sc he d ule d visits or per ma ne ntl y wit h dra w fr o m st u d y was ma de 
≥2 4 wee ks p ost Da y 1
h.
F ull P E at Pre Q a n d S C R 1 i ncl u des ar m circ u mfere nce (at Pre Q) a n d hei g ht pl us waist circ u mfere nce (at Pre Q & S C R 1); ot her wise, brief P E f or o pe n A Es/a b n or mal 
la b orat or y tests, o nl y
i.
At Visit 4/ Baseli ne reflects si n gle- bli n d place b o; st arti n g D a y 1 reflects d o u ble-bli n d r a n d o mize d st u d y i nter ve nti o n wit h dis pe ns ati o n at eac h sc he d uled o n -site Visit 
t hr o u g h Wee k 4 0 
j.
Perf or me d at o n -site visits w he n st u d y i nter ve nti o n is ret ur ne d, o nl y ; of n ote, partici pa nts will n ot be offere d st u d y i nter ve nti o n p ost last sc he d ule d d ose
k.
C o m plete d b y partici pa nts, at h o me ( or o n -site) o n s p o ns or-pr o vi de d e P R O de vice at set fre q ue nc y (e g, o nce-a- da y o n selecte d da ys or o ver 1 4 -da y i nter val) as pr o m pte d b y 
de vice/site (see Ta ble 4 )
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
S o A -T a ble A 2: Bl o o d a n d Uri ne C ollecti o ns i n St u dy C 2 5 4 1 0 1 3
Visit I de ntifier
Pre Q
S C R 1
S C R 2
R u n-I n
B aseli ne
Tre at m e nt P h ase
[ All c ollecti o ns bef ore m or ni n g d ose of st u d y i nter ve nti o n ±c o n me ds, w he n 
a p plic a ble , exce pt t h ose state d s pecificall y as p ost d ose ]
F oll o w
- u p
I P D/ C o r St u d y D/C c
Wee ks
a R el ati ve t o D osi n g o n D a y 1
- 6
- 2
0
2
4
6
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 0
5 2 b
Visit #
0
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
O n -site ( x) [wit h Tele p h o ne ( T )b] visits
x 
x 
x
x or T
x 
x 
x 
x 
x 
x 
x 
x
T
x
T
x
T
x
T
x 
x
T
x
Bl o o d c ollecti o n (f oll o wi n g o ver ni g ht f ast of ≥8- h o urs) f or –
N o Bl o o d or Uri ne C ollecti o ns
N o Bl o o d or Uri ne C ollecti o ns
N o Bl o o d or Uri ne C ollecti o ns
N o Bl o o d or Uri ne C ollecti o ns
N o Bl o o d or Uri ne C ollecti o ns
N o Bl o o d or Uri ne C ollecti o ns
F S H (fe males o nl y), ser ol o g y ( H Bs A g, H C V A b, 
HI V), a1 -a ntitr y psi n, cer ul o plas mi n
x d
x d
% C D T
x d
x d
x d
x
x
x
He mat ol o g y, c he mistr y, c oa g ulati o n
x d
x d
x d
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x e
x
Pre g na nc y (fe males o nly )
x d
x d
x d
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x e
x
Tri gl yceri des, direct L D L -C, H D L -C, t otal c h olester ol
x d
x d
x d
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x e
x
H b A 1 C, Plas ma Gl uc ose
x d
x d
x d
x 
x 
x 
x 
x 
x 
x 
x 
x
Direct V L D L, A p o A 1, A p o B t otal, A p o B 1 0 0, A p o B 4 8, 
A p o C 3, A p o E
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
P C S K 9, plas ma i ns uli n, a di p o necti n, C K 1 8- M 3 0, 
C K 1 8 -M 6 5, Pr o C 3, Pr o C 6, E L F test, hs -C R P
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
Pre d ose P K - D G A T 2i a n d A C Ci f
x 
x
x 
x 
x
x
x
P ost d ose P K - D G A T 2i a n d A C Ci f,g
x g
x g
x g
x g
S p ot uri ne c ollecti o n f or –
Uri ne dr u g test
x d
x d
x d
Uri nal ysis (a n d micr osc o p y w he n a p pr o pri ate ) 
xd
x d
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x e
x
O n -site pre g na nc y test ( W O C B P o nly )
x h
x h
x h
x h
x h
x h
x h
x h
x h
x h
x h
x 
x 
x e
x
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
S o A -T a ble A 2: Bl o o d a n d Uri ne C ollecti o ns i n St u dy C 2 5 4 1 0 1 3
Visit I de ntifier
Pre Q
S C R 1
S C R 2
R u n-I n
B aseli ne
Tre at m e nt P h ase
[ All c ollecti o ns bef ore m or ni n g d ose of st u d y i nter ve nti o n ±c o n me ds, w he n 
a p plic a ble , exce pt t h ose state d s pecificall y as p ost d ose ]
F oll o w
- u p
I P D/ C o r St u d y D/ Cc
Wee ks
a R el ati ve t o D osi n g o n D a y 1
- 6
- 2
0
2
4
6
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 0
5 2 b
Visit #
0
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
a.
Defi ne d relati ve t o Da y 1 wit h per mitte d ± 4- da y wi n d o w f or eac h visit starti n g at Visit 4/ Baseli ne; f or e xa m ple: Wee k -2 = 1 4 ( ± 4) da ys bef ore Da y 1; Wee k 4 = 2 8 ( ± 4) da ys 
p ost Da y 1
b.
R u n -I n Visit re q uire d t o be o n site if c ha n ges t o bac k gr o u n d me dicati o ns are bei n g ma de – ot her wise, R u n -I n Visit per mitte d as a tele p h o ne c o ntact o n t he sa me d a y  or u p t o 4
da ys p ost c o n d uct of S C R 2 li ver bi o ps y; p ost r a n d o miz ati o n , tele p h o ne c o ntact vi sits ca n be s witc he d t o o n-site visits f or f oll o w u p of T E A Es a n d/ or a b n or mal la b orat or y 
tests; Wee k 5 2 visit at ≥2 8 - a n d ≤3 5 - da ys p ost last d ose of st u d y i nter ve nti o n
c.
Pr oce d ures t o be perf or me d as s o o n as practicall y p ossi ble after decisi o n t o st o p st u d y i nter ve nti o n b ut sta y i n st u d y wit h c o nti n uati o n of sc he d ule d visits or per ma ne ntl y 
wit h dra w fr o m st u d y 
d.
Test res ults t o be re vie we d b y me dicall y q ualifie d site staff a n d dee me d acce pta ble bef ore pr o gressi o n t o ne xt visit; f or e xa m ple: Pre Q res ults m ust b e re vie we d pri or t o 
c o n d uct of S C R 1
e.
C ollecti o ns t o occ ur o nl y if visit is a n o n-site visit; c ollecti o ns t o be s ki p pe d if visit is via tele p h o ne c o ntact
f.
I n a d diti o n t o bl o o d c ollecti o n, date a n d ti me of bl o o d dra w a n d date/ti me of pre vi o us t w o d oses pri or to eac h bl o o d dra w relate d t o P K t o be ca pt ure d as part of sites’ s o urce 
d oc u me nts 
g.
C ollecti o n t o occ ur bet wee n 0. 5 - 1. 5 h o urs p ost d ose (at Wee k 2 a n d Wee k 8 visits), bet wee n 1. 5-2. 5 h o urs p ost d ose (at Wee k 1 2 visit), a n d bet wee n 3 -8 h o urs p ost d ose (at 
We e k 1 6 visit)
h.
At eac h of t hese visits, test res ults t o be re vie we d b y a me dicall y q ualifie d site staff a n d dee me d acce pta ble t o c o nti n ue pa rtici pati o n i n st u d y
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
2. I N T R O D U C TI O N
T he c urre nt st u d y  ai ms t o e val uate t w o, orall y a d mi nistere d, i n vesti gati o nal a ge nts –
P F - 0 6 8 6 5 5 7 1, a s mall m olec ule t hat selecti vel y i n hi bits D G A T 2 a n d t he c oa d mi nistrati o n of 
P F - 0 6 8 6 5 5 7 1 wit h P F -0 5 2 2 1 3 0 4, a selecti ve, re versi ble, i n hi bit or of A C C , f or t he treat me nt 
of N A S H wit h li ver fi br osis. I n t he cli nical pr o g ra m, t his is t he first st u d y t o e val uate t he 
st u d y i nter ve nti o ns i n partici pa nts wit h bi o ps y-pr o ve n N A S H wit h fi br osis sta ge 2 or 3
(referre d t o as F 2 or F 3), as assesse d by s p o ns or -i de ntifie d ce ntral pat h ol o gist(s), usi n g t he 
N A S H C R N defi niti o n . I n t his d oc u me nt, t he c o m p o u n ds are referre d t o as D G A T 2i (f or 
P F -0 6 8 6 5 5 7 1) or D G A T 2i + A C Ci (f or P F-0 6 8 6 5 5 7 1 w he n c oa d mi nistere d wit h 
P F -0 5 2 2 1 3 0 4). 
D G A Ts catal y ze t he ter mi nal ste p i n tri gl yceri de s ynt hesis; s pecificall y , t he esterificati o n of 
a fatty aci d wit h D A G res ulti n g i n t he f or mati o n of tri glyc eri de.1 I n ma m mals, 2 str uct urall y 
u nrelate d D G A T e nz y m es ( D G A T 1 a n d D G A T 2) ha ve bee n c haracterize d. D G A T 1 is hi g hl y 
e x presse d i n t he i ntesti ne a n d pla y s a ce ntral r ole i n fat a bs or pti o n 2 w hereas D G A T 2 is 
hi g hl y e x p resse d i n li ver a n d a di p ose.3 D G A T 2i is p ost ulate d t o decrease he patic tri glyc eri de
s ynt hesis a n d he patic li pi d b ur de n i n N A F L D a n d N A S H. Base d o n o bser vati o ns i n 
n o ncli nical st u dies c o n d ucte d, it is h y p ot hesize d t hat D G A T 2i will i m pact b ot h p h y si ol o gical 
dri vers c o ntri b uti n g t o N A S H via direct i n hi biti o n of li ver tri gl yc eri de s y nt hesis, as well as 
a da pti ve res p o nses lea di n g t o re d ucti o n i n he patic D N L. F oll o wi n g 2 wee ks of d osi n g i n 
partici pa nts wit h N A F L D, D G A T 2i has bee n s h o w n t o re d uce li ver fat i n a d ose -res p o nsi ve 
ma n ner.
A C C is a bi oti n car b o x yl ase t hat catal yzes t he A T P de pe n de nt c o n de nsati o n of acet yl -C o A 
a n d car b o nate t o f or m mal o n y l-C o A. 4 I n hi biti o n of A C C sti m ulates fatt y aci d o xi dati o n, 
s u p presses he patic D N L, a n d re d uces steat osis i n a ni mal m o dels a n d i n h u ma ns. 5 A C Ci has 
bee n s h o w n t o decrease he patic D N L (i n healt h y partici pa nts f oll o wi n g 1 4 -da y s of d osi n g), 
re d uce li ver steat osis (i n partici pa nts wit h N A F L D), as well as re d uce mar kers of li ver 
i nfla m mati o n ( A L T, A S T) a n d mar kers of a p o pt otic acti vit y ( C K 1 8-M 3 0 a n d C K 1 8 - M 6 5), i n 
partici pa nts wit h pres u me d N A S H f oll o wi n g 1 6 w ee ks of d osi n g. H o we ver, t hese p ote ntiall y 
be neficial effects, i n partici pa nts wit h N A F L D/ pres u me d N A S H, were acc o m pa nie d wit h 
mar ke d ele vati o ns i n faste d ser u m tri gl yceri des , a k n o w n c o nse q ue nce of he patic A C C 
i n hi biti o n5, a n d ot her li pi d para meters (ie, re d ucti o ns i n direct L D L-C, H D L -C, 
a p oli p o pr otei n A 1 al o n g wit h i ncreases i n n o n -H D L , V L D L, a p oli p o pr otei n B, C 3, a n d E, 
a n d n o c ha n ge i n t otal c h olester ol) w hic h pr o hi bit a d mi nistrati o n of A C Ci al o ne. I n 
n o ncli nical m o del of N A F L D/ N A S H, c oa d mi nistrati o n of D G A T 2i + A C Ci has bee n s h o w n 
t o be m ore efficaci o us at l o weri n g he patic steat osis, a n d re d uci n g i nfla m mati o n a n d fi br osis 
e n d p oi nts, t ha n eit her D G A T 2i or A C Ci al o ne. I n a d diti o n, c oa d mi nistrati o n of 
D G A T 2i + A C Ci f ull y re verse d t he i ncreases i n circ ulati n g tri glyc eri des o bser ve d wit h A C Ci 
al o ne – o verc o mi n g t he k n o w n mec ha nistic c o nse q ue nce of he patic A C Ci t h o u g ht t o be a 
res ult of ster ol re g ulat or y ele me nt bi n di n g pr otei n acti vati o n. Cli nicall y , t he effect of A C Ci 
al o ne o n ser u m tri gl yceri des has bee n s h o w n t o be miti gate d f oll o wi n g 6 -wee k of d osi n g of 
D G A T 2i + A C Ci i n partici pa nts wit h N A F L D – w hile mai ntai ni n g effecti ve re d ucti o n i n 
he patic steat osis.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
It is a ntici pate d t hat via c oa d mi nistrati o n of D G A T 2i + A C Ci , he patic li pi d meta b olis m will 
be m o d ulate d i n disti nct a n d c o m ple me ntar y  w a ys, p ote ntiall y res ulti n g i n greater efficac y 
t ha n D G A T 2i a d mi nistere d al o ne. D G A T 2i al o ne a n d D G A T 2i + A C Ci are c urre ntl y bei n g 
de vel o pe d f or t he treat me nt of N A S H wit h li ver fi br osis. A C Ci al o ne is n ot pla n ne d f or 
e val uati o n i n t his st u d y gi ve n t he a ntici pate d a d verse d o w nstrea m c o nse q ue nce of i n hi biti n g 
he patic D N L i ncl u di n g t he alrea d y i de ntifie d a d verse reacti o n of ele vate d ser u m tri gl yc eri de 
a n d acc o m pa n yi n g c ha n ges i n ot her li pi d para meters w hic h are u n desira ble gi ve n t heir 
p ote ntial i m plicati o ns f or l o n g ter m car di o meta b olic healt h u nless s ufficie ntl y  miti gate d 
es peciall y c o nsi deri n g t he p o p ulati o n wit h N A S H alrea d y m a y  ha ve u n derl y i n g d ysli pi de mia 
a n d are at a n i ncrease d car di o vasc ular ris k. 6
2. 1. St u d y R ati o n ale 
T he c urre nt st u d y  is t he first cli nical trial s pecificall y desi g ne d t o e val uate t he effect of t w o, 
orall y  a d mi nistere d, i n vesti gati o nal a ge nts – D G A T 2i al o n e, a d mi nistere d BI D, a n d 
D G A T 2i + A C Ci a d mi nistere d BI D (c o m pare d t o place b o) – o n res ol uti o n of N A S H or 
i m pr o ve me nt i n li ver fi br osis, as assesse d hist ol o gicall y ( via li ver bi o psy) . A d diti o nall y , 
e x pl orat or y assess me nt of n o n-i n vasi ve i ma gi n g-base d a n d bl o o d - base d c ollecti o ns are 
pla n ne d t o e na ble p ote ntial i de ntificati o n of n o n -i n vasi ve mar kers of disease a n d/ or treat me nt 
res p o nse – i n t he tar get a d ult p o p ulati o n.
T he st u d y  i ncl u des a n e val uati o n of d ose -ra n gi n g, d ose-fi n di n g wit h t he st u d y i nter ve ntio n 
ad mi nistere d orall y, t wice -dail y f or u p t o 4 8 wee ks , wit h t he partici pa nts ra n d o mize d t o 1 of 
9 ( Ori gi nal P r ot oc ol) or 1 of 7 ( Pr ot oc ol A me n d me nt 1 ) treat me nt ar ms. Partici pa nts will be 
assi g ne d d o u ble -bli n d, d o u ble -d u m m y  a d mi nistrati o n of place b o, 1 of u p t o 6 d oses/ d osi n g 
re gi me ns of D G A T 2i al o ne, or 1 of 2 d ose-le vels of D G A T 2i + A C Ci – refer t o Ta ble 3 . T h e
pri mar y  o bjecti ve i ncl u des e val uati o n of t he effect of D G A T 2i a n d D G A T 2i + A C Ci o n li ver 
hist ol o g y  wit h a ke y sec o n dar y o bjecti ve bei n g c haracterizati o n of t he safet y/t olera bility i n 
t he tar get p o p ulati o n – ie, partici pa nts wit h bi o ps y-pr o ve n N A S H wit h F 2 or F 3 fi br osis, as 
assesse d b y s p o ns or -i de ntifie d ce ntral pat h ol o gist(s). T he o bser ve d data fr o m t his st u d y , 
c o m bi ne d wit h t he t otalit y of t he data ge nerate d i n t he pr o gra m, will be utilize d t o refi ne 
d ose(s), a n d d osi n g re gi me ns t o ta ke f or war d i nt o P has e 3.
2. 2. B ac k gr o u n d 
T he W orl d Gastr oe nter ol o g y Or ga nizati o n lists N A F L D a n d N A S H as t he m ost i m p orta nt 
c o n diti o ns c o ntri b uti n g t o t he gl o bal healt h b ur de n d ue t o li ver diseases, wit h N A S H 
ac k n o wle d ge d as a p ote ntiall y  fatal c o n diti o n lea di n g t o cirr h osis, li ver fail ure, a n d H C C. 6
N A S H is dia g n ose d cli nicall y  b y li ver bi o ps y de m o nstrati n g steat osis, i nfla m mati o n, a n d 
c yt ol o gical ball o o ni n g of li ver he pat oc ytes, ofte n wit h var yi n g de grees of fi br osis. N A S H 
pr o gresses wit h i ncreasi n g se verit y of fi br osis, wit h cirr h osis de vel o pi n g i n a s u bset of 
partici pa nts 7 a n d a c o m m o n c o m plicati o n of cirr h osis bei n g H C C. 8 N A S H is a s u bset of 
N A F L D ( defi ne d as prese nce of ≥5 % he patic steat osis i n t he a bse nce of ot her li ver disease 
eti ol o gies) 9 ,1 0 t hat is ass ociate d wit h i ncrease d all-ca use m ortalit y, cirr h osis a n d e n d sta ge 
li ver disease, i ncrease d car di o vasc ular m ortalit y, a n d i ncrease d i nci de nce of b ot h li ver relate d 
a n d n o n -li ver relate d ca ncers.7 ,8 Patie nts wit h N A S H ma y  be asy m pt o matic or ha ve 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
n o n ‑s pecific sy m pt o ms s uc h as fati g ue, des pite ha vi n g si g nifica nt disease o n li ver bi o ps y  a n d 
ass ociate d ris k f or p r o gressi o n t o cirr h osis a n d li ver‑relate d m ortalit y.
I n a meta-a nal ys is, t he gl o bal pre vale nce of N A F L D was esti mate d at 2 5 %, wit h t he 
pre vale nce of N A S H i n t he s u bset wit h bi o ps y -pr o ve n N A F L D assesse d at 5 9 %. 9 T he 
maj orit y  of t he p o p ulati o n wit h N A F L D has si m ple steat osis w hic h has, i n ge neral, a be ni g n 
cli nical c o urse. A pr o p orti o n of partici pa nts wit h N A F L D pr o gress t o ha vi n g he pat ocell ular 
ball o o ni n g a n d l o b ular i nfla m mati o n – ta ki n g cl ose t o a deca de t o pr o gress fr o m 1 sta ge t o 
t he ne xt a n d 3 0- 4 0 ye ars t o de vel o p cirr h osis; h o we ver, a s maller s u bset of partici pa nts 
pr o gress ver y  ra pi dl y ( wit hi n 1 0 years) t o li ver cirr h osis fr o m N A F L D. 9 Patie nts wit h N A S H 
ma y  be asy m pt o matic or ha ve n o n-s pecific s y m pt o ms s uc h as fati g ue, des pite ha vi n g 
si g nifica nt disease o n li ver bi o ps y a n d ass ociate d ris k f or pr o gressi o n t o cirr h osis a n d 
liver -relate d m ortalit y. T he 5-year ( 6 7 %) a n d 1 0 -ye ar ( 3 8 %) s ur vi val rates i n partici pa nts 
wit h N A S H is si g nifica ntl y  differe nt t ha n i n t h ose wit h N A F L D.6 T he p o ole d li ver -s pecific 
a n d o verall m ortalit y i nci de nce rate esti mates a m o n g t h ose wit h N A F L D were calc ulate d at 
0. 8 a n d 1 5. 4, res pecti vel y , per 1, 0 0 0 pers o n - years. In c o ntrast, a m o n gst t he p o p ulati o n wit h 
N A S H, t he i nci de nce rate esti mates were 1 1. 8 (li ver-s pecific) a n d 2 5. 6 ( o verall) m ortality. 9
Ele vate d rates of he patic D N L ha ve bee n re p orte d t o be a disti ncti ve c haracteristic of 
N A F L D. 1 0 Cli nicall y , t h ose wit h ele vate d li ver fat s h o we d a m ore t ha n 3-f ol d i ncrease i n t he 
rate of he patic D N L relati ve t o partici pa nts wit h n or mal li ver fat, b ut n o differe nces bet wee n 
t he gr o u ps were detecte d i n a di p ose F F A fl u x or i n pr o d ucti o n of V L D L fr o m F F As. 
F urt her m ore, as e xe m plifie d b y  ot her meta b olic dis or ders (e g, t yp e 2 dia betes, d y sli pi de mias, 
etc), it is p ossi ble t hat a si n gle dr u g ma y be i ns ufficie nt t o s uccessf ully treat N A S H a n d 
t heref ore, c o m bi nati o n t hera py is bei n g c o nsi dere d as a n earl y i nter ve nti o n strate g y . 
M ore o ver, it is u n k n o w n if t he effect o bser ve d o n li ver fat will tra nslate t o cli nicall y  
mea ni n gf ul i m pr o ve me nt i n hist ol o gical e n d p oi nts o n bi o ps y . As desi g ne d, t his pr ot oc ol 
per mits testi n g c oa d mi nistrati o n of D G A T 2i + A C Ci w hic h is a ntici pate d t o m o d ulate 
he patic li pi d meta b olis m i n disti nct a n d c o m ple me ntar y  w a ys, s u g gesti n g t hat 
c oa d mi nistrati o n ma y pr o vi de greater efficac y t ha n D G A T 2i al o ne w hile miti gati n g t he 
o bser ve d ele vati o ns i n ser u m tri gl yc eri des (a n d ot her a d verse li pi d-relate d c ha n ges) o bser ve d 
wit h A C Ci al o ne.
2. 2. 1. N o ncli nic al O ver vie w 
D G A T 2i a n d A C Ci ha ve eac h i n di vi d uall y bee n e va l uate d i n a c o m pre he nsi ve n o ncli nical 
safety pac ka ge t hat i ncl u de d 
 a n d 
 t o xicit y st u dies u p t o 
a n d 
m o nt hs d urati o n, res pecti vel y , a n d i n re pr o d ucti ve a n d de vel o p me ntal t o xic ol o g y st u dies i n 
 a n d  
, a n d t o get her (ie, D G A T2i + A C Ci) i n c o m bi nati o n t o xicit y  st u dies i n 
 u p t o 
wee ks i n d urati o n.
F or D G A T 2i al o ne,  
 fi n di n gs were i de ntifie d i n  
 or 
. At 
t he N O A E L i n t he 
 st u d y i n 
, e x p os ure mar gi ns relati ve t o a 
hi g hest cli nical d ose of 3 0 0 m g BI D were  
 a n d  
 t he  
 h u ma n C ma x a n d 
A U C 2 4, res pecti vel y. At t he N O A E L i n t he 
 st u d y i n 
, e x p os ure mar gi ns were 
 a n d 
 t he  
 h u ma n C ma x a n d A U C 2 4, 
res pecti vel y.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
F or A C Ci al o ne, all a d verse fi n di n gs were relate d t o t he
 
 
. At t he N O A E L i n t he 
 st u d y i n 
, e x p os ure mar gi ns relati ve t o t he hi g hest cli nical d ose of 
m g / da y 
( wit h m ost c o nser vati ve Q D d osi n g a n d mar gi ns f or Cma x ) were  
 a n d  
, t he pre dicte d 
h u ma n  
 C ma x a n d A U C 2 4, res pecti vel y, a n d at t he N O A E L i n t he 
 st u d y i n 
 e x p os ure mar gi ns were  
 a n d  
 t he pre dicte d  
 h u ma n C ma x a n d A U C 2 4, 
res pecti vely.
D G A T 2i + A C Ci were e val uate d i n 
 t o xicit y st u dies u p t o 
 
d urati o n. All fi n di n gs were attri b ute d t o 
 were i de ntifie d 
i n 
 a d mi nistere d D G A T 2i + A C Ci. E x p os ure mar gi ns i n t he 
 st u d y i n 
 relati ve t o a D G A T 2i cli nical d ose of 
 were  
 a n d  
, 
t he pre dicte d h u ma n  
 C ma x a n d A U C 2 4, res pecti vel y, a n d e x p os ure mar gi ns relati ve 
t o a A C Ci cli nical d ose of 
 m g/ da y ( wit h m ost c o nser vati ve Q D d osi n g a n d mar gi ns f or 
C ma x ) were  
 a n d  
 t he pre dicte d  
 h u ma n Cma x a n d A U C 2 4, res pecti vely.
2. 2. 2. Cli nic al O ver vie w
As of t he iss u a nce of t his Pr ot oc ol A me n d me nt 1 , acr oss t he cli nical st u dies c o m plete d wit h 
D G A T 2i al o ne (
st u dies), A C Ci al o ne ( 
 st u dies) a n d D G A T 2i + A C Ci ( 
 st u dies), 
u ni q ue partici pa nts ha ve bee n ra n d o mize d, wit h 
 (
%) e x p ose d t o place b o, 
 
(
%) e x p ose d t o D G A T 2i al o ne, 
 (
%) e x p ose d t o A C Ci al o ne, 
(
%) e x p ose d t o 
D G A T 2i + A C Ci , 
 
%) e x p ose d t o D G A T 2i + metf or mi n, a n d 
(
%) e x p ose d t o 
metf or mi n al o ne . D G A T 2i al o ne has bee n e val uate d as si n gle oral d oses u p t o 1 5 0 0 m g, 
re peate d d oses u p t o 1 8 0 0 m g/ da y (a d mi nistere d Q 8 H) f or u p t o 1 4 d a y s, a n d re peate d d oses 
of 6 0 0 m g/ da y  (a d mi nistere d Q 1 2 H) f or u p t o 6 wee ks. A C Ci al o ne has bee n a d mi nistere d at 
si n gle, oral d oses u p t o 2 4 0 m g, re peate d ( ≤1 4 -da y s) d oses u p t o 2 0 0 m g/ da y (a d mi nistere d 
Q D a n d Q 1 2 H), a n d r e peate d (≤1 6 wee ks) d oses u p t o 5 0 m g/ da y  (a d mi nistere d Q D).
D G A T 2i + A C Ci has bee n e val uate d at a si n gle c oa d mi nistere d d ose le vel of 3 0 0 m g BI D 
( D G A T 2i) + 1 5 m g BI D ( A C Ci).
D G A T 2i al o ne or as D G A T 2i + A C Ci has bee n e val uate d i n
P hase 1 st u dies i n a d ults ( wit h 
 partici pa nts ra n d o mize d) a n d  
 st u dies (
P hase 1 b a n d
P hase 2a) i n partici pa nts 
wit h N A F L D ( wit h 
ra n d o mize d). A C Ci al o e has bee n e val uate d i n  
 P hase 1 st u dies 
i n a d ults (wit h  
 partici pa nts ra n d o mize d) a n d o ne P hase 2a, d ose -ra n gi n g st u dy i n 
partici pa nts wit h N A F L D ( n = 3 0 5, ra n d o mize d i ncl u di n g n = 2 0 8 wit h pres u me d N A S H). 
A d mi nistrati o n of D G A T 2i al o ne has bee n f o u n d t o be
 
 U p o n re peate d a d mi nistrati o n of 
D G A T 2i, acr oss t he 2 0 -f ol d d ose ra n ge e val uate d (ie, 9 0 t o 1 8 0 0 m g/ da y), T E A Es re p orte d 
i n ≥ partici pa nts acr oss all ar ms e val uate d were hea dac he (
%), diarr hea 
%), fati g ue 
(
%), pr urit us (
%), a b d o mi nal pai n 
%), a nd na usea (
%). U p o n re peate d a d mi nistrati o n of 
A C Ci, acr oss a 1 0 0 -f ol d d ose ra n ge e val uate d (ie, 2- t o 2 0 0- m g/ da y ), t he all-ca usalit y 
T E A Es re p orte d i n ≥
% of partici pa nts were hea dac he 
%), diarr h oea (
%), 
h y pertri gl y ceri dae mia 
%), a n d na usea 
%).
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
Gi ve n D G A T 2i is a 
, as 
e x pecte d, 
 
 were n ote d. D osi n g wit h A C Ci al o ne res ulte d i n
 
 
refer t o Secti o n 2. 3. 1. C oa d mi nistrati o n of D G A T 2i + A C Ci has bee n s h o w n t o  
 
 t o eit her a ge nt a d mi nistere d al o ne. H o we ver, o n 
a vera ge, D G A T 2i + A C Ci has bee n s h o w n t o miti gat e t he A C Ci-i n d uce d ele vati o ns i n ser u m 
tri glyceri des, A p o C 3, a n d n o n -H D L . No a p pare nt a b n or malities were n ote d i n ot her 
safety -relate d assess me nts s uc h as 
 
wit h D G A T 2i, A C Ci, a n d D G A T 2i + A C Ci . 
U p o n re peate d d osi n g of D G A T 2i wit h sta n dar d meals, C ma x was ac hie ve d at
 
p ost d ose . Stea d y-state plas ma c o nce ntrati o ns were ac hie ve d b y 
, a n d t he mea n 
ter mi nal 
 D osi n g i n t he faste d state res ulte d i n l o wer e x p os ures 
(ie, 
 a n d 
 t ha n w he n a  
 m g D G A T 2 i d ose was 
a d mi nistere d wit h a sta n dar d meal). F oll o wi n g oral d osi n g of A C Ci wit h a hi g h -fat/ hi g h-
cal oric meal , Cma x wa s ac hie ve d at
 p ost-d ose, a n d t he mea n ter mi nal 
 T here was 
 o n e x p os ure wit h d osi n g of A C Ci 
i n t he faste d vers us fe d state. C oa d mi nistrati o n of D G A T 2i (
) a n d A C Ci (
 
) has bee n s h o w n t o res ult i n a sli g ht  
 i n t he s yste mic e x p os ure of A C Ci – wit h 
a dj uste d ge o metric mea n ( 9 0 % CI) of
 (f or Cma x ) a n d 
 
 (f or A U Cta u). T here was 
 o n t he s yste mic e x p os ure of D G A T 2i, w he n 
c oa d mi nistere d wit h A C Ci, wit h a dj uste d ge o metric mea n 
 (f or Cma x a n d A U C ta u). 
2. 3. Be nefit/ Ris k Assess me nt
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es wit h D G A T 2i al o ne, D G A T 2i + A C Ci, a n d A C Ci al o ne ca n be f o u n d i n t he I B 
f or D G A T 2i a n d 
f or A C Ci, w hic h will ser ve as t he 
S R S Ds f or t his st u d y . 
A hi g h le vel s u m mar y  of p ote ntial ris ks as well as be nefits are offere d i n Secti o n 2. 3. 1 a n d 
Secti o n 2. 3. 2 , bel o w. 
P ote nti al Ris k of 
Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or Ris k
Miti g ati o n Str ate g y
St u d y I nter ve nti o n – D G A T 2i
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
P ote nti al Ris k of 
Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or Ris k
Miti g ati o n Str ate g y
St u d y I nter ve nti o n – A C Ci ( as p art of D G A T 2i + A C Ci )
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
P ote nti al Ris k of 
Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or Ris k
Miti g ati o n Str ate g y
St u d y Pr oce d ures
C o n d uct of u p t o 2 li ver 
bi o psies d uri n g st u d y 
Pr oce d ure is relati vel y safe wit h < 1 % 
ris k of maj or c o m plicati o ns1 1; p ote ntial 
ris ks i ncl u de –

I ncrease d a n xiet y – es peciall y wit h 
2 n d bi o ps y 

Pai n w hic h ca n last f or da ys p ost 
pr oce d ure

Blee di n g fr o m nee dle bi o ps y site 

Per m itti n g pre-pr oce d ure use of 
a n xi ol ytics t o ma na ge a n xiet y 

All o wa nce f or use of a nal gesics f or
p ost pr oce d ure pai n ma na ge me nt 

St u d y re q uire me nt of p ost-
pr oce d ure cl ose o bser vati o n peri o d 
of at least 2 -4 h o urs f or a n y 
a b d o mi nal s y m pt o ms, br uisi n g, 
pl us a v oi di n g hea v y lifti n g f or ≥4 8 
h o urs p ost pr oce d ure

After 1 st bi o ps y a n d bef ore 
ra n d o mizati o n, acti vel y elicit
partici pa nts ’ willi n g ness t o 
u n der g o 2 n d bi o ps y
C o n d uct of 4 
M RI -P D F F assess me nts 
d uri n g st u d y 
(i n 5 0 % of partici pa nts 
i n I ma gi n g s u b-st u d y)
Pr oce d ure is relati vel y safe; p ote ntial 
ris k f or n o n- e val ua ble i ma ges i ncl u de –

T o o m uc h m oti o n, f or e xa m ple, d ue 
t o i ncrease d a n xiet y, cla ustr o p h o bia

Ferric i m pla nts/ de vices, 
para ma g netic o bjects w it hi n/ o n 
b o d y, ferric -c o ntai ni n g tatt o os i n 
area of i nterest (a b d o me n, c hest, 
ar ms)

Per m itti n g pre-pr oce d ure use of 
a n xi ol ytics t o ma na ge a n xiet y 

E xcl u di n g partici pa nts, fr o m 
I ma gi n g s u b -st u d y, if t he y ha ve 
c o ntrai n dicati o ns f or M RI

Clear c o m m u nicati o n via I C D of 
pre parati o n f or eac h visit 
i ncl u di n g d urati o n of fast bef ore 
pr oce d ures/ visits
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
P ote nti al Ris k of 
Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or Ris k
Miti g ati o n Str ate g y

Mi ni m u m d urati o n of a pri ori fast 
n ot f oll o we d 
Ot her F act ors P ote nti all y I m p acti n g St u d y Res ults
Eli gi ble p o p ulati o n m ust 
ha ve N A S H (ie, t otal 
N A S sc ore ≥4 w it h ≥1 
sc ore f or steat osis, 
i nfla m mati o n, a n d 
ball o o ni n g pl us fi br osis 
sta ge of eit her F 2 or F 3)
Assess me nt of pri mar y e n d p oi nt c o ul d 
be p ote ntiall y c o m pr o mise d if n o n -
eli gi ble p o p ulati o n is ra n d o mize d 

Tria ge strate g y wit h d o u ble -
c o nfir m ati o n via n o n -i n vasi ve 
tests1 2 use d as part of eli gi bilit y t o 
c o nfir m pres u me d N A S H stat us 
bef ore pr ocee di n g wit h 
scree ni n g/ baseli ne li ver bi o ps y

Sta n dar dizati o n of bi o ps y 
ac q uisiti o n, pr ocessi n g, stai ni n g 
e mpl o y e d t o e ns ure e val ua ble 
tiss ue (li mit n o n-e val ua ble tiss ue 
sa m ple c ollecti o ns)

Deter mi nati o n of eli gi bilit y base d 
o n li ver bi o ps y ma de ce ntrall y b y 2 
pat h ol o gist s wit h c o nse ns us 
re q uire me nt bet wee n pat h ol o gists’ 
ma n dat or y 
D isti ncti o n of dr u g-
i n d uce d li ver i nj ur y 
fr o m disease-relate d 
baseli ne ele vati o ns i n 
L F Ts
P o p ulati o n eli gi ble li kel y t o ha ve 
ele vate d A L T a n d A S T (t h o u g h n ot 
Al kali ne p h os p hatase, t otal bilir u bi n)

St u d y re q uires d o u ble -c o nfir m ati o n
of sta ble A L T, A S T, al kali ne 
p h os p hatase (ie, ≤5 0 % 
varia bilit y 1 3) pl us t otal bilir u bi n 
≤U L N bef ore pr ocee di n g wit h 
scree ni n g/ baseli ne li ver bi o ps y
C oa d mi nistrati o n of D G A T 2i + A C Ci , base d o n c o m plete d t o xicit y st u dies i n  
 a n d 
 d oes 
 fi n di n gs a b o ve a n d 
 
 In St u d y  C 2 5 4 1 0 1 3, a n y a d verse cli nical i m pact of t he 
a b o ve fi n di n gs are e x pecte d t o de pe n d o n t he se verit y of t he p ote ntial reacti o n, a n d are 
mi ni mize d t hr o u g h – ( 1) t he pr o p ose d fre q ue nt visits t o site t o per mit cl ose o versi g ht of 
partici pa nts’ safet y via me dical m o nit ori n g of a ra n ge of cli nical assess me nts i ncl u di n g 
safety-relate d la b orat or y tests, 1 2-lea d E C Gs, vitals, assess me nt of A Es; ( 2) i ncl usi o n of 
pr o visi o ns f or ma na ge me nt of gl yc e mic c o ntr ol ( refer t o A p pe n di x 1 0 ) a n d t he 
 
– na mel y , 
 (refer t o 
A p pe n di x 1 1 ) 
 (refer t o A p pe n di x 1 2 ); a n d ( 3) i nstit uti o n of an
E -D M C (refer t o Secti o n 9. 6 ) t o u n derta ke u n bli n de d, peri o dic re vie ws of t he safet y data, 
w hile t he st u d y  is o n-g oi n g, a n d ma ke rec o m me n dati o n(s) as t o w het her 1 or m ore ar ms 
s h o ul d be pa use d/ disc o nti n ue d a m o n gst t he pla n ne d acti vities.
2. 3. 2. Be nefit Assess me nt
T he c urre nt st u d y is t he first ti me t hat D G A T 2i a n d D G A T 2i + A C Ci is bei n g a d mi nistere d 
t o t he tar get p o p ulati o n – ie, t h ose wit h bi o ps y-c o nfir me d N A S H a n d li ver fi br osis sta ge of 
F 2 or F 3 , as assesse d by s p o ns or-i de ntifie d ce ntral pat h ol o gist(s). F or t he partici pa nts of t his 
st u d y, cl ose m o nit ori n g of t heir me dical c o n diti o n a n d safety will occ ur as o utli ne d i n t his 
pr ot oc ol. I n t he Ori gi nal P r ot oc ol, f or e ver y 9 partici pa nts ra n d o mize d, 8 w h o recei ve 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
D G A T 2i or D G A T 2i + A C Ci ma y  p ote ntiall y deri ve be nefit fr o m t he desire d p har mac ol o g y, 
na mel y , re versal of he patic steat osis , decrease i n he patic i nfla m mati o n a n d i m pr o ve me nt i n 
he patic fi br osis. F oll o wi n g i m ple me ntati o n of Pr ot oc ol A me n d me nt 1 , f or e ver y 7
partici pa nts ra n d o mize d, 6 w h o recei ve D G A T 2i or D G A T 2i + A C Ci ma y  p ote ntiall y deri ve 
be nefit. T h ose ra n d o mize d t o place b o ( 1 i n e ver y 9 [ Ori gi nal P r ot oc ol] or 1 i n e ver y  7
[Pr ot oc ol A me n d me nt 1 ] partici pa nts) are n ot e x pecte d t o o btai n a n y s pecific be nefit, be y o n d 
cl ose m o nit ori n g of t heir me dical c o n diti o n a n d safet y . All partici pa nts will recei ve ge neral, 
sta n dar d- of-care g ui da nce/c o u nseli n g re gar di n g t he o verall be nefits of diet/e xercise.
2. 3. 3. O ver all Be nefit/ Ris k C o ncl usi o n
Acc o u nti n g f or t he meas ures ta ke n t o mi ni mize ris k t o partici pa nts e nr olle d i n t his st u d y , t he 
p ote ntial ris ks i de ntifie d i n ass ociati o n wit h D G A T 2i a n d D G A T 2i + A C Ci are j ustifie d b y 
t he a ntici pate d be nefits t hat ma y be aff or de d t o partici pa nts wit h bi o ps y-pr o ve n N A S H wit h 
F 2 or F 3 fi br osis.
3. O B J E C TI V E S, E S TI M A N D S, A N D E N D P OI N T S
O bjecti ves
Esti m a n ds
E n d p oi nts
Pri m ar y: 
T o e val uate t he effect of a ra n ge 
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, i n p artici p a nts 
wit h bi o psy c o nfir me d N A S H 
a n d fi br osis, o n res ol uti o n of 
N A S H wit h o ut w orse ni n g of 
fi br osis or i m pr ove me nt i n 
fi br osis by ≥1 st a ge wit h o ut 
w orse ni n g of N A S H, or b ot h
Usi n g a c o m p osite esti ma n d strate g y i n 
partici pa nts wit h bi o ps y -c o nfir me d N A S H a n d 
fi br osis, esti mate t he treat me nt effect of D G A T 2i 
d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o 
D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of 
‘cli nical res p o n ders’, defi ne d as partici pa nts 
ac hie vi n g ce ntrall y a dj u dica te d: res ol uti o n of 
N A S H wit h o ut w orse ni n g of fi br osis or 
i m pr o ve me nt i n fi br osis b y ≥1 sta ge wit h o ut 
w orse ni n g of N A S H, or b ot h, at Wee k 4 8 a n d 
treati n g all cases of wit h dra wal fr o m treat me nt f or 
lac k of efficac y or t olerati o n as n o n-res p o n ders
All treat me nt effect c o ntrasts will be o btai ne d 
t hr o u g h fitti n g t he Ba yesia n d ose-res p o nse 
a n d/ or e x p os ure -res p o nse m o dels wit h a l o git 
tra nsf or mati o n, or l o gistic re gressi o n m o dels
Pr o p orti o n of partici pa nts 
ac hie vi n g res ol uti o n of N A S H 
wit h o ut w orse ni n g of fi br osis or
i m pr o ve me nt i n fi br osis b y ≥1 
sta ge wit h o ut w orse ni n g of N A S H 
or b ot h, base d o n assess me nt b y 
s p o ns or-i de ntifie d ce ntral
pat h ol o gist(s), at Wee k 4 8
Sec o n d ar y: 
T o e val uate t he effect of a ra n ge
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, o n liver f at
Usi n g a h y p ot hetical esti ma n d strate g y, i n 
partici pa nts wit h bi o ps y -c o nfir me d N A S H a n d 
fi br osis, esti mate t he treat me nt effect of D G A T 2i 
d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o 
D G A T 2i al o ne, i n ter ms of t he p o p ulati o n le vel 
a vera ge perce nt a ge c ha n ge fr o m baseli ne i n li ver 
fat (assesse d via M RI-P D F F) at Wee k 4 8 , 
ass u mi n g all partici pa nts ha d re mai ne d i n t he trial 
a n d recei ve d treat me nt as pla n ne d wit h o ut 
wit h dra wal u p t o 4 8 wee ks . E n d p oi nt data 
c ollecte d after treat me nt wit h dra wal will be 
cens ore d.
All treat me nt effect c o ntrasts will be o btai ne d 
t hr o u g h fitti n g t he Ba yesia n d ose-res p o nse 
Perce nt c ha n ge i n li ver fat 
(assesse d via M RI-P D F F i n 
s u bst u d y p o p ulati o n), at Wee k 4 8
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
O bjecti ves
Esti m a n ds
E n d p oi nts
a n d/ or e x p os ure -res p o nse m o dels, or 
A N C O V A m o dels
T o e val uate t he effect of a ra n ge 
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, i n p artici p a nts 
ac hievi n g i m pr ove me nt i n 
differe nt res p o n der defi niti o ns
Usi n g a c o m p osite esti ma n d strate g y i n 
partici pa nts wit h bi o ps y -c o nfir me d N A S H a n d 
fi br osis, esti mate t he treat me nt effect of D G A T 2i 
d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, r elati ve t o 
D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of 
‘cli nical res p o n ders’, defi ne d as partici pa nts 
ac hie vi n g ce ntrall y a dj u dicate d res ol uti o n of 
N A S H wit h o ut w orse ni n g of fi br osis at Wee k 4 8 
a n d treati n g all cases of wit h dra wal fr o m treat me nt 
f or lac k of efficac y or t olerati o n as n o n-res p o n ders
All treat me nt effect c o ntrasts will be o btai ne d 
t hr o u g h fitti n g t he Ba yesia n d ose-res p o nse 
a n d/ or e x p os ure -res p o nse m o dels wit h a l o git 
tra nsf or mati o n, or l o gistic re gressi o n m o dels
Si milar esti ma n ds will be asses se d f or:
I m pr o ve me nt i n fi br osis b y ≥1 sta ge, wit h o ut 
w orse ni n g of N A S H
I m pr o ve me nt i n fi br osis b y ≥2 sta ges, wit h o ut 
w orse ni n g of N A S H
I m pr o ve me nt of ≥2 p oi nts i n T otal N A F L D 
Acti vit y Sc ore ( N A S)
Pr o p orti o n of partici pa nts 
ac hie vi n g i m pr o ve me nt i n differe nt 
res p o n der defi niti o ns base d o n 
assess me nt b y s p o ns or -i de ntifie d 
ce ntral pat h ol o gist(s) at Wee k 4 8 –

Res ol uti o n of N A S H, wit h o ut 
w orse ni n g of fi br osis

I m pr o ve me nt i n fi br osis b y ≥1
sta ge, wit h o ut w orse ni n g of 
N A S H

I m pr o ve me nt i n fi br osis b y ≥2
sta ges, wit h o ut w orse ni n g of 
N A S H

I m pr o ve me nt of ≥2 p oi nts i n 
T otal N A S
T o assess t he s afety a n d 
t oler a bility wit h a ra n ge of 
D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne
Assess me nt of T E A Es, safet y-
relate d cli nical la b orat or y tests, 
vital si g ns, a n d 1 2 -lea d E C Gs, o ver 
ti me u p t o Wee k 4 8
Terti ar y/ E x pl or at or y: 
T o e val uate t he effect of a ra n ge 
of D G A T 2i d oses a d mi nistere d 
al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n 
of D G A T 2i + A C Ci relati ve t o 
D G A T 2i al o ne, i n partici pa nts 
wit h w orse ni n g of bi o ps y 
e n d p oi nt c o m p o ne n ts
Pr o p orti o n of partici pa nts wit h 
w orse ni n g i n li ver bi o ps y e n d p oi nt 
c o m p o ne nts base d o n assess me nt 
b y s p o ns or -i de ntifie d ce ntral
pat h ol o gist(s) at Wee k 4 8 –

Pr o gressi o n of fi br osis b y 
≥1 sta ge

W orse ni n g
of ≥2 p oi nts i n T otal 
N A S
F or all e n d p oi nts, baseli ne is defi ne d as t he e val ua ble res ult cl osest pri or t o d osi n g o n Da y 1/ Visit 5
A d diti o nal tertiar y /e x pl orat or y o bjecti ves a n d e n d p oi nts are liste d i n Secti o n 9. 4. 7 .
4. S T U D Y D E SI G N
4. 1. O ver all Desi g n
T his is a m ultice nter, m ulti nati o nal, ra n d o mize d, d o u ble -bli n d, d o u ble -d u m m y , place b o-
c o ntr olle d, d ose ra n gi n g/ fi n di n g, u p t o 9 -ar ms, parallel-gr o u p st u d y . T he st u d y i nter ve nti o ns 
i ncl u de place b o a d mi nistere d BI D, 4 acti ve d oses of D G A T 2i wit h t otal dail y d ose s plit a n d 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
a d mi nistere d BI D, 2 acti ve d oses of D G A T 2i wit h t otal dail y  d ose a d mi nistere d Q D i n t he 
O ri gi nal P r ot oc ol ( wit h d u m m y place b o for 2 n d d ose eac h da y  t o preser ve t he bli n d), a n d 
2 acti ve d oses of D G A T 2i + A C Ci a d mi nistere d BI D . D osi n g of all ar ms is acc o m m o date d 
via a d mi nistrati o n of 3 ta blets per d ose, BI D, a n d pr o p ose d usi n g blister pac ke d s u p plies t o 
mi ni mizi n g d osi n g err ors a n d e n ha nce c o m plia nce – refer t o Ta ble 3 i n Secti o n 6 ; wit h a n 
a d de d meas ure w herei n sp o ns or - pr o vi de d e P R O de vices t o be pr o vi de d t o eac h partici pa nt 
[refer t o Secti o n 8. 1. 3 ] will be a ut o -pr o gra m me d t o offer peri o dic re mi n ders t o e n ha nce 
c o m plia nce wit h d osi n g of st u d y i nter ve nti o ns.
Deter mi nati o n of eli gi bilit y will occ ur via a se q ue ntial, 2 -ste p pr ocess starti n g wit h Pre Q. 
Partici pa nts i de ntifie d t o be eli gi ble base d o n Pre Q will tra nsiti o n t o t he mai n st u d y (ie, 
S C R 1) . O nce c o nfir me d t o be eli gi ble base d o n t he n o n-i n vasi ve assess me nts, partici pa nts 
will pr o gress t o S C R 2 a n d u n der g o li ver bi o ps y. T he d o u ble -c o nfir m ati o n via n o n -i n vasi ve 
assess me nts (at Pre Q a n d S C R 1) will e na ble pr o gressi o n of o nl y t he selecte d s u bset of 
partici pa nts, m o re li kely t o ha ve bi o ps y-pr o ve n N A S H wit h F 2 -F 3 fi br osis o n bi o ps y , as 
assesse d b y s p o ns or -i de ntifie d ce ntral pat h ol o gist(s).
O nce c o nfir me d t o be eli gi ble, partici pa nts will be i nf or me d of t he scree ni n g/ baseli ne li ver 
bi o ps y  res ults at t he ne xt o n- site visit (ie, eit her R u n -I n/Visit 3 or Baseli ne/ Visit 4 ). If 
c ha n ges i n bac k gr o u n d me dicati o ns (eit her pr ot oc ol ma n date d or t o i m pr o ve disease 
ma na ge me nt) are pla n ne d, t he R u n -I n/ Visit 3 m ust be a n o n -site visit c o n d ucte d p ost 
a vaila bilit y of S C R 2 li ver bi o ps y res ults fr o m t he s p o ns or-i de ntifie d ce ntral la b orat ory.
S ta bilizati o n of c o nc o mita nt / bac k gr o u n d treat me nt(s) re q uire d f or at least 4-wee ks bef ore 
tra nsiti o n t o Baseli ne/ Visit 4 – refer t o Secti o n 6. 5 . A ll eli gi ble partici pa nts will c o m plete t he 
R u n -I n peri o d, f oll o we d b y Visit 4/ Baseli ne . 
O n D a y 1/ Visit 5, partici pa nts w h o meet ra n d o mizati o n criteria ( Secti o n 5. 3 ) will be assi g ne d
t o recei ve 1 of 9 ( Ori gi nal P r ot oc ol) or 1 of 7 ( Pr ot oc ol A me n d me nt 1 ) d o u ble -bli n d, d o u ble -
d u m m y  re gi me ns f or a d urati o n of u p t o 4 8 wee ks ( 3 3 6 ± 4 d a y s). 
A t otal of 2 2 visits (fr o m Pre Q t o 2n d f oll o w-u p visit) – e nc o m passi n g a c o m bi nati o n of o n-
site visits a n d tele p h o ne c o ntact s – are e n visi o ne d . F or a gi ve n partici pa nt , ti me i n t he st u d y 
ma y  ra n ge fr o m 62 wee ks ( mi ni m u m) t o p ote ntiall y  6 8 wee ks ( ma xi m u m) – refer t o Fi g ure 1 . 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
Fi g ure 1 .
O ver all St u d y Desi g n
A p pr o xi matel y  3 5 0 partici pa nts ( 5 0 per ar m) wit h bi o ps y  c o nfir me d N A S H wit h F 2-F 3 
fi br osis, as assesse d b y s p o ns or -i de ntifie d ce ntral pat h ol o gist(s) , will be ra n d o ml y  assi g ne d 
t o t he st u d y i nter ve nti o n t o e ns ure a p pr o xi matel y 2 8 0 e val ua ble partici pa nts ( 4 0 per ar m) 
offer e val ua ble data f or t he pri mar y  o bjecti ve of t he st u d y.
4. 2. Scie ntific R ati o n ale f or St u d y Desi g n
Re d ucti o n i n he patic steat osis wit h D G A T 2i al o ne, A C Ci al o ne, a n d D G A T 2i + A C Ci ha ve 
bee n s h o w n i n partici pa nts wit h N A F L D wit h d osi n g of t he i nter ve nti o n f or as little as 
2 wee ks ( D G A T 2i al o ne) a n d 6 wee ks ( D G A T 2i al o ne pl us D G A T 2i + A C Ci ), a n d u p t o 
1 6 wee ks ( wit h A C Ci al o ne). Tra nslati o n of effect o n li ver steat osis t o hist ol o gical 
i m pr o ve me nt i n N A S H or li ver fi br osis is t he pri mar y f oc us of t he c urre nt st u d y a n d he nce 
t he pri mar y e n d p oi nt is pr o p ose d as pr o p orti o n of partici pa nts ac hie vi n g N A S H res ol uti o n 
( wit h o ut w orse ni n g fi br osis) or i m pr o ve me nt i n fi br osis ( wit h o ut w orse ni n g N A S H) or b ot h. 
Ac k n o wle d gi n g t he pri mar y  p har mac ol o g y of D G A T 2i a n d D G A T 2i + A C Ci tar gets he patic 
li pi d s y nt hesis h yp ot hesize d t o res ult i n re d uci n g i nfla m mati o n a n d fi br osis, t he d urati o n of 
d osi n g wit h st u d y  i nter ve nti o ns is pr o p ose d as 4 8 wee ks, i n li ne wit h m ulti ple re g ulat or y 
g ui da nce d oc u me nts f or a ge nts i n de vel o p me nt f or t he treat me nt of N A S H wit h li ver fi br osis. 
I n t he c urre nt st u d y, eli gi ble p o p ulati o n is li mite d t o t h ose wit h bi o ps y-pr o ve n N A S H wit h 
fi br osis sta ge F 2 or F 3, sta n dar dize d t o t he N A S H-C R N defi niti o n 1 4, a n d i n li ne wit h nat ural 
hist or y  st u dies i n dicati n g se verity of li ver fi br osis o n hist ol o g y bei n g t he o nl y i n de pe n de nt 
pre dict or of li ver -relate d m or bi dit y a n d m ortalit y1 5. H o we ver, t his st u d y  i ncl u des t w o disti nct 
p hases wit h n o n -i n vasi ve assess me nts t o i de ntif y t h ose m ore li kely t o ha ve N A S H wit h 
fi br osis bef ore partici pa nts are pr o gresse d t o t he scree ni n g/ baseli ne li ver bi o ps y. As s uc h, 
t w o se parate i nf or me d c o nse nts will be o btai ne d – 1 st li mite d t o Pre Q visit o nl y; a n d 2n d f or 
t he mai n st u d y o nl y i n t h ose dee me d t o meet eli gi bilit y criteria base d o n n o n -i n vasi ve 
pr oce d ures c o m plete d at Pre Q ( pl us, a n a d diti o n al pr ovisi o n/flexi bility f or t h ose partici pati n g 
Pr e- Q u alifi c ati o n
(1 st n o n-i n v a si v e a s s e s s m e nt s)
S cr e e n 2
( Ultr a s o u n d- g ui d e d li v er B x)
R u n-I n a
(      or o n sit e)
B a s eli n e 
[ Si n gl e- Bli n d Pl a c e b o ( BI D)]
R a n d o mi z ati o n / D a y 1
W e e k 4 8
( Ultr a s o u n d- g ui d e d li v er B x)
F/ U # 1
F/ U # 2
W e e k 2
S cr e e n 1
(2 n d n o n-i n v a si v e a s s e s s m e nt s)
W e e k 4
W e e k 6
W e e k 8
W e e k 1 2
W e e k 1 6
W e e k 2 4
W e e k 3 2
W e e k 4 0
S cr e e ni n g P h a s e 
Tr e at m e nt P h a s e 
F oll o w -u p
a.
R u n -I n/ Vi sit 3 r e q uir e d t o b e o n sit e if c h a n g e s t o b a c k gr o u n d m e di c ati o n s ( pr ot o c ol m a n d at e d or c h a n g e s t o i m pr o v e di s e a s e m a n a g e m e nt) ar e b ei n g m a d e; 
ot h er wi s e, t hi s vi sit p er mitt e d a s a t el e p h o n e c o nt a ct o n t h e s a m e d a y, or u p t o 4 d a y s, p o st c o n d u ct of S C R 2 li v er bi o p s y
b.
St a bili z ati o n p eri o d d efi n e d a s i nt er v al of ti m e fr o m R u n -I n/ Vi sit 3 ( o n-sit e or t el e p h o n e c o nt a ct) t o D a y 1/ Vi sit 5
1 0 - t o 1 6- w e e k s
At l e a st 6 w e e k s b
1 4 ± 4 d a y s
4 8 w e e k s ± 4 d a y s
~ 5 2 w e e k s
M RI -P D F F i n ~ 5 0 % 
of r a n d o mi z e d 
[I m a gi n g S u b- st u d y]
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
i n Ima gi n g S u bst u d y  t o offer de dicate d c o nse nt f or t his pr oce d ure cl oser t o Baseli ne 
M RI -P D F F or at t he ti me of c o nse nt o btai ne d at S C R 1) . P o p ulati o n i de ntifie d t o be 
c o nsi dere d f or Pre Q will i ncl u de t h ose wit h c o m m o n c o n diti o ns i de ntifie d as ris k fact ors 
ass ociate d w it h N A F L D.1 6 I n a d diti o n, eli gi ble p o p ulati o n i de ntifie d t o be o ver wei g ht, o bese, 
as well as m or bi dl y  o bese t h o u g h u p per li mit of acce pta ble B MI ca p pe d at 4 5 k g/ m 2. 
Bet wee n t he Pre Q a n d S C R 1 visits , ma n y  of t he n o n -i n vasi ve pr oce d ures a n d cli nical 
la b orat ory tests assesse d are i de ntical – t his is m oti vate d b y t he i nte nt t o c o nfir m t hat t he 
p o p ulati o n pr o gresse d t o li ver bi o ps y  at S C R 2 is c o nsiste ntl y c haracterize d. As a meas ure of 
a d diti o nal dili ge nce a n d as a n atte m pt t o re m o ve varia bilit y  d ue t o differe nces fr o m 
la b orat or y-t o-la b orat or y, t he cli nical la b orat or y tests assesse d at Pre Q a n d S C R 1 are 
pr o p ose d t o be a nal y ze d b y t he s p o ns or-i de ntifie d ce ntral la b orat or y. T he n o n-i n vasi ve 
assess me nts t o narr o w t he p o p ulati o n ulti matel y  u n der g oi n g scree ni n g/ baseli ne li ver bi o ps y 
c o nsist of d o u ble -c o nfir m ati o n bet wee n assess me nt at Pre Q a n d S C R 1 of: – (a) bl o o d-base d 
mar kers of li ver f u ncti o n (ie, A L T, A S T, al kali ne p h os p hatase, t otal bilir u bi n) a n d e ns uri n g 
partici pa nts ha ve sta ble res ults ( defi ne d b y ≤5 0 % varia bilit y i n A L T/ A S T /al kali ne 
p h os p hatase 1 3 pl us t otal bilir u bi n ≤U L N, u nless Gil bert’s s y n dr o me); ( b) c o nsiste nt prese nce 
of c o nc o mita nt ris k fact ors ass ociate d wit h N A F L D ; a n d (c) e val uati o n of F A S T T M sc ore1 2
(a c o m p osite of Fi br o Sca n ® deri ve d C A P T M a n d V C T E T M pl us A S T) t o i de ntif y  at-ris k 
partici pa nts of pr o gressi ve N A S H . T he F A S T T M sc ore t hres h ol d of ≥0. 3 0 f or eli gi bilit y was 
deri ve d usi n g i n di vi d ual -le vel data c o-o w ne d b y Ec h o Se ns, t he ma n ufact urer of Fi br o Sca n ® , 
a n d s hare d wit h t he sp o ns or f or t he p ur p oses of desi g ni n g t his pr ot oc ol . T he t hres h ol d of 
C A P T M ≥2 8 0 d B/ m pl us V C T E T M bet wee n 8. 0 a n d 2 0. 0 k Pa, i ncl u si ve, is per mitte d t o 
acc o u nt f or t he li mite d c ases w here ev al u a ble Fi br o Sca n ® res ults are hi g hl y s u g gesti ve of 
pres u me d N A S H wit h fi br osis 1 7 b ut t he F A S T T M sc ore is bel o w 0. 3 0.
I n t his st u dy, base d o n a c o m bi nati o n of t h or o u g h me dical hist or y (i ncl u di n g assess me nt of 
et ha n ol i nta ke a n d a d mi nistrati o n of t he i ntervie w-versi o n of t he A U DI T 1 0 -ite m 
q uesti o n naire 1 8), a n d cli nical la b orat or y tests (i ncl u di n g G G T a n d % C D T), 
me dicall y - q ualifie d site-staff will be re q uire d t o r ule-o ut alc o h ol -base d as well as ot her 
ca uses of he patic steat osis /i nfla m mati o n/fi br osis, a n d e ns ure t hat t he p o p ulati o n e nr olle d is 
c o nfir me d, as best as p ossi ble, t o ha ve N A S H wit h F 2 -F 3 li ver fi br osis .1 9 T hese asse ss me nts 
( A U DI T a n d % C D T) will be re- assesse d pri or t o ra n d o mizati o n a n d at e n d of d osi n g t o 
c o nfir m t hat w hile i n t he st u d y  alc o h ol i nta ke re mai ne d i n m o derati o n. Partici pa nts wit h 
pre vi o usl y  c o nfir me d ge netic p ol ym or p his ms, f or e xa m ple, P N P L A 3 carriers, a re eli gi ble 
gi ve n t hese p ol y m or p his ms are k n o w n t o m o dif y /i ncrease ris k f or steat o he patitis b ut d o n ot 
b y  t he msel ves ca use steat o he patitis.
A n e x plicit i nte nt i n t his st u d y  is t o  
 t h ose wit h 
 i m pair me nt 
 a n d  
 i m pair me nt (ie, 
 via s pecific eli gi bilit y criteria (refer t o
Secti o n 5. 1 a n d Secti o n 5. 2 ). T his is i n li ne wit h t he cli nical data t o date s h o wi n g 
 
i ncrease i n plas ma e x p os ure i n 
 
 f or A C Ci a n d D G A T 2i i n partici pa nts wit h 
 
c o m pare d t o healt h y partici pa nts; as well as 
 c o nfir me d t o 
re prese nt <
% of u nc ha n ge d dr u g – f or b ot h D G A T 2i a n d A C Ci. T he  
 cleara nce 
mec ha nis m f or D G A T 2i a n d A C Ci is pre dicte d t o be
. T h us, t he 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2
i ncl usi o n/e xcl usi o n criteria ha ve bee n defi ne d t o hel p li mit p har mac o ki netic varia bilit y  w hile 
als o ca pt uri n g a p o p ulati o n t hat is c haracteristic of t he i nte n de d tar get p o p ulati o n. Bl o o d 
sa m ples ( b ot h pre- a n d p ost -d ose) t o per mit p o p ulati o n - p har mac o ki netic a nal ysis will be 
c ollecte d t o f urt her e xa mi ne t he effect of de m o gra p hics o n p har mac o ki netic varia bilit y .
A pri ori , t o per mit a n e val uati o n of p ote ntial differe nces i n treat me nt res p o nse i n N A S H wit h 
F 2 vers us N A S H wit h F 3 fi br osis wit h D G A T 2i a n d D G A T 2i + A C Ci , t his st u d y e m pl o ys 
stratificati o n base d o n de gree of fi br osis ( F 2 vs F 3). I n a d diti o n, t his st u d y will i de ntif y t he 
p o p ulati o n wit h a n d wit h o ut a dia g n osis of T 2 D M base d o n H b A 1 C res ult ≥6. 5 % a n d/ or 
c urre nt use of a p pr ove d a ge nts f or gl yce mic c o ntr ol (Secti o n 6. 5. 1 ). T his is t o per mit a n 
assess me nt of w het her D G A T 2i a n d/ or D G A T 2i + A C Ci de m o nstrate i ns uli n se nsitizati o n 
pr o perties si milar t o t he effect o bser ve d wit h A C Ci al o ne i n t he 1 6 -wee k, P hase 2a st u d y i n 
partici pa nts wit h N A F L D.
Be y o n d t he assess me nt o n hist ol o gical e n d p oi nts, t he c urre nt st u d y als o u n derta kes 
assess me nt f or p ote ntial i m pr o ve me nt o n n o n -i n vasi ve bi o mar kers – b ot h i ma gi n g a n d bl o o d -
base d. Assess me nt of li ver fat a n d li ver stiff ness usi n g ultras o u n d -base d Fi br o Sca n ® i n t he 
e ntire p o p ulati o n a n d li ver fat via t he vali date d t o ol f or cli nical assess me nt of he patic 
steat osis7 - M RI -P D F F (i n I ma gi n g S u bst u d y ) is pla n ne d. T he bl o o d- base d para meters 
i ncl u de mar kers of li ver f u ncti o n tests ( A LT, A S T, Al kali ne p h os p hatase, G G T, T otal 
bilir u bi n), N A S H -relate d bi o mar kers2 1 ( 3-para meter deri ve d E L F T M Sc ore, mar ker of li ver 
fi br osis use d t o trac k disease pr o gressi o n; C K 1 8-M 3 0 a n d C K 1 8 -M 6 5, ma r kers of a p o pt otic 
acti vit y; Pr o C 3 , a mar ker of fi bri n o ge nesis; Pr o C 6, a mar ker of fi bri n olys is), glyc e mic 
para meters ( H b A 1 C, F P G, F PI, H O M A -I R, a di p o necti n), a n d fasti n g li pi d 
para meters/ mar kers of tar get e n ga ge me nt (t otal c h olester ol, tri gl yc eri des, direct L D L-C, 
H D L -C, direct V L D L, a p oli p o pr otei n A 1, B t otal, B1 0 0, B4 8, C 3, a n d E pl us P C S K 9, hs -C R P). 
 c ollecti o ns is pla n ne d t o 
e na ble 
 
 F urt her m ore, rece nt researc h has i n dicate d t hat t here is a n 
u nrec o g nize d s y m pt o m b ur de n wit h N A S H. I n partic ular , a b d o mi nal pai n, a n d fati g ue, were 
i de ntifie d as rele va nt i n s p o ns or-c o n d uct e d patie nt i nter vie ws a n d f o u n d t o be res p o nsi ve t o 
hist ol o gical c ha n ge i n a trial wit h o betic h olic aci d .2 2 I ncl usi o n of eP R Os i n t he c urre nt st u d y
will all o w testi n g of t his h y p ot hesis, a n d o pti mizati o n of eP R Os ta ke n f or war d i nt o P hase 3 . 
S uc h data m a y  als o be val ua ble i n s u p p orti n g hist ol o g y  as a s urr o gate o utc o me i n f ut ure 
healt h tec h n ol o g y  assess me nts. I n t his st u d y, baseli ne, w he n o btai ne d will be d o ne at Visit 
4/ Baseli ne or w hile partici pa nts are recei vi n g si n gle -bli n d place b o – refer t o Ta ble 4 .
F or t he assess me nt of li ver fat (eit her via Fi br o Sca n ® [i n t he e ntire p o p ulati o n] or M RI-P D F F 
[i n t he Ima gi n g S u bst u d y]), partici pa nts will be re q uire d t o fast ( water per mitte d) f or 
≥4 - h o urs gi ve n t he a bilit y of f o o d t o i m pact t he res ults. As a n a d diti o nal meas ure t o li mit 
varia bilit y , atte m pts will be ma de t o sta n dar dize t he n o mi nal ti me of t hese t w o assess me nts. 
T he cl oc k ti me of da y  w he n t hese assess me nts are ma de s h o ul d fall wit hi n a practical 
wi n d o w ( ± 2 -h o urs) relati ve t o cl oc k ti me at Pre Q f or Fi br o Sca n® a n d Baseli ne (ie, bet wee n 
Visit 4/ Baseli ne a n d Visit 5/ Da y  1 f or M RI-P D F F , i n t he I ma gi n g S u bst u d y ), as m uch as 
practicall y p ossi ble . Serial assess me nts p ost ra n d o mizati o n via M RI-P D F F a n d Fi br o Sca n ®
are pla n ne d t o per mit a mi xe d -m o del -re peate d-meas ure a nal ys is t here by all o wi n g f or 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3
e val uati o n of dr u g effect l o n git u di nall y  a n d, at eac h visit, i ncl u di n g e n d of d osi n g wit h t he 
st u d y i nter ve nti o n – ie, Wee k 4 8 / Visit 1 9. 
W hile t he cli nical e x perie nce wit h D G A T 2i a n d D G A T 2i + A C Ci is li mite d t o ma xi m u m of 
, tra nsiti o n t o 4 8 wee ks of d osi n g i n t he c urre nt st u d y is dee me d t o be acce pta ble 
gi ve n: (a) l oss - of-f u ncti o n m utati o n i n D G A T 22 3 – T y r 2 8 5 X – p he n ot y picall y has n o 
cli nicall y si g nifica nt prese ntati o n ot her t ha n a n ass ociati o n wit h decrease d H D L-C, wit h 
i m plicati o ns of t his o bser vati o ns u n k n o w n; ( b) c hr o nic t o xicit y st u dies wit h D G A T 2i i n  
 
( u p t o 
) a n d 
 ( u p t o 
) wit h d osi n g u p t o 
 d ose 
(
) di d n ot res ult i n a n y a d verse fi n di n gs pl us i n t o xicit y st u d y wit h 
D G A T 2i + A C Ci i n 
 ( u p t o 
), fi n di n gs were i n li ne wit h t h ose re p orte d 
wit h a d mi nistrati o n of 
; a n d (c)
 was n ot i de ntifie d wit h 1 4 da y  d osi n g at 
 t ha n t he t o p d ose of D G A T 2i i n t he c urre nt st u d y 
( 6 0 0 m g/ da y ). Des pite t his safet y pr ofile, gi ve n t he tra nsiti o n t o t he pr o p ose d 4 8 wee ks of 
d osi n g i n t his st u d y, meas ures t o e ns ure partici pa nt safety are i ncl u de d – ( a) fre q ue nt (e ver y 
2- wee k), o ut patie nt visits u p t o Wee k 8/ Visit 9, f oll o we d b y c o ntact wit h sites e ver y 4 wee k s, 
eit her as o ut patie nt visits or tele p h o ne c o ntact, u p t o Wee k 4 8/ Visit 1 9 wit h pr o visi o ns f or 
u n pla n ne d visits f or f oll o w -u p of A Es (refer t o Secti o n 8. 3. 3 ) a n d cli nicall y si g nifica nt 
la b orat or y res ults (refer t o Secti o n 8. 2. 5 ); ( b) as m uc h as pr actic ally d o a ble , t he use of sa me -
da y  s hi p ment of safet y- relate d bl o o d/ uri ne sa m ples t o s p o ns or-i de ntifie d ce ntral la b orat or y 
wit h ra pi d t ur n -ar o u n d of safety-relate d res ults a n d ma na ge me nt of metf or mi n d ose as well 
as o verall gl yc e mic c o ntr ol ( A p pe n di x 1 0 ); (c) sta n dar dizati o n of bli n de d ma na ge me nt of t he 
 wit h a d mi nistrati o n of A C Ci – na mel y 
 i n 
 (refer t o A p pe n di x 1 1 ) a n d 
 (refer t o 
A p pe n di x 1 2 ); ( d) use of a dj u dicati o n c o m mittee (f or li ver - a n d C V - e ve nts) a n d a n E-D M C 
(refer t o Secti o n 9. 6 ) t o u n derta ke u n bli n de d re vie w of safet y data p ost ra n d o mizati o n, at a 
mi ni m u m, of a p pr o xi matel y 3 3 %, 6 7 %, a n d 1 0 0 % of pla n ne d t otal sa m ple size i n Pr ot oc ol 
A me n d me nt 1 ; a n d (e) peri o dic bli n de d re vie w of safety b y t he sp o ns ors’ cli nical tea m 
me m bers t o assess f or p ote ntial tri g ger f or a d diti o nal E- D M C u n bli n de d re vie w(s) of 
c u m ulati n g safet y data w hile t he st u d y  is on- g oi n g.
Plas ma e x p os ure of A C Ci f oll o wi n g a hi g h-fat/ hi g h-cal oric brea kfast was  
 relati ve t o 
a d mi nistrati o n of A C Ci f oll o wi n g a n o ver ni g ht fast; h o we ver, plas ma e x p os ure of D G A T 2i 
is  
 by 
% ( A U C i nf) a n d 
% ( Cma x ) w he n a d mi nistere d f oll o wi n g a n o ver ni g ht fast 
vers us wit h sta n dar d meal. As s uc h, a d mi nistrati o n of t he st u d y  i nter ve nti o ns i n t his st u d y
will be re q ueste d t o occ ur wit h t he m or ni n g (a n d e ve ni n g) meals – gi ve n t he i m p orta nce of 
re g ular meals t o t he sta n dar d- of-care diet c o u nselli n g f or t he pla n ne d p o p ulati o n.
F or all partici pa nts , a st a biliz ati o n peri o d of at least 4 -wee ks pri or t o Baseli ne/ Visit 4 
(ie, 6- wee ks pri or t o Da y 1/ Visit 5) is ma n dat or y  f or sta bilizi n g bac k gr o u n d me dicati o ns 
(i ncl u di n g si m pl y c o m plia nce) a n d acc o m pa n yi ng m o nit ori n g para meters i n or der t o 
mi ni mize place b o res p o nse p ost ra n d o mizati o n . T his ca n be ac hie ve d via c o n d uct of t he 
R u n -I n/ Visit 3 eit her as –

A n o n -site visit after a vaila bilit y of S C R 2 li ver bi o ps y res ults fr o m t he s p o ns or-
i de ntifie d ce ntral la b orat or y if c ha n ges t o bac k gr o u n d me dicati o ns eit her pr ot oc ol 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
ma n date d or c ha n ges t o i m pr o ve disease ma na ge me nt ( refer t o Secti o n 6. 5 ) are 
pla n ne d ;

Or a tele p h o ne c o ntact o n t he sa me d a y , or u p t o 4 da y s, p ost c o n d uct of S C R 2 
li ver bi o ps y if n o c ha n ge i n d ose(s) of bac k gr o u n d me dicati o ns is dee me d t o be 
cli nicall y necessar y.
I n a d diti o n, a fi xe d, si n gle-bli n d, 2 - wee k baseli ne peri o d (ie, Visit 4/ Baseli ne t o 1-d a y  pri or 
t o Visit 5/ Da y  1 is i ncl u de d i n t his st u d y wit h t he e x plicit p ur p ose of fa miliarizi n g t he 
partici pa nts wit h t he d osi n g i nstr ucti o ns f or t he st u d y i nter ve nti o n (refer t o Ta ble 3 ), a n d t o 
e xcl u de partici pa nts w h o are n ot c o m plia nt wit h t he si n gle -bli n d place b o pri or t o 
ra n d o mizati o n i n a n atte m pt t o mi ni mize me dicati o ns err ors p ost ra n d o mizati o n.
4. 2. 1. P artici p a nts of c hil d -be ari n g p ote nti al
 are n ot a vaila ble f or D G A T 2i, or D G A T 2i + A C Ci . 
I n t he c o m plete d, 
 st u dies wit h D G A T 2i al o ne a n d 
A C Ci al o ne (a n d he nce D G A T 2i + A C Ci i n t his st u d y) fi n di n gs ha ve bee n 
– refer t o 
Secti o n 2. 3. 1 . T heref ore, t he use of a 
 met h o d of c o ntr ace pti o n is 
b y  fe males of c hil d beari n g p ote ntial - refer t o Secti o n 5. 4. 1 a n d A p pe n di x 4 f or a d diti o nal 
details.
T he p ote ntial ris k of e x p os ure , 
, t o D G A T 2i or D G A T 2i + A C C i i n a fe male 
se x ual part ner of c hil d beari n g p ote ntial of a male partici pa nt i n t his st u d y  is 
. As s uc h,
use of 
is
 i n t he male partici pa nts. 
T he calc ulate d safet y mar gi n is 
 bet wee n t he esti mate d part ner e x p os ure d ue t o 
se mi nal tra nsfer a n d t he N O A E L f or 
 i n 
n o ncli nical st u dies. T he safet y mar gi n of 
 is base d o n a p plyi n g a 
 safety 
fact or f or i nters pecies e xtra p olati o n a n d a 
 safety fact or f or s usce pti ble p o p ulati o ns. 2 4
 will be c ollecte d a n d st ore d f or 
 w hic h ma y, f or 
e xa m ple, pr o vi de greater u n dersta n di n g of t he st u d y  i nterve nti o n. C o m pari n g t he  
, 
, a n d 
 of partici pa nts w h o res p o n d well a n d t h ose 
w h o res p o n d p o orl y t o treat me nt ma y  hel p t o better defi ne t he m ost a p pr o priate gr o u p of 
partici pa nts i n w hic h t o tar get a gi ve n treat me nt . C ollecti n g 
 f or 
 
 a n d retai ni n g t he m i n t he  
 ma ke it 
p ossi ble t o better u n dersta n d t he i n vesti gati o nal pr o d uct’s 
 
 
 Refer t o Secti o n 8. 7 a n d A p pe n di x 5 , f or 
a d diti o nal details. 
Pr o vi di n g 
 is a re q uire d st u dy acti vit y f or st u d y sites a n d partici pa nts, 
u nless pr o hi bite d b y  l ocal re g ulati o ns or E C decisi o n.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
4. 2. 3. P artici p a nt I n p ut I nt o St u d y Desi g n 
Patie nt pa nels/i nter vie ws were c o n d ucte d t o gai n i n p ut fr o m a d ults wit h ( pres u me d) N A S H 
o n t he w or ki n g draft pr ot oc ol . T he i n p ut offere d, a nd its’ i nc or p orati o n , is s u m marize d i n
Ta ble 1. 
T a ble 1 . 
P artici p a nt I n p ut i nt o C 2 5 4 1 0 1 3 St u d y Desi g n
P artici p a nt Fee d b ac k
I m pleme nt ati o n Pl a n ne d ( or incl u de d herei n)
O verall St u d y Desi g n – d e e m e d 
reas o na ble b ut str o n g desire t o k n o w 
rati o nale f or –

W h y  st u d y i nter ve nti o n mi g ht w or k

R is ks/ p ote ntial be nefits

Visit sc he d ule a n d a n y pre parati o n 
nee de d a hea d of eac h visit

C ost (a n d c o mpe nsati o n) of 
partici pati o n, if a n y
As part of I C D clearl y (a n d si m pl y) artic ulate –

Mec ha nis m of acti o n a n d “reas o n t o belie ve”

Bala nce d pers pecti ve re gar di n g p ote ntial be nefit a n d 
p ote ntial ris ks

R ati o nale f or list of all pla n ne d pr oce d ures a n d 
hi g hli g hti n g t hat t hese are at n o c ost t o partici pa nts

R estricti o ns (e g, re q uire d faste d d urati o n) a n d w h y t hese 
are i m p orta nt 
o
Pl us , w hat t o d o if t he y f or get t o d o a re q uire d pre -
visit pre parati o n (e g, arri ve n o n -faste d, p ost A M d ose 
of st u d y i nter v e nti o n, ha ve n ot c o m plete d e P R O)

P la n ne d c o m pe nsati o n str uct ure ( n ot si m pl y at e n d of st u d y 
partici pati o n)
Re q uire me nt of Li ver Bi o ps y – n ot
preferre d b ut w ill d o it s o l o n g as –

T here is n o ot her o pti o n

It hel ps t heir (a n d ma y be ot hers) 
me dical ma na ge me nt 

Use of tria ge t o pr o gress o nl y t h ose t o bi o ps y w h o are 
m o re li kel y t o q ualif y f or t he st u d y

Li mit st u d y t o a ma xi m u m of 2 bi o psies pl us 1 of t hese is 
per mitte d t o be a rece nt hist orical bi o ps y, if a vail a ble, t o 
ser ve as scree ni n g/ baseli ne bi o ps y

Re q uire e x perie nce d s pecialist w h o will ser ve as 
i n vesti gat or t o perf or m bi o ps y
o
I ncrease p ositi ve i m pressi o n of partici pa nts p ost 1st
bi o ps y t o e na ble hi g her pr o ba bilit y of partici pa nts 
i nterest i n 2n d bi o ps y

Re q uire c o m m u nicati o n of S C R 2 bi o ps y res ults as re p orte d 
b y s p o ns or -i de ntifie d ce ntral la b orat or y t o be a face-t o-face 
i nteracti o n (ie, at eit her t he o n -site Visit 3/ R u n-I n or 
Visit 4/ Baseli ne ) wit h t he i n vesti gat or 

Per m it use of a n xi ol ytics al o n g wit h l ocal sta n dar d-of -care 
f or t y pe of nee dle; h o we ver, dictate ga u ge t o be li mite d t o 
1 of 2 t o e ns ure e val ua ble tiss ue is c ollecte d – refer t o 
Secti o n 8. 1. 1
D urati o n of eac h o ut patie nt visit pl us nee d 
f or p ote ntial visits t o differe nt l ocati o ns 
(e g, t o site, ra di ol o g y, i ma gi n g facilit y) –

3- 4 h o u rs is l o n g b ut d oa ble s o l o n g 
as sc he d ule is k n o w n a pri ori 

T here has t o be s o me fle xi bilit y f or 
w he n t o c o m plete eac h visit (e g, ± 1 -2 
da ys)

A n d t here nee ds t o be c o m pe nsati o n 
f or ti me a n d tra vel 

Visit wi n d o w  ke pt fle xi ble fr o m Pre Q t o Visit 3/ R u n-I n –
refer t o Fi g ure 1

Eac h visit starti n g at Visit 4/ Baseli ne de vise d wit h ± 4 -d a y  
wi n d o w  f or ease of partici pa nt a n d site

All o w a nce ma de f or pr oce d ures t hat ma y re q uire visits t o 
differe nt l ocati o ns t o be d o ne o v er multi ple da ys ( n ot all o n 
t he sa me da y)

E ns ure ca pt ure of c o mpe nsati o n f or ti me a n d 
i nc o n ve nie nce, i n c o m plia nce wit h G C P
Pill b ur de n – 3 pills/ d ose x 2/ da y is n ot 
attracti ve, es peciall y 2 bei n g lar ge + 1 
s mall

Blister pac k desi g ne d wit h vis ual c ues f or A M vs P M d ose 
(e g, differe nt c ol ors f or t he 3 c ol u m ns c o veri n g A M d ose 
vs P M d ose)
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
T a ble 1. 
P artici p a nt I n p ut i nt o C 2 5 4 1 0 1 3 St u d y Desi g n
P artici p a nt Fee d b ac k
I m pleme nt ati o n Pl a n ne d ( or incl u de d herei n)

B ut pill b ur de n is ma na gea ble si nce
alrea d y ta ki n g ma n y m ore pills per 
da y o n a si milar sc he d ule

Li ke set- u p of blister pac ks (a n d n ot 
b ottles)

As k t hat ta blets be c oate d as t he y are 
easier t o s wall o w

Eac h blister car d = 7 -da ys of d osi n g 

I ncl usi o n of peri o dic d osi n g re mi n ders as part of sp o ns or -
pr o vi de d e P R O de vice t o be ta ke n h o me b y partici pa nts
Bl o o d dra ws – d o n ot li ke t o o ma n y t u bes 
dr a w n at a ti me

I nterest i n k n o w i n g w h y s o ma n y 
t u bes are nee de d

Wa nte d res ults t o be s hare d wit h t he m 
as st u d y is g oi n g o n ( or at e n d of 
st u d y)

Vali date d D G A T 2i a n d A C Ci P K assa y t o per mit use of 
 a n d a 
 assa y b ot h a nal ytes à sa ve d
 per P K dra w b y  c o mbi ni n g assa y

Gr o u pe d a nal ytes t o be assa ye d, b y ve n d or, t o li mit 
n u m ber of t u bes of bl o o d dra w n

Bala nce nee d f or e ns uri n g partici pa nt safet y (ie, wit h 
i nc o n ve nie nce of visits a n d bl o o d dra ws) a n d kee pi n g 
t he m e n ga ge d ( b y s witc hi n g o n -site visits t o tele p h o ne 
c o ntact)
P R Os – t here is willi n g ness t o c o m plete 
dail y 2 mi n at -h o me q uesti o n naire pl us
2 0 mi n i n -cli nic q uesti o n naire 5 ti mes 
d uri n g st u d y o n electr o nic de vices

Li ke i dea of electr o nic vs pa per 
e ntries

A ut o -re mi n ders wo ul d be hel pf ul 

Wa nt t o k n o w c o nse q ue nce of 
c o m pleti n g late i n t he da y

Q ualit y a n d acc urac y of tra nslati o ns 
fr o m E n glis h t o nati ve la n g ua ge of 
partici pa nts i m p orta nt 

I mple m e ntati o n pla n ne d as electr o nic sp o ns or -pr o vi de d 
de vices wit h t he a d de d feat ure of r e mi n ders f or e P R O 
c o m pleti o n

N o pla ns t o a pri ori defi ne w he n o n a gi ve n da y e P R Os 
s h o ul d be c o m plete d 

Pla n t o f oll o w  tra nslati o n pr ocess t hat i ncl u des c o g niti ve 
de briefi n g i n nati ve la n g ua ge t o e ns ure c ult ural 
e q ui vale nc y
Willi n g ness t o sta y i n st u d y off st u d y dr u g 
ra n ge d al o n g wit h pers o nal m oti vat ors 

Be nefit nee de d t o be t here – e g, 
access t o t heir data t o hel p f ut ure 
treat me nt or ma na ge me nt of t heir 
disease , a se nse of bel o n gi n g/ bei n g 
val ue d, lear ni n g of st u d y pr o gress 

U n derst o o d c o m mit me nt t o st u d y a n d 
i mp orta nce of ha vi n g c o m plete data

B ut t here is c o ncer n wit h ha vi n g t o 
wit hsta n d t he 2 n d bi o ps y i n t hat case

A g gre gate le vel s u m mar y of st u d y res ults i n la y la n g ua ge 
pla n ne d at e n d of st u d y – refer t o Secti o n 1 0. 1. 5

Pe n di n g I R B/ E C a p pr ov al, pla n t o i mple me nt partici pa nt -
f oc use d c o m m u nicati o ns; e g, ke y milest o nes i n st u d y, 
pers o nalize d messa ge at ke y pers o nal dates f or i n di vi d ual 
partici pa nt s – c o m m u nicate d via, f or ex a m ple, s ocial 
me dia, e -mail, te xt messa ges, pri nt material c o veri n g ‘ti ps -
of -t he-d a y ’
4. 3. J ustific ati o n f or D ose
F or t he a d mi nistrati o n of D G A T 2i as m o n ot hera p y as well as c oa d mi nist rati o n wit h A C Ci i n 
t his st u d y, selecti o n of doses t o be e val uate d were i nf or me d b y re d ucti o n i n li ver fat o bser ve d
f oll o wi n g 2 wee k s of d osi n g wit h D G A T 2i i n St u d y  C 2 5 4 1 0 0 5, 6 wee k s of d osi n g of
D G A T 2i al o ne, A C Ci al o ne, a n d c oa d mi nistrati o n i n St u d y C 3 7 1 1 0 0 1 , as well as 1 6 wee ks 
of d osi n g wit h A C Ci al o ne i n St u d y C 1 1 7 1 0 0 2.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
E x p os ure -res p o nse a nalysis of re d ucti o n i n li ver fat a n d a vera ge D G A T 2i c o nce ntrati o ns 
o bser ve d i n St u d y  C 2 5 4 1 0 0 5 i nf or me d D G A T 2i m o n ot hera p y d ose-ra n gi n g d ose selecti o n –
refer t o Ta ble 2 . T he 
of re d ucti o n i n li ver fat was esti mate d t o be 
 
. A d ose of a p pr o xi matel y 2 5 m g BI D ( 5 0 m g t otal daily d ose) was pr ojecte d 
t o ac hie ve a vera ge c o nce ntrati o ns near t he 
usi n g a preli mi nar y  p o p ulati o n 
p har mac o ki netic m o del de vel o pe d usi n g si n gle -d ose a n d m ulti ple -d ose P K data fr o m 
pre vi o us cli nical st u dies wit h D G A T 2i . Ho we ver, t he 
base d o n t he hist ol o gical effect 
o n li ver is u n k n o w n des pite a li kel y  c orrelati o n bet wee n re d ucti o n i n li ver fat a n d hist ol o gical 
c ha n ges e vi de nt o n li ver bi o ps y . A 3 0 0 m g BI D d ose ( 6 0 0 m g t otal dail y d ose) was pr ojecte d 
t o ac hie ve 
. M o del pre dicti o ns of re d ucti o n i n li ver fat base d o n  
 
 were als o c o n d ucte d. Base d o n t hese m o del a nal ys es, D G A T 2i d oses of 2 5, 7 5, 
1 5 0, a n d 3 0 0 m g BI D were c h ose n f or e val uati o n i n t his st u d y.
I n t he O ri gi nal Pr ot oc ol, a n e val uati o n of efficac y wit h Q D a d mi nistrati o n of D G A T 2i al o ne 
was als o pla n ne d base d o n t he  
 effect o n li ver fat at 5 0 m g BI D i n S t u d y C 2 5 4 1 0 0 5. 
D G A T 2i d oses of 1 5 0 m g Q D a n d 3 0 0 m g Q D were selecte d t o c o m pare wit h BI D re gi me ns 
at t he sa me dail y d ose ( 7 5 m g BI D a n d 1 5 0 m g  BI D) t o per mit e val uati o n of w het her 
ac hie vi n g a si milar 
res ults i n  
 efficac y - Ta ble 2. T he 
 f or 
 effect o n he patic fat f or 
 vers us  
 re gi me n of D G A T 2i al one f or me d t he basis 
f or t he strate gic decisi o n t o de pri oritize e val uati o n of sa me t otal dail y d ose – a d mi nistere d 
BI D or Q D via Pr ot oc ol A me n d me nt 1 . Wit h t he i nte nt t o n o l o n ger p urs ue t he scie ntific 
e val uati o n of Q D d osi n g re gi me n, data will be a nal y ze d b y  t otal dail y d ose of D G A T 2i 
al o ne, re gar dless of w het her it was a d mi nistere d BI D or Q D.
T a ble 2.
 
D G A T 2i
T ot al D ail y 
D ose ( m g)
Pl ace b o -A dj uste d C h a n ge fr o m  B aseli ne 
( %), Me di a n ( 9 0 % CI) at 2 Wee ks
Pl ace b o -A dj uste d C h a n ge fr o m  B aseli ne ( %),
Me di a n ( 9 0 % CI) at 6 W ee ks
Q D
BI D
Q D
BI D
5 0
1 5 0
3 0 0
6 0 0
Base d o n t he preli mi nar y p o p ulati o n p har mac o ki netic m o del, a vera ge dail y D G A T 2 
i n hi biti o n base d o n i n vitr o p ote nc y (
) was pr ojecte d t o be a p pr o xi matel y 
%, 
%, 
%  
% at d oses of 2 5, 7 5, 1 5 0 a n d 3 0 0 m g a d mi nistere d BI D, res pecti vel y, a n d 
% a n d 
% at D G A T 2i d oses of 1 5 0 a n d 3 0 0 m g a d mi nistere d Q D.
A d mi nistrati o n of D G A T 2i 3 0 0 m g BI D a n d A C Ci 1 5 m g BI D al o ne a n d w he n 
c oa d mi nist ere d o ver 6 wee ks i n partici pa nts wit h N A F L D , a place b o-a dj uste d LS mea n 
re d ucti o n i n li ver fat of ≥4 0 % was o bser ve d i n all ar ms. I n ad diti o n , o n a vera ge, ser u m 
tri glyceri de i ncreases o bser ve d w it h A C Ci al o ne were miti gate d b y  c oa d mi nistrati o n wit h 
D G A T 2i. It is a ntici pate d t hat via c oa d mi nistrati o n of D G A T 2i + A C Ci , he patic li pi d 
meta b olis m will be m o d ulate d i n disti nct a n d c o m ple me ntar y  wa ys, p ote ntiall y res ulti n g i n 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
 efficac y t ha n D G A T 2i a d mi nistere d al o ne. As s uc h , t his st u d y als o i ncl u des a n
e val uati o n of 2 d ose gr o u p c o m bi nati o ns of D G A T 2i a n d A C Ci i n or der t o assess i m pact o n 
li ver hist ol o g y c o m pare d t o D G A T 2i al o ne. 
D G A T 2i 3 0 0 m g BI D + A C Ci 1 0 m g BI D was selecte d as t he hi g h d ose c o m bi nati o n f or t he 
c urre nt st u d y . T his hi g h d ose c o m bi nati o n c o ntai ns t he sa me D G A T 2i d ose assesse d i n 
St u d y C 3 7 1 1 0 0 1 ( D G A T 2i 3 0 0 m g BI D + A C Ci 1 5 m g BI D) t h o u g h a sli g htl y  l o wer A C Ci 
d ose i s pr o p ose d i n t his st u d y ac k n o wle d gi n g t hat w hile miti gati o n of A C Ci -i n d uce d effect 
o n ser u m tri gl yc eri des wit h c oa d mi nistrati o n of D G A T 2i was see n , o n a vera ge, t his res p o nse 
ha d a ra n ge of u p t o 2 8 % i ncrease i n ser u m tri gl yceri des (ie, u p per 9 0 % CI = 2 7. 9 9 % f or 
place b o - a dj uste d c ha n ge fr o m baseli ne f or D G A T 2i + A C Ci ) i n St u d y  C 3 7 1 1 0 0 1. T he l o w 
d ose c o m bi nati o n c h ose n is D G A T 2i 1 5 0 m g BI D + A C Ci 5 m g BI D, half of t he hi g h d ose 
c o m bi nati o n f or eac h c o m p o ne nt. H o we ver, wit h b ot h D G A T 2i + A C Ci d ose -le vels, t he 
D G A T 2i t o A C Ci d ose rati o is mai ntai ne d at 3 0: 1 (ie, 6 0 0: 2 0 a n d 3 0 0: 1 0) . The d oses of 
A C Ci selecte d ( 5 m g BI D a n d 1 0 m g BI D) f or c oa d mi nistrati o n wit h D G A T 2i als o ali g n 
wit h o bser ve d data fr o m St u d y  C 1 1 7 1 0 0 2 w here a d mi nistrati o n of 2 m g Q D of A C Ci al o ne 
res ulte d i n place b o-li ke effect, a n d A C Ci d oses of ≥1 0 m g Q D res ulte d i n p har mac ol o gical 
e vi de nce of pert ur bati o n wit h clear e vi de nce of d ose-relate d re d ucti o n i n li ver fat, A L T, 
A S T, as well as mar kers of a p o pt otic acti vit y  ( C K 1 8-M 3 0 a n d C K 1 8 -M 6 5). A C Ci d oses 
 are n ot pr o p ose d i n t he c urre nt st u d y gi ve n t he  
 
li n ka ge bet wee n c ha n ges i n li ver fat, A L T, A S T, a n d a p o pt otic mar kers a n d i m pr o ve me nts 
o n hist ol o gical e n d p oi nts assesse d via li ver bi o ps y. 
 
, a BI D d osi n g regi me n was selecte d t o matc h t he d osi n g 
i nstr ucti o ns f or t he D G A T 2i BI D ar ms.  
D G A T 2i a n d A C Ci d oses selecte d ha ve bee n de m o nstrate d t o be safe a n d well -t olerate d i n 
pre vi o us cli nical st u dies a n d are s u p p orte d b y t he 
 
st u dies c o m plete d i n 
 a n d 
 f or eac h of t he a ge nts al o ne a n d 
 c o m bi nati o n 
t o xicit y st u d y i n  
. I n t he c urre nt st u d y, the hi g hest D G A T 2i d ose ( 3 0 0 m g BI D) a n d 
A C Ci d ose ( 1 0 m g BI D) pr o p ose d are  
 (f or D G A T 2i) a n d  
 (f or A C Ci)  
 
t ha n t he  
 re peate d d ose e val uate d f or eac h a ge nt i n pre vi o us cli nical st u dies (refer t o 
Secti o n 2. 2. 2 ) as well as aff or d 
 safet y mar gi ns co m pare d t o c o m plete d 
 
(refer t o Secti o n 2. 2. 1 ).
T he o verall selecti o n of d oses of D G A T 2i a n d A C Ci were als o i nfl ue nce d b y t he ai m t o 
e val uate t he st u d y o bjecti ves usi n g t he ta blet stre n gt hs a vaila ble (ie, 
 
) as efficie ntl y as p ossi ble. As pr o p ose d, t he d ose-ra n ge 
pla n ne d will necessitate eac h partici pa nt t o self -a d mi nister 3 ta blets/ d ose, t wice -a-d a y , i n 
or der t o mai ntai n t he d o u ble -bli n d, d o u ble -d u m m y desi g n of t he st u d y . T o ai d c o m plia nce b y 
t he partici pa nts, st u d y i nter ve nti o n will be pac ka ge d a n d dis pe nse d as blister car ds ( n ot 
b ottles) wit h eac h car d per mitti n g 7 d a y s of d osi n g – refer t o Secti o n 6 .
4. 4. E n d of St u d y Defi niti o n
E n d of st u d y is defi ne d as t he date of c o n d uct of t he ver y last 2n d F oll o w -u p visit i n a 
partici pa nt ra n d o mize d i nt o t his trial, gl o ball y.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
5. S T U D Y P O P U L A TI O N
T his st u d y  ca n f ulfill its o bjecti ves o nl y if a p pr o priate partici pa nts 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 partici pa nts 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 me dical co 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 partici pa nt is s uita ble f or t his 
pr ot oc ol. 
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o 
k n o w n as pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
5. 1. I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y:
A ge a n d Se x:
1.
Male or fe male partici pa nts bet wee n t he a ges of 1 8 ( or t he mi ni m u m c o u ntr y -s pecific a ge 
of c o nse nt if > 1 8) a n d 7 5 y ears, i ncl usi ve, at Pr e Q a n d S C R 1 ;

Refer t o A p pe n di x 4 f or 
 f or male (A p pe n di x 4. 1 ) a n d fe male 
(A p pe n di x 4. 2 ) partici pa nts.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics:
2.
At Pre Q a n d S C R 1 , meet ≥2 of t he f oll o wi n g criteria [ f or l a b or at ory p ar a meters, res ults 
m ust be as assesse d b y t he s p o ns or -i de ntifie d ce ntral la b orat or y, wit h a si n gle re peat 
per mitte d t o assess eli gi bilit y , at eac h of t hese 2 visits , if nee de d] –

F P G ≥1 0 0 m g/ d L ( 5. 6 m m ol/ L), or o n p har mac ol o gical a ge nts wit h ex plicit 
p ur p ose of i m pr o vi n g gl y ce mic c o ntr ol (refer t o Secti o n 6. 5. 1 );

Fasti n g ser u m H D L -C < 4 0 m g/ d L ( 1 m m ol/ L) f or males a n d < 5 0 m g / d L 
( 1. 3 m m ol/ L ) f or fe males, or o n p har mac ol o gical a ge nts wit h ex plicit p ur p ose t o 
i ncrease H D L- C (refer t o Secti o n 6. 5. 2 );

Fasti n g ser u m T G ≥1 5 0 m g/ d L ( 1. 7 m m ol/ L), or o n p har mac ol o gical a ge nts wit h 
ex plicit p ur p ose t o decrease T G (refer t o Secti o n 6. 5. 2 );

Seate d B P ≥1 3 0 / 8 5 m m H g, or o n p har mac ol o gical a ge nts wit h ex plicit p ur p ose
f or B P c o ntr ol (refer t o Secti o n 6. 5. 3 );

Waist circ u mfere nce ≥4 0 i nc hes ( 1 0 2 c m) f or males a n d ≥3 5 i nc hes ( 8 9 c m) f or 
fe males.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
3.
Meet t he f oll o wi n g criteria, base d o n a n ev alu a ble Fi br o Sca n ® as defi ne d i n 
Secti o n 8. 1. 2. 1 ( ± A S T as assesse d b y s p o ns or -i de ntifie d ce ntral la b orat or y); wit h a si n gle 
re peat assess me nt per mitte d t o assess eli gi bilit y, if nee de d, at eac h of t hese 2 visits;

A t Pre Q a n d S C R 1, F A S T T M sc ore ≥0. 3 0, deri ve d usi n g s p o ns or -pr o vi de d N A S H 
t o ol;
O R

A t Pre Q a n d S C R 1, meet a c o m bi nati o n of –

C A P T M ≥2 8 0 d B/ m pl us

V C T E T M bet wee n 8 . 0 a n d 2 0. 0 k Pa , i ncl usi ve;

Eli gi bilit y  usi n g t his n o n-i n vasi ve assess me nt m ust occ ur pri or t o c o n d uct of 
scree ni n g/baseli ne li ver bi o ps y  at S C R 2 . 
4.
At S C R 2, ultr as o u n d -g ui de d (a n d i n li mite d c ases, ot her i ma gi n g tec h ni q ue(s) as 
o utli ne d i n Secti o n 8. 1. 1 ), perc uta ne o us , li ver bi o ps y meeti n g t he N A S H C R N 
defi niti o n 1 4 as deter mi ne d b y s p o ns or i de ntifie d ce ntral pat h ol o gist(s) as f oll o ws –

A t otal N A S sc ore of ≥4 (a n d u p t o t otal sc ore of 8) c o m prisi n g of steat osis gra de 
≥1, pl us i nfla m mati o n gra de of ≥1 , pl us ball o o ni n g gra de of ≥1;

Al o n g wit h fi br osis of F 2 or F 3 ;
N O T E : A hist oric al bi o ps y  ma y be acce pte d if perf or me d ≤1 2 wee ks pri or t o S C R 2
a n d tiss ue sli des are accessi ble t o t he sp o ns or -i de ntifie d ce ntral pat h ol o gist(s) f or 
deter mi nati o n of eli gi bilit y (a n d t o ser ve as baseli ne); i n s uc h cases, 

E li gi bilit y base d o n i ncl usi o n criteri o n 3 at Pre Q a n d S C R 1 is n ot re q uire d;

S C R 2 date reflects date of s hi p me nt of hist oric al tiss ue sa m ple t o s p o ns or-
i de ntifie d ce ntral la b orat or y after c o nfir mati o n of eli gi bilit y base d o n 
assess me nts perf or me d at Pre Q a n d S C R 1 visits ;

I n all c ases, date of pr oce d ure of t he li ver bi o psy use d t o deter mi ne e li gi bilit y 
(a n d ser ve as baseli ne) m ust be ≤2 4 wee ks pri or t o Da y  1.
5.
Partici pa nts w h o are willi n g a n d a ble t o c o m pl y wit h all sc he d ule d visits, treat me nt pla n, 
la b orat or y tests, lifestyl e c o nsi derati o ns, a n d ot her st u d y pr oce d ures –

I ncl u di n g f oll o wi n g c om pleti o n of scree ni n g/ baseli ne li ver bi o ps y, partici pa nts 
m ust c o nfir m willi n g ness t o u n der g o t he 2 n d bi o ps y , w hile i n st u d y.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1
Wei g ht:
6.
B MI
≥2 5 . 0 k g/ m 2 (f or sites i n Africa, E ur o pe, N ort h/ S o ut h A merica ) or ≥2 2. 5 k g/ m 2 (f or 
sites i n Asia) wit h u p per li mit of 4 5 k g/ m 2 (i ncl u di n g r o u n di n g t o a ma xi m u m of 
4 5. 1 k g/ m 2, calc ulate d usi n g s p o ns or-pr o vi de d N A S H t o ol) at Pre Q a n d S C R 1 wit h a 
si n gle re peat assess me nt of b o d y wei g ht a n d/ or B MI per mitte d o n a differe nt d ay t o 
assess eli gi bilit y, if nee de d, at eac h of t hese 2 visits ;

I n all cases, eli gi bilit y m ust c o nf or m t o a bilit y t o ascertai n ev al u a ble Fi br o Sca n ®
(Secti o n 8. 1. 2. 1 ) a n d c o n d uct of perc ut a ne o us li ver bi o ps y (Secti o n 8. 1. 1 ).
7.
B o d y wei g ht m ust be sta ble ( ie, n ot var y  b y ≥5 % f or at least 1 2 wee ks bef ore S C R 1 ).
I nf or me d C o nse nt:
8.
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n A p pe n di x 1 , w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restr icti o ns liste d i n t he IC Ds a n d i n t his pr ot oc ol 
at Pre Q a n d S C R 1 ;

F or partici pa nts w h o q ualif y  base d o n Pre Q pr oce d ures, at S C R 1, e vi de nce of a 
se p ar ate 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 partici pa nt has bee n i nf or me d of all perti ne nt as pects of t he mai n st u d y, is 
re q uire d;

Pl us, a n a d diti o n al pr ovisi o n/flexi bility f or t h ose partici pati n g i n I ma gi n g 
S u bst u d y  t o offer de dicate d c o nse nt f or t his pr oce d ure cl oser ( b ut pri or) t o
Baseli ne M RI- P D F F or at t he ti me of c o nse nt o btai ne d at S C R 1. 
5. 2. E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a ny of t he f oll o wi n g criteria a p pl y :
Me dic al C o n diti o ns:
1.
C urre nt si g nifica nt alc o h ol c o ns u m pti o n at eit her Pre Q or S C R 1 defi ne d as a n y  o ne of 
t hese para meters – wit h a si n gle re peat assess me nt of la b orat or y -relate d para meters 
per mitte d usi n g sp o ns or -i de ntifie d ce ntral la b orat or y, t o assess eli gi bilit y, if nee de d, at 
eac h of t hese 2 visits : 

> 1 4 dri n ks/ wee k ( me n) a n d > 7 dri n ks/ wee k ( w o me n) w here 1 dri n k = 5 o u nces 
( 1 5 0 m L ) of wi ne or 1 2 o u nces ( 3 6 0 m L) of beer or 1. 5 o u nces ( 4 5 m L) of har d 
li q u or;

% C D T (car b o h y drate deficie nt tra nsferri n) ≥1. 5 x U L N ;

T otal sc ore of ≥8 o n t he A U DI T q uesti o n naire .
2.
E vi de nce of ot her ca uses of li ver disease at eit her Pre Q or S C R 1 , i ncl u di n g a n y of t he 
f oll o wi n g – wit h a si n gle re peat assess me nt of la b orat or y -relate d para meters per mitte d 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
usi n g sp o ns or -i de ntifie d ce ntral la b orat or y, t o assess eli gi bilit y, if nee de d, at eac h of 
t hese 2 visits : 

A lc o h olic steat o he patitis;

C o m pe nsate d a n d dec o m pe nsate d cirr h osis;

Acti ve viral he patitis B – defi ne d b y prese nce of H Bs A g;

A cti ve viral he patitis C – defi ne d as prese nce of H C V A b;

T h ose w h o are c ure d a re eli gi ble s o l o n g as t here is e vi de nce of S V R f or 
≥3 ye ars, defi ne d as ne gati ve H C V R N A res ult ;

HI V i nfecti o n defi ne d as prese nce of HI V a nti b o d y ;

H e pat ocell ular carci n o ma or ot her t y pes of li ver ca ncer;

Wils o n’s disease, defi ne d as cer ul o plas mi n le vel < 0. 1 g/ L; 

A 1 A T deficie nc y , defi ne d as A 1 A T le vel < L L N; 

U p per gastr oi ntesti nal blee d d ue t o es o p ha geal varices, li ver tra ns pla nt , or c urre nt 
M E L D- Na sc ore2 5 > 1 2; 

Hist ol o gical prese nce of cirr h osis o n scree ni n g/ baseli ne li ver bi o ps y.
3.
Hist or y  of pa ncreatitis, at Pre Q .
4.
A n y  c o n diti o n p ossi bl y affecti n g dr u g a bs or pti o n (e g, pri or bariatric s ur ger y, 
gastrect o m y, ileal resecti o n) at Pre Q ;

Partici pa nts w h o ha ve u n der g o ne c h olec ystect o m y a n d/ or a p pe n dect o m y are 
eli gible f or t his st u d y  s o l o n g as t he s ur ger y occ urre d > 6 m o nt hs pri or t o Pre Q .
5.
Dia g n osis of T 2 D M w hic h re q uires ma na ge me nt wit h > 3 me dicati o ns wit hi n 1 2 wee ks 
pri or t o S C R 1 or ma na ge me nt wit h e xcl u de d a ge nts f or gl yc e mic c o ntr ol – refer t o
Secti o n 6. 5. 1 .
6.
D y sli pi de mia w hic h re q uires ma na ge me nt wit h > 3 li pi d-m o dif y i n g a ge nts wit hi n 
1 2 wee ks pri or t o S C R 1 or use of e xcl u de d a ge nts f or li pi d ma na ge me nt –

I n a d diti o n, s pecific restricti o ns nee d t o be satisfie d at S C R 1 i n or der t o pr o gress 

T h ose o n ge mfi br ozil or l o vastati n will nee d t o a gree t o be s witc he d t o 
a n ot her a ge nt o nce dee me d eli gi ble (ie, at i nitiati o n of R u n- I n) a n d f or 
d urati o n of st u d y ;

T h ose o n stati ns will be per mitte d base d o n re vie w of t he t otal dail y  d ose –
refer t o Secti o n 6. 5. 2 .
7.
At Pre Q or S C R 1, t h ose wit h se vere h y p erte nsi o n defi ne d as seate d s ys t olic B P 
≥1 8 0 m m H g , diast olic B P ≥1 0 5 m m H g , or b ot h, wit h a si n gle re peat per mitte d, if 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3
nee de d, t o assess eli gi bilit y  at eac h of t hese 2 visits; a n d/ or ma na ge d wit h > 3 a ge nts t o 
c o ntr ol B P wit hi n 1 2 wee ks pri or t o S C R 1 (refer t o Secti o n 6. 5. 3 f or acce pta ble 
me dicati o ns) -

B P m ust be assesse d usi n g a bl o o d press ure c uff size a vaila ble at i n di vi d ual sites 
a n d c o m pati ble wit h t he ar m circ u mfere nce of t he partici pa nt – refer t o
Secti o n 8. 2. 4 ;

Partici pa nts wit h s eate d B P ≥1 6 0/ 1 0 0 m m H g at Pre Q or S C R 1 m ust use t he R u n -
I n peri o d t o re vise/a dj ust me dicati o ns t o i m pr o ve B P c o ntr ol wit h B P -relate d 
ra n d o mizati o n criteria met bef ore d osi n g o n Da y 1/ Visit 5 – refer t o Secti o n 5. 3 .
8.
Car di o vasc ular e ve nt wit hi n 1 2 m o nt hs pri or t o Pre Q ; ie:

A hist or y  of my o car dial i nfarcti o n, str o ke, tra nsie nt isc he mic attac k or 
re vasc ularizati o n pr oce d ure t o pre ve nt a ny of t hese e ve nts;

Rece nt hist or y  of c o n gesti ve heart fail ure ( N Y H A class III or I V) or u nsta ble 
a n gi na.
9.
Rece nt ( wit hi n 5 years of Pre Q ) s yste mically a d mi nistere d treat me nts f or mali g na nc y 
i ncl u di n g ( b ut n ot li mite d t o) t he use of c he m ot hera p y, ra di ot hera py, or i m m u n ot hera p y;

Or a n y ot her acti ve mali g na nc y  ( wit hi n 3 years of Pre Q), e xce pt f or a de q uat el y 
treate d basal cell or s q ua m o us cell s ki n ca ncer, or carci n o ma i n sit u.
1 0. Ot her me dical or ps y c hiatric c o n diti o n i ncl u di n g rece nt ( wit hi n t he past year) or acti ve 
s uici dal i deati o n/ be ha vi or or la b orat or y a b n or malit y t hat ma y i ncrease t he ris k of st u d y 
par tici pati o n or, i n t he i n vesti gat or’s j u d g me nt, ma ke t he partici pa nt i na p pr o priate f or t he 
st u d y.
Pri or/ C o nc o mit a nt T her a p y:
1 1. At S C R 1, o n a n y  pr o hi bite d c o nc o mita nt me dicati o n(s) or t h ose u n willi n g/ u na ble t o 
s witc h t o per mitte d c o nc o mita nt me dicati o n(s) – refer t o Secti o n 6. 5. 5 .
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce:
1 2. K n o w n pri or partici pati o n i n a trial i n v ol vi n g D G A T 2i or A C Ci (ie, ra n d o mize d a n d 
recei ve d at least 1 d ose of st u d y i nter ve nti o n, i ncl u di n g place b o).
1 3. Pre vi o us a d mi nistrati o n wit h a n i n vesti gati o nal dr u g or vacci ne wit hi n 3 0 da y s (or as 
deter mi ne d b y t he l ocal re q uire me nt) o r 5 half -li ves prece di n g t he first d ose of st u d y 
i nter ve nti o n use d i n t his st u d y ( w hic he ver is l o n ger);
N O T E : a d mi nistrati o n of i nvesti g ati o n al C O VI D- 1 9 vacci nes ( 1 d ose or 2 n d d ose of 
2 -d ose re gi me n) d uri n g t he scree ni n g p hase is all o we d u p t o 3 0 da y s pri or t o Visit 
4/ Baseli ne ; f or a d diti o nal g ui da nce re gar di n g a d mi nistrati o n of C O VI D 1 9 vacci nes, 
refer t o Secti o n 8. 2 ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4

C O VI D - 1 9 vacci nes a ut h orize d u n der a n E U A are n ot c o nsi dere d 
i n vesti gati o nal.
Di a g n ostic Assess me nts:
1 4. Res ults as re p orte d b y s p o ns or -i de ntifie d ce ntral la b orat or y, at eit her Pre Q or S C R 1 , as 
bel o w wit h a si n gle re peat assess me nt per mitte d usi n g sp o ns or -i de ntifie d ce ntral 
la b orat or y, t o assess eli gi bilit y, if nee de d, at eac h of t hese 2 visits :

A L T < 0. 5 x U L N or > 5 x U L N;

A S T > 5 x U L N;

A L P > 2 x U L N ; 

D irect bilir u bi n > U L N;

T otal bilir u bi n > U L N e xce pt w he n p artici pa nts has a hist or y of Gil bert sy n dr o me
w here t otal bilir u bi n > U L N w o ul d be eli gi ble f or t his st u d y  pr o vi de d direct 
bilir u bi n le vel is ≤U L N, a n d he m o gl o bi n a n d retic ul oc y te c o u nt are wit hi n t he 
refere nce ra n ge of t he s p o ns or-i de ntifie d ce ntral la b orat or y;
N O T E: If t here is a > 5 0 % varia bilit y bet wee n t he PreQ a n d S C R 1 res ults f or 
A L T, A S T, or al kali ne p h os p hatase or t otal bilir u bi n is > U LN, t hese L F Ts 
m ust be re peate d 1 a d diti o nal ti me, ≥2 wee ks after S C R 1 , wit h t he varia bilit y 
bet wee n t he Pre Q a n d t he 1 a d diti o nal meas ure me nt c o nfir me d t o be ≤5 0 % f or 
A L T, A S T, a n d al kali ne p h os p hatase, a n d t otal bilir u bi n ≤U L N, a n d wit hi n 
t he para meters a b o ve t o c o nfir m eli gi bilit y pri or t o pr o gressi n g t o c o n d uct of 
li ver bi o ps y at S C R 2;

H b A 1 C > 9 % ( 7 5 m m ol/ m ol), as assesse d usi n g N G S P certifie d met h o d a n d 
sta n dar dize d t o D C C T assa y;

Fasti n g Plas ma Gl uc ose > 2 7 0 m g/ d L (1 5 m m ol/ L) ;

Fasti n g ser u m tri gl yceri des > 4 0 0 m g/ d L ( 4. 5 m m ol/ L );

Platelet c o u nt < L L N ;

I N R ≥1. 3 ;

Al b u mi n < L L N ;

e G F R ( usi n g C K D -E PI -C y stati n-C) of < 3 0 ml/ mi n/ 1. 7 3 m 2;

A p ositi ve uri ne dr u g test f or illicit dr u gs ( wit h t his 1 assess me nt n ot per mitte d t o 
be re peate d at eac h visit t o c o nfir m eli gi bilit y ).
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5
1 5. At Pre Q or S C R 1, s u pi ne 1 2-lea d E C G de m o nstrati n g Q Tc i nter val > 4 8 0 msec or Q R S 
i nter val > 1 2 0 msec;

If Q Tc i nter val e xcee ds 4 8 0 msec or Q R S i nter val e xcee d 1 2 0 msec, t he 1 2 -lea d 
E C G s h o ul d be re peate d t wice ( o n t he sa me or differe nt da y ) a n d t he aver a ge of 
t hree Q Tc / Q R S i nter vals use d t o deter mi ne eli gi bilit y ;

N O T E : if u nc orrecte d Q T i nter val is > 4 8 0 msec, t his i nter val m ust be rate-
c orrecte d usi n g t he Fri dericia met h o d, wit h t he res ulti n g Q Tc F use d f or decisi o n 
ma ki n g a n d re p orti n g.
Ot her E xcl usi o ns:
1 6. Partici pa nts meeti n g criteria f or c o ntrai n dicati o n t o u n der g oi n g i ma gi n g assess me nts at 
eit her Pre Q or S C R 1 ;

Acti ve place me nt of me dical de vices i n/ o n t h oracic ca vit y – s uc h as pace ma kers, 
defi brillat ors [as t hese i nterfere wit h use of Fi br o Sca n ® a n d M RI];

I n a d diti o n, f or partici pa nts i n t he Ima gi n g S u bst u d y , hist or y/e vi de nce of a n y of 
t he f oll o wi n g –

C o ntrai n dicati o n t o M RI s uc h as ferric i m pla nt;

Hist or y  of se vere cla ustr o p h o bia i m pacti n g a bilit y t o perf or m M RI d uri n g 
t he st u d y eve n des pite mil d se dati o n/treat me nt wit h a n a n xi ol y tic;

I na bilit y t o lie still wit hi n t he e n vir o n me nt of t he M RI sca n ner or mai ntai n 
a breat h h ol d f or t he re q uire d peri o d t o ac q uire i ma ges eve n des pite mil d 
se dati o n/treat me nt wit h a n a n xi ol ytic;

I na bilit y t o fit i nsi de t he site-s pecific M RI mac hi ne a n d its’ res pecti ve bore size t o 
per mit ac q uisiti o n of a n ev al u a ble M RI  – refer t o Secti o n 8. 1. 2. 2 .
1 7. I n vesti gat or site staff or Pfizer e m pl o yees directl y i n v ol ve d i n t he c o n d uct of t he st u d y , 
site staff ot her wise s u per vise d b y t he i n vesti gat or, a n d t heir res pecti ve fa mil y me m bers.
5. 3. R a n d o miz ati o n Criteri a
A c o m p uter -ge nerate d ra n d o mizati o n c o de usi n g t he met h o d of ra n d o m per m ute d bl oc ks will 
be utilize d t o ra n d o mize partici pa nts e q uall y bala nce d acr oss t he 9 st u d y i nter ve nti o ns 
( Ori gi nal Pr ot oc ol) or t he 7 st u d y i nter ve nti o ns (Pr ot oc ol A me n d me nt 1 ) o n D a y 1 / Visit 5
pri or t o t he first d ose of t he d o u ble- bli n d, d o u ble -d u m m y  st u d y i nter ve nti o n pr o vi de d 
partici pa nts satisf y  all t he f oll o wi n g criteria:

Eli gi bilit y  criteria o utli ne d i n Secti o n 5. 1 a n d Secti o n 5. 2 ;

I ncl u di n g rec o nfir mi n g t hat partici pa nts are willi n g ness t o u n der g o t he 2 n d
bi o ps y , w hile i n t he st u d y;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6

A ne gati ve uri ne dr u g test f or illicit dr u gs f or sa m ple c ollecte d at Visit 4/ Baseli ne, 
as re p orte d b y s p o ns or -i de ntifie d ce ntral la b orat or y;

Fasti n g ( ≥8 h o urs o ver ni g ht, wit h water per mitte d) ser u m tri gl y ceri de res ult of 
≤4 0 0 m g/ d L ( 4. 5 m m ol/ L), f or sa m ple c ollecte d at Visit 4/ Baseli ne , as re p orte d 
b y s p o ns or-i de ntifie d ce ntral la b orat or y

A si n gle re peat assess me nt per mitte d usi n g s p o ns or -i de ntifie d ce ntral 
la b orat or y, t h o u g h res ults of t his re peat, w he n d o ne, m ust be a vaila ble a he a d
of ra n d o mizati o n;

Fasti n g ( ≥8 h o urs o ver ni g ht, wit h water per mitte d) plas ma gl uc ose res ult of 
≤2 7 0 m g/ d L ( 1 5 m m ol/ L), f or sa m ple c ollecte d at Visit 4/ Baseli ne , as re p orte d b y
s p o ns or-i de ntifie d ce ntral la b orat or y

A si n gle re peat assess me nt per mitte d usi n g s p o ns or -i de ntifie d ce ntral 
la b orat or y, t h o u g h res ults of t his re peat, w he n d o ne, m ust be a vaila ble a he a d
of ra n d o mizati o n;

I n fe m ales, a ne gati ve ser u m pre g na nc y test res ult at Visit 4/ Baseli ne, as re p orte d 
b y  s p o ns or-i de ntifie d ce ntral la b orat or y;

Pl us , i n fe males of c hil d beari n g p ote ntial, uri ne pre g na nc y  test o n 
D a y 1/ Visit 5, as re p orte d o n-site usi n g s u p plies offere d b y s p o ns or-
i de ntifie d ce ntral la b orat or y, are ne gati ve f or pre g na nc y – refer t o 
Secti o n 8. 2. 6 ;

I n t h ose wit h hy perte nsi o n, B P c o ntr olle d via a dj ust me nt of c o nc o mita nt 
me dicati o ns f or B P c o ntr ol d uri n g t he R u n -I n peri o d wit h seate d B P o n 
D a y 1/ Visit 5 of < 1 6 0/ 1 0 0 m m H g ;

N ote d t o be ≥9 0 % a n d ≤1 1 0 % c o m plia nt wit h d oses a d mi nistere d ( base d o n 
ta blet c o u nt) wit h t he si n gle-bli n d place b o a d mi nistere d fr o m Visit 4/ Baseli ne t o 
1 d ay bef ore D a y  1/ Visit 5, i ncl usi ve – refer t o Secti o n 6. 4 ; 

T otal sc ore of < 8 o n t he A U DI T q uesti o n naire, as assesse d o n Da y  1/ Visit 5.
St u d y will e m pl o y a p pr o xi matel y e q ual stratificati o n acr oss F 2 vs F 3 sta ges of fi br osis o n 
scree ni n g/ baseli ne li ver bi o ps y. I n a d diti o n, atte m pts will be ma de t o bala nce ra n d o mizati o n 
acr oss t he st u d y i nter ve nti o n ar ms i n t he I ma gi n g S u bst u d y (ie, M RI-P D F F) .
5. 4. Lifest yle C o nsi der ati o ns
After c o nfir mati o n of eli gi bilit y  acr oss Pre Q, S C R 1, a n d S C R 2, at Visit 3/ R u n -I n
(c o n d ucte d eit her via tele p h o ne c o ntact or as a n o n-site visit), partici pa nts will be i nstr ucte d 
t o mai ntai n t he g ui deli nes descri be d bel o w f or t he d urati o n of t heir partici pati o n i n t he st u d y . 
T hese g ui deli nes m ust be rei terate d o n Da y  1/ Visit 5.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7
5. 4. 1. C o ntr ace pti o n
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 p artici p a nt of c hil d be ari n g 
p ote nti al , will c o nfir m t hat t he partici pa nt has selecte d a n a p pr o priate met h o d of 
c o ntrace pti o n f or t he i n di vi d ual partic i pa nt fr o m t he per mitte d list of c o ntrace pti o n met h o ds 
(see A p pe n di x 4 ) a n d will c o nfir m t hat t he partici pa nt 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 S o A -Ta ble A 1 , t he i n vesti gat or or desi g nee 
will i nf or m t he partici pa nt 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 orrectl y a n d d oc u me nt t he c o n versati o n a n d t he partici pa nt’s affir mati o n i n t he partici pa nt’s 
c hart ( partici pa nts nee d t o affir m t heir 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 
partici pa nt 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 partici pa nt or part ner.
5. 4. 2.
Me als a n d Diet ar y Restricti o ns

Partici pa nts m ust a bstai n fr o m all f o o d a n d dri n k (e xce pt water) f o r ≥8 h o urs pri or t o 
a n y bl o o d sa m ple c ollecti o ns f or cli nical la b orat or y tests, a n d t he pre d ose P K- a n d 
e x pl orat or y bi o mar ker-relate d c ollecti o ns;

Water ma y  be c o ns u me d as desire d (a d li bit u m);

Partici pa nts m ust a bstai n fr o m all f o o d a n d dri n k (t h o u g h water is per mi tte d) fo r 
≥4 h o urs pri or t o –

C o n d uct of t he Fi br o S ca n ® assess me nt 

A n y M RI -P D F F assess me nt (if partici pati n g i n I ma gi n g S u bst u d y )

Bli n de d st u d y  i nter ve nti o n m ust be a d mi nistere d t wice-a-d a y  wit h –

M or ni n g d ose at a p pr o xi matel y  0 8: 0 0 A M ( ± 2 h o urs), l ocal ti me wit h 
brea kfast/ meal

Sec o n d d ose, at a p pr o xi matel y ≥8 a n d ≤1 2 h o urs after t he m or ni n g d ose, wit h t he 
e ve ni n g meal;

At sc he d ule d o ut patie nt visits t o t he site, i n t he m or ni n g, fr o m Visit 4/ Bas eli ne 
t hr o u g h Wee k 4 8/ Visit 1 9 , partici pa nts m ust be i nstr ucte d t o arri ve wit h o ut ha vi n g 
c o ns u me d t he m or ni n g meal/ brea kfast a n d wit h o ut ta ki n g t he m or ni n g d ose of t he 
st u d y i nter ve nti o n a n d c o nc o mita nt me dicati o ns f or ma na ge me nt of gl y ce mic c o ntr ol 
(Secti o n 6. 5. 1 ), li pi d c o ntr ol (Secti o n 6. 5. 2 ), a n d bl o o d press ure ( Secti o n 6. 5. 3 );

At Visit 4/ Baseli ne t hr o u g h Wee k 4 8/ Visit 1 9, i ncl usi ve, f oll o wi n g c o m pleti o n of 
all pre d ose pr oce d ures, t he m or ni n g meal will be c o ns u me d wit h a b o ve-
me nti o ne d me dicati o ns at t he site ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8

T he m or ni n g meal d uri n g site visits will be eit her pr o vi de d b y t he site, or t he 
partici pa nt pr o vi de d a v o uc her [ or si milar] b y  t he site t o p urc hase t he meal
bef ore arri vi n g at t he site f or eac h visit .

Partici pa nts will be c o u nsele d o n a p pr o priate dietar y  a n d lifestyl e g ui deli nes, at 
Visit 3/ R u n -I n (c o n d ucte d eit her via tele p h o ne c o ntact or a n o n -site visit) a n d a gai n
at t he o n -site visit o n Da y 1/ Visit 5 :

C o u nseli n g o n dietar y g ui deli nes s h o ul d be i n di vi d ualize d i n acc or da nce wit h 
l ocal me dical sta n dar ds of care f or t hese partici pa nts a n d a p pr o priate f or t he 
c o nc o mita nt me dical c o n diti o n(s) of eac h partici pa nt;

Partici pa nts will be as ke d t o mai ntai n t hese g ui d eli nes t hr o u g h o ut t he st u d y (ie, 
u p t o t he 1st F oll o w - u p/ Visit 2 0). 
5. 4. 3. Alc o h ol, C affei ne, a n d T o b acc o

I nta ke of alc o h ol is per mitte d i n m o derati o n – refer t o excl usi o n criteri o n 1 i n 
Secti o n 5. 2 f or li mits o n a m o u nt of alc o h ol c o ns u m pti o n;

C o ns u m pti o n of caffei nate d dri n ks a n d nic oti ne -c o ntai ni n g pr o d ucts is per mitte d 
d uri n g partici pati o n i n t he st u d y ; h o we ver –

T here ma y  be a nee d f or brief i nterr u pti o n w hile at t he site a n d/ or i ma gi n g 
facilit y, de pe n di n g o n l ocal p olic y;

C o ns u m pti o n is pr o hi bite d for at least 1 h o ur pri or t o a n y  vital si g n meas ure me nt.
5. 4. 4. Acti vit y
Partici pa nts will n ot be per mitte d t o e n ga ge i n p h ysicall y stre n u o us e xercise (f or e xa m ple: 
hea v y lifti n g, wei g ht trai ni n g, calist he nics, a n d aer o bics) –

Wit hi n 4 8 h o urs bef ore eac h bl o o d sa m ple c ollecti o n f or cli nical la b orat or y  tests f or t he 
d urati o n of partici pati o n i n t he st u d y ;

Wit hi n 4 8 h o urs after c o m pleti o n of t he li ver bi o ps y pr oce d ure

P h y sical acti vit y at a n i n di vi d ual partici pa nt’s n or mal pace is per mitte d.
5. 4. 5. O ut p atie nt Visits t o Site 

Eac h o ut patie nt visit t o t he site ( or I ma gi n g / Ra di ol o g y facilit y) is e n visi o ne d t o occ ur 
wit h t he p artici p a nt arrivi n g at t he site bet wee n a p pr o xi matel y  6 A M a n d 1 0 A M 
wit h eac h visit lasti n g a p pr o xi matel y  2 h o urs ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9

At selecte d visits , t o per mit c ollecti o n of p ost d ose bl o o d sa m ples f or P K, 
partici pa nts ma y  eit her e xte n d t heir sta y o n-site after d osi n g or lea ve a n d ret ur n 
later t he s a me d ay – refer t o Secti o n 8. 5 f or details. 
5. 4. 6. O ut p atie nt Visits t o I m a gi n g/ R a di ol o g y F acilit y 

Ultras o u n d -g ui de d per c uta ne o us li ver bi o ps y of t he ri g ht l o be, s h o ul d be perf or me d, 
f oll o wi n g ≥4 -h o ur fast, b y  trai ne d, me dically- q ualifie d i n vesti gat or – refer t o 
Secti o n 8. 1. 1 f or a d diti o nal details.

Assess me nt via Fi br o Sca n ® , (i n t he e ntire st u d y p o p ulati o n), will occ ur eit her at t he 
site or t he i ma gi n g facilit y, de pe n di n g o n w here t he Fi br o Sca n® de vice is l ocate d ;

H o we ver, t he l ocati o n of t he de vice m ust be ke pt c o nsiste nt at i n di vi d ual sites 
t hr o u g h o ut st u dy e xec uti o n;

Assess me nt t o occ ur at t he sa me ti me of da y  (± 2 h o urs) relati ve t o Fi br o Sca n ®
assess me nt c o m plete d at Pre Q , as m uc h as pr actic ally p ossi ble – refer t o
Secti o n 8. 1. 2. 1 f or a d diti o nal details. 

Assess me nt of M RI -P D F F (i n t he I ma gi n g S u bst u d y  p o p ulati o n), t o occ ur at t he sa me 
ti me of da y (± 2 h o urs) relati ve t o Baseli ne M RI -P D F F c o m plete d bet wee n 
Visit 4/ Bas eli ne a n d pri or t o 1 st d ose i n Da y  1/ Visit 5, as m uc h as pr actic ally 
p ossi ble ; refer t o Secti o n 8. 1. 2. 2 f or a d diti o nal details.
5. 5. Scree n F ail ures
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y  b ut 
are n ot s u bse q ue ntl y ra n d o ml y assi g ne d t o st u d y i nter ve nti o n/e ntere d i n t he st u d y. A mi ni mal 
set of scree n fail ure i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure 
partici pa nts t o meet t he C O N S O R T p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m 
re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, a n d 
a n y S A E.
T he li mite d p artici pa nts w h o scree n faile d, u n der t he Ori gi nal P r ot oc ol e xcl usi vel y relate d t o 
t he i ncl usi o n criteri o n # 3 , i ncl usi o n criteri o n # 4 , a n d/ or i ncl usi o n criteri o n # 6 , ca n be 
re-scree ne d after Healt h A ut h orit y  ( w here a p plica ble) a n d I R B/ E C a p pr o vals of Pr ot oc ol 
A me n d me nt 1 – if t he a me n de d eli gi bilit y criteria ca n be met . I n a d diti o n , i n r are cases, 
partici pa nts m a y  be re-scree ne d; h o we ver, t his is per mitte d o nly w he n, d ue t o 
l o gistic al/ a d mi nistr ative c o nstr ai nts , t he ma xi m u m peri o d bet wee n Pre Q a n d Da y  1/ Visit 5, 
of 1 6 wee ks, is e xcee de d;

All suc h cases m ust be re vie we d wit h a me m ber of t he sp o ns or’s Cli nical tea m bef ore
t he gi ve n partici pa nt is re-c o nse nte d;

A ll Pre Q a n d S C R 1 pr oce d ures m ust be re peate d u n der a ne w 8 -di git S SI D n u m ber ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0

Partici pa nts m ust be dee me d t o meet all t he eli gi bilit y  criteria i ncl u di n g hist ol o gical 
assess me nt of N A S H wit h F 2 o r F 3 fi br osis o n S C R 2 li ver bi o ps y, as assesse d b y 
s p o ns or-i de ntifie d ce ntral pat h ol o gist(s).
6. S T U D Y I N T E R V E N TI O N
St u d y  i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), 
place b o, me dical de vice(s), or st u d y  pr oce d ure(s) i nte n de d t o be a d mi nistere d t o a st u d y 
partici pa nt acc or di n g t o t he st u d y  pr ot oc ol.
F or t he p ur p oses of t his pr ot oc ol, st u d y i nter ve nti o n refers t o all of t he f oll o wi n g:

Place b o matc hi n g D G A T 2i;

Place b o matc hi n g A C Ci;

D G A T 2i;

A C Ci.
6. 1. St u d y I nter ve nti o n(s) A d mi nistere d
T he f oll o wi n g ta blet stre n gt hs will be pr o vi de d ce ntrall y b y t he s p o ns or f or use as st u d y 
i nter ve nti o n:

F or D G A T 2i –
 P F-0 6 8 6 5 5 7 1 ta blets a n d matc hi n g 
place b o;

F or A C Ci –
 P F- 0 5 2 2 1 3 0 4 ta blets a n d matc hi n g place b o.
T he st u d y  i nter ve nti o n a b o ve, will be pac ka ge d t o get her i n bli n de d blister car ds, acc or di n g t o 
t he treat me nt ar ms as n ote d i n Ta ble 3, a n d will be dis pe nse d b y  t he I R T syste m i n s ufficie nt 
q ua ntities t o e na ble d osi n g d uri n g t he i nter vals bet wee n visits o utli ne d i n t he S o A -Ta ble A 1 .
O ne e xtra blister car d will be dis pe nse d at e ac h dis pe nsati o n visit t o s u p p ort t he fle xi bilit y 
pr o vi de d b y t he visit wi n d o ws. Eac h bli n de d blister car d s u p p orts oral d osi n g f or 7 d a y s a n d 
will be la bele d acc or di n g t o i n di vi d ual c o u ntr y  re g ulat or y re q uire me nts. Acr oss t he 
9 ( Ori gi nal P r ot oc ol) or 7 ( Pr ot oc ol A me n d me nt 1 ) treat me nt ar ms, d o u ble-bli n d, d o u ble -
d u m m y  a d mi nistrati o n of st u d y i nter ve nti o n will be mai ntai ne d as o utli ne d i n Ta ble 3 . Eac h 
d ose w ill c o nsist of 3 ta blets, ie, 2 lar ge ta blets ( D G A T 2i/ matc hi n g place b o) a n d 1 s mall 
ta blet ( A C Ci/ matc hi n g place b o).
T a ble 3.  
D o u ble -bli n d, D o u ble - d u m m y Re gi me ns i n St u d y C 2 5 4 1 0 1 3
Re gi m e n
D ose 
D G A T 2i
A C Ci
T a blet stre n gt h ( m g)
Pl ace b o/ 0
Pl ace b o/ 0
A
Place b o
A M
2
-
-
-
1
-
-
P M
2
-
-
-
1
-
-
B
D G A T 2i 
2 5 m g BI D
A M
1
1
-
-
1
-
-
P M
1
1
-
-
1
-
-
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1
T a ble 3.  
D o u ble -bli n d, D o u ble - d u m m y Re gi me ns i n St u d y C 2 5 4 1 0 1 3
Re gi m e n
D ose 
D G A T 2i
A C Ci
T a blet stre n gt h ( m g)
Pl ace b o/ 0
Pl ace b o/ 0
C
D G A T 2i 
7 5 m g BI D
A M
-
1
1
-
1
-
-
P M
-
1
1
-
1
-
-
D
D G A T 2i 
1 5 0 m g BI D
A M
1
-
-
1
1
-
-
P M
1
-
-
1
1
-
-
E
D G A T 2i 
3 0 0 m g BI D
A M
-
-
-
2
1
-
-
P M
-
-
2
1
-
-
F a
D G A T 2i 
1 5 0 m g Q D
A M
1
-
-
1
1
-
-
P M
2
-
-
1
-
-
G b
D G A T 2i 
3 0 0 m g Q D
A M
-
-
-
2
1
-
-
P M
2
-
-
1
-
-
H
D G A T 2i 
( 1 5 0 m g BI D) + A C Ci ( 5 m g BI D)
A M
1
-
-
1
-
1
-
P M
1
-
-
1
-
1
-
I
D G A T 2i 
( 3 0 0 m g BI D) + A C Ci ( 1 0 m g BI D)
A M
-
-
-
2
-
-
1
P M
-
-
-
2
-
-
1
a. Partici pa nts ra n d o mize d t o Re gi me n F as part of t he O ri gi nal P r ot oc ol will be s witc he d t o Re gi me n C at t heir
ne xt o n -site visit, a n d ne w  ra n d o mizati o n t o Re gi me n F will cease, after Healt h A ut h orit y ( w here a p plica ble) 
a n d I R B/ E C a p pr o val s of Pr ot oc ol A me n d me nt 1 – wi t h t he d o u ble-bli n d , d o u ble-d u m m y desi g n mai ntai ne d ; 
b. Partici pa nts ra n d o mize d t o Re gi me n G as part of t he O ri gi nal P r ot oc ol will be s witc he d t o Re gi me n D at t heir 
ne xt o n -site visit, a n d ne w  ra n d o mizati o n t o Re gi me n G will cease, after Healt h A ut h orit y ( w here a p plica ble) 
a n d I R B/ E C a p pr o val s of Pr ot oc ol A me n d me nt 1 – wi t h t he d o u ble-bli n d , d o u ble-d u m m y desi g n mai ntai ne d
6. 1. 1. A d mi nistr ati o n
Partici pa nts will eit her self -a d mi nister o n-site ( d uri n g sc he d ule d visits) or at h o me wit h 
meals – t wice- a-d a y  as o utli ne d i n Secti o n 5. 4. 2 . Partici pa nts will s wall o w t he st u d y 
i nter ve nti o n w h ole a n d will n ot ma ni p ulate or c he w t he st u d y i nter ve nti o n pri or t o 
s wall o wi n g. A n d eac h da y, partici pa nts will be i nstr ucte d t o c o ns u me orall y, t he 3 ta blets 
wit h t he m or ni n g mea l a n d 3 ta blets wit h t he e ve ni n g meal.
6. 2. Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
1.
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  i nter ve nti o ns recei ve d a n d a n y discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u dy i nter ve nti o n. 
2.
O nl y  partici pa nts enr olle d i n t he st u d y  ma y recei ve st u d y i nter ve nti o n a n d o nl y 
a ut h orize d site staff ma y  s u p pl y or a d mi nister st u d y i nter ve nti o n. All st u d y i nter ve nti o ns 
m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or 
a ut o mate d rec or di n g) ar ea i n acc or da nce wit h t he la bele d st ora ge c o n diti o ns wit h access 
li mite d t o t he i n vesti gat or a n d a ut h orize d site staff. 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 m ust be d oc u me nte d a n d a vaila ble 
u p o n re q uest. Data f or n o n w or ki n g da ys m ust i n dicate t he mi ni m u m a n d ma xi m u m 
te m perat ures si nce pre vi o usl y d oc u me nte d f or all site st ora ge l ocati o ns u p o n ret ur n t o 
b usi ness.
3.
A n y  e xc ursi o ns fr o m t he st u d y i nter ve nti o n la bel st ora ge c o n diti o ns s h o ul d be re p orte d t o 
Pfizer u p o n disc o ver y  al o n g wit h a ny acti o ns ta ke n. T he site s h o ul d acti vel y  p urs ue 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
o pti o ns f or ret ur ni n g t he st u d y  i nter ve nti o n 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. O nce a n e xc ursi o n is i de ntifie d, t he st u d y i nter ve nti o n m ust 
be q uara nti ne d a n d n ot use d u ntil Pfizer pr o vi des per missi o n t o use t he st u d y  
i nter ve nti o n. S pecific details re gar di n g t he defi niti o n of a n e xc ursi o n a n d 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.
4.
A n y  st ora ge c o n diti o ns state d i n t he 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 la bel.
5.
St u d y  i nter ve nti o ns s h o ul d be st ore d i n t heir ori gi nal c o ntai ners.
6.
Site staff will i nstr uct partici pa nts o n t he pr o per st ora ge re q uire me nts f or ta ke - h o me 
st u d y i nter ve nti o n.
7.
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u dy i nter ve nti o n acc o u nta bilit y , rec o nciliati o n, a n d rec or d mai nte na nce 
(ie, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds), s uc h as t he I P A L or s p o ns or-
a p pr o ve d e q ui vale nt. All st u d y  i nter ve nti o ns will be acc o u nte d f or usi n g a st u d y 
i nter ve nti o n acc o u nta bilit y f or m/rec or d. All st u d y i nter ve nti o n t hat is ta ke n h o me b y  t he 
partici pa nt, b ot h use d a n d u n use d, m ust be ret u r ne d t o t he i n vesti gat or b y t he partici pa nt. 
Ret ur ne d st u d y  i nter ve nti o n m ust n ot be re dis pe nse d t o t he partici pa nts.
8.
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y  i nter ve nti o ns 
are pr o vi de d i n t he IP ma n ual. All destr ucti o n m u st be a de q uatel y d oc u me nte d. If 
destr ucti o n is a ut h orize d t o ta ke place at t he i n vesti gat or site, t he i n vesti gat or m ust e ns ure 
t hat t he materials are destr o ye 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 instr ucti o ns pr o vi de d b y  Pfizer.
U p o n i de ntificati o n of a pr o d uct c o m plai nt, n otif y t he s p o ns or wit hi n 1 b usi ness da y  of 
disc o ver y  as descri be d i n t he IP ma n ual.
6. 2. 1. Pre p ar ati o n a n d Dis pe nsi n g
A q ualifie d staff me m ber will dis pe nse t he st u d y  i nter ve nti o n usi n g t he I RT s y ste m via 
u ni q ue c o ntai ner n u m bers o n t he blister car ds pr o vi de d, i n q ua ntities a p pr o priate acc or di n g t o 
t he S o A -Ta ble A 1 . A sec o n d staff me m ber will verif y  t he dis pe nsi n g. 
T he partici pa nt 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 blister car ds 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 all blister car ds, b ot h use d a n d u n use d t o t he site 
at t he ne xt o n -site st u d y visit.
6. 3. Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
6. 3. 1. All oc ati o n t o St u d y I nter ve nti o n
A p pr o xi matel y  3 5 0 partici pa nts will be ra n d o mize d i n a bala nce d rati o t o recei ve eit her 
d o u ble -bli n d, d o u ble -d u m m y  place b o, 1 of u p t o 6 d oses/ d osi n g re gi me ns of D G A T 2i al o ne, 
or 1 of 2 d ose -le vels of D G A T 2i + A C Ci . A c o m p uter-ge nerate d ra n d o mizati o n c o de usi n g 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
t he met h o d of ra n d o m per m ute d bl oc ks will be utilize d t o assi g n partici pa nts t o 1 of t he 
9 ( Ori gi nal P r ot oc ol) or 7 ( Pr ot oc ol A me n d me nt 1 ) st u d y i nter ve nti o ns o n Da y 1/ Visit 5.
Partici pa nts ra n d o mize d u n der t he Ori gi nal Pr ot oc ol will re mai n ra n d o mize d u n der Pr ot oc ol 
A me n d me nt 1 , a n d will retai n t heir ori gi nal ra n d o mizati o n n u m ber – r efer t o Ta ble 3 f or 
details o n ma na ge me nt of t he d o u ble- bli n de d treat me nt assi g n me nt bet wee n Ori gi nal a n d 
A me n d me nt 1 of t his pr ot oc ol. 
All ocati o n of partici pa nts t o treat me nt gr o u ps will pr ocee d t hr o u g h t he use of a n I R T s ys te m 
(IW R). 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 mite d t o t he user’s I D a n d pass w or d, t he pr ot oc ol 
n u m ber, a n d t h e u ni q ue 8-di git partici pa nt n u m ber. 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, ra n d o mizati o n n u m ber, a n d D U or c o ntai ner n u m ber(s) fr o m 
t he IR T s ys te m. T he I R T s yste m will pr o vi de a c o nfir mati o n re p ort c o ntai ni n g t he partici pa nt 
n u m ber, ra n d o mizati o n n u m ber, a n d D U or c o ntai ner n u m ber(s) 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 he st u d y  i nter ve nti o n will be dis pe nse d at t he st u d y visits s u m marize d i n t he S o A -Ta ble A 1 ;
wit h ret ur ne d st u d y i nter ve nti o n n ot re dis pe nse d t o t he partici pa nts.
T he st u d y -s pecific IR T refere nce ma n ual a n d I P 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 us e of t he I R T s ys te m.
6. 3. 2. Bre a ki n g t he Bli n d 
T he bli n d s h o ul d o nly be br o ke n i n e mer ge nc y  sit uati o ns f or reas o ns of partici pa nt safety a n d
w he n k n o wi n g t he s pecific st u d y  i nter ve nti o n t hat t he partici pa nt recei ve d alters t he c o urse of 
me dical ma na ge me nt . 
T he I RT will be pr o gra m me d wit h bli n d -brea ki n g i nstr ucti o ns. I n case of a n e mer ge nc y , t he 
i n vesti gat or has t he s ole res p o nsi bilit y f or deter mi ni n g if u n bli n di n g of a partici pa nt’s 
treat me nt assi g n me nt is warra nte d. Partici pa nt safet y m ust al wa ys be t he first co nsi derati o n 
i n ma ki n g s uc h a deter mi nati o n. If t he i n vesti gat or deci des t hat u n bli n di n g is warra nte d, t he 
i n vesti gat or s h o ul d ma ke e ver y eff ort t o c o ntact t he s p o ns or pri or t o u n bli n di n g a 
partici pa nt’s treat me nt assi g n me nt u nless t his c o ul d dela y  f urt her ma na ge me nt of t he 
partici pa nt. If a partici pa nt’s treat me nt assi g n me nt is u n bli n de d, t he s p o ns or m ust be n otifie d 
wit hi n 2 4 h o urs after brea ki n g t he bli n d. T he date a n d reas o n t hat t he bli n d was br o ke n m ust 
be rec or de d i n t he s o urce d oc u me ntati o n a n d C R F.
6. 4. St u d y I nter ve nti o n C o m pli a nce 
C o m plia nce wit h st u d y  i nter ve nti o n will be assesse d at eac h o n-site visit starti n g o n 
D a y 1/ Visit 5 a n d c o nti n ui n g till Wee k 4 8/ Visit 1 9 - refer t o S o A -Ta ble A 1 . C o m plia nce (as 
assesse d b y c o u nti n g blister pac ks a n d/ or ta blets) will be defi ne d as self -a d mi nistrati o n, b y 
t he partici pa nts, of:

Baseli ne peri o d (ie, Visit 4 t o 1 da y  pri or t o Visit 5 ): ≥9 0 % a n d ≤1 1 0 % c o m plia nce wit h 
si n gle-bli n d, st u d y i nter ve nti o n – base d o n n u m ber of d oses a d mi nistere d f or t he s pecific
d urati o n of a d mi nistrati o n; f or ex a m ple, t o re m ai n q u alifie d f or ra n d o mizati o n –
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 4

If d urati o n of d osi n g was 1 0 da y s, partici pa nt ca n miss a ma xi m u m of 2 d ose s (or
ta ke a ma xi m u m of 2 e xtra d ose s)

If d urati o n of d osi n g was 1 8 da y s, partici pa nt ca n miss a ma xi m u m of 3 d oses (or
ta ke a ma xi m u m of 3 e xtra d oses )

D a y  1/ Visit 5 t o last da y of d osi n g or Wee k 4 8/ Visit 1 9 ): ≥8 0 % c o m plia nce wit h 
self-a d mi nistrati o n of t he st u d y i nter ve nti o n is e x pecte d 

I n vesti gat ors m ust cl osel y m o nit or n o n-c o m plia nt partici pa nts i n or der t o e n ha nce 
partici pa nts’ a d here nce t o t he st u d y  i nter ve nti o n;

P ost r a n d o miz ati o n , at eac h dis pe nsati o n visit (refer t o S o A -Ta ble A 1 ),
partici pa nts w h o are < 8 0 % c o m plia nt m ust be re -e d ucate d o n t he i m p orta nce 
of dail y  self-a d mi nistrati o n of st u d y i nter ve nti o n;

Over all ai m : mai ntai n ≥8 0 % c o m plia nce o ver t he d urati o n of d osi n g wit h 
d o u ble -bli n d , d o u ble-d u m m y st u d y i nter ve nti o n.
6. 5. C o nc o mit a nt T her a p y
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 wit h i n dicati o n of use. 
I n a d diti o n, a ge nts use d f or glyc e mic c o ntr ol, li pi d c o ntr ol, a n d bl o o d press ure c o ntr ol, dail y 
d ose, a n d start a n d st o p dates of a d mi nistrati o n m ust be ca pt ure d. All partici pa nts m ust be 
q uesti o ne d a b o ut c o nc o mita nt me dicati o n at eac h o ut patie nt visit t o t he site. 
Me dicati o ns starte d bef ore
D a y 1/ Visit 5 will be d oc u me nte d as pri or me dicati o ns. 
Me dicati o ns starte d after d osi n g of d o u ble -bli n d , d o u ble-d u m m y st u d y i nter ve nti o n o n 
D a y 1/ Visit 5 a n d u ntil t he 2 n d F oll o w - u p/ Visit 2 1, i ncl usi ve, will be d oc u me nte d as 
c o nc o mita nt me dicati o ns.
Gi ve n t he d urati o n of t he d osi n g p hase i n t his st u d y (ie, u p t o 4 8 wee ks), it is li kel y t hat 
c ha n ges i n bac k gr o u n d me dicati o ns will be nee de d as part of sta n dar d - of-care t o ma na ge 
c o nc o mita nt me dical c o n diti o ns. F or t hree s pecific cate g or y of me dicati o ns – ie, th ose f or 
gl yc e mic c o ntr ol, li pi d c o ntr ol , a n d B P c o ntr ol – g ui da nce offere d herei n is re q ueste d t o be 
c o nsi dere d w he n deter mi ni n g h o w best t o mai ntai n c o ntr ol. 
6. 5. 1. Me dic ati o n f or Gl yce mic C o ntr ol
Partici pa nts are per mitte d t o be o n sta ble d oses of u p t o a m a x i m u m of 3 a ge nts f or glyce mic 
c o ntr ol , f or ≥1 2 wee ks pri or t o S C R 1 a n d u ntil 1 st o n -site F oll o w- u p/Visit 2 0, acr oss t he 
c o u ntr y-s pecific a p pr o ve d classes of a ge nts f or gl yce mic c o ntr ol (e g, bi g ua ni des, D P PIV 
i n hi bit ors, S G LT 2 i n hi bit ors, s ul p h o n yl ureas, -gl uc osi dase i n hi bit ors, me gliti ni de 
a nal o g ues);

T h ose o n t hiaz oli di ne di o nes/P P A R (e g, pi o glitaz o ne) m ust be o n a sta ble d ose f or 
≥2 4 wee ks bef ore S C R 1 ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 5

T h ose o n metf or mi n at d oses > 1 g m/ da y  will nee d t o a gree t o decrease t he d ose b y 
o ne- t hir d or o ne-half ( g ui de d b y a vaila ble ta blet stre n gt hs) starti n g at a n o n -site 
Visit 3/ R u n -I n c o n d ucte d after c o nfir mati o n of eli gi bilit y o n S C R 2 li ver bi o ps y, wit h 
u p war d a dj ust me nt i n metf or mi n d ose per mitte d p ost ra n d o mizati o n base d o n F P G 
res ults – refer t o A p pe n di x 1 0 ;

I ncl u di n g o nce d o u ble -bli n d, d o u ble -d u m m y  st u d y i nter ve nti o n is st o p pe d;

T h ose o n i ns uli n m ust be o n sta ble d oses f or ≥1 2 wee ks bef ore S C R 1 ;

S h ort ter m use of sli di n g scal e i ns uli n t o ma na ge gl yce mic c o ntr ol d uri n g a 
c o nc o mita nt ac ute me dical c o n diti o n is acce pta ble s o l o n g as partici pa nt is 
me dicall y  sta ble at S C R 1;

T h ose o n G L P 1r a g o nists m ust be o n sta ble d oses f o r ≥1 2 wee ks bef ore S C R 1.
I n or der t o e ns ure a p pr o priate glyc e mic c o ntr ol , per l ocal/i n-c o u ntr y sta n dar d- of-care, a n d
c o nsi deri n g the d urati o n of d osi n g wit h st u d y i nter ve nti o n (ie, 4 8 wee ks) , it ma y be necessar y 
t o a dj ust t he d ose(s) of a ge nts f or glyce mic c o ntr ol p ost ra n d o mizati o n – r efer t o 
A p pe n di x 1 0 f or sp o ns or -s u g geste d g ui dance.
6. 5. 2. Li pi d -m o dif yi n g M e dic ati o n s
Partici pa nts are per mitte d t o be o n sta ble d oses of u p t o a m a xi m u m of 3 li pi d -m o difyi n g 
or al a ge nts , f or ≥1 2 wee ks pri or t o S C R 1 a n d u ntil t he 1st o n -site F oll o w- u p/Visit 2 0 , acr oss 
t he c o u ntr y-s pecific, a p pr o ve d classes of a ge nts i ncl u di n g t he f oll o wi n g:

T h ose o n selecte d stati ns w hic h are B C R P s u bstrates will o nl y be per mitte d if o n:

R os u vastati n d oses u p t o 1 0 m g/ da y ;

At or va stati n d oses u p t o 4 0 m g/ da y;

Si m vastati n or Fl u vastati n d oses u p t o half- ma xi m u m i n -c o u ntr y a p pr o ve d d ose;
N O T E : pra vastati n a n d pita vastati n are per mitte d at d oses u p t o t he ma xi m u m 
a p pr o ve d, i n -c o u ntr y d ose;

Bile aci d se q uestra nts s uc h as c h olest yr a mi ne, c olesti p ol , as well as c olese vala m ;

F i bric aci d deri vati ves s uc h as fe n ofi brate, bezafi brate, pe mafi brate;

Nic oti nic aci d/ niaci n;

Ezeti mi be ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 6

Als o per mitte d are o ver -t he-c o u nter/ n o n - prescri pti o n s u p ple me nts k n o w n t o i m pr o ve 
li pi d c o ntr ol – s uc h as o me ga -3 fatt y  aci d, eic osa pe ntae n oic aci d .
N O T E : partici pa nts re q uiri n g use of pare nterall y  a d mi nistere d P C S K 9 i n hi bit ors are n ot
per mitte d i n t his st u d y; t hese a ge nts
 wit h t he a bilit y t o assess effect of D G A T 2i 
a n d D G A T 2i + A C Ci o n 
.
T he use of 
per mitte d starti n g at Visit 3/ R u n -I n a n d u ntil t he 1 o n -site F oll o w- u p/Visit 2 0;

P artici pa nts o n eit her of t hese a ge nts, at S C R 1 , will nee d t o a gree t o be s witc he d t o 
a n ot her acce pta ble a ge nt st arti n g at a n o n-site Visit 3/ R u n- I n c o n d ucte d after
c o nfir mati o n of eli gi bilit y o n S C R 2 li ver bi o psy wit h sta ble d ose of t he acce pta ble 
a ge nt ac hie ve d f or ≥6 wee ks bef ore Da y  1/ Visit 5, i n or der t o c o nti n ue t o 
ra nd o mizati o n i n t his st u d y;

I n t he case of 
, t he i nte nt w o ul d t o be t o s witc h t o a n ot her stati n at a n 
e q ui vale nt d ose f or effect o n LD L - C, as o utli ne d bel o w 2 6 –
Le vel of I nte nsit y 
Hi g h
M o der ate
L o w
L D L -C l o weri n g 
≥5 0 %
3 0 % - 4 9 %
< 3 0 %
 d ail y d ose 
N ot 
a vaila ble
4 0 m g
2 0 m g
E q uiv ale nt d aily d ose (i n m g) of 
a n ot her per mitte d st ati n i n 
C 2 5 4 1 0 1 3 , see a b ove 
I n or der t o e ns ure a p pr o priate ma na ge me nt of t he i de ntifie d a d verse dr u g reacti o n of ele vate d 
fasti n g ser u m tri glyc eri des, it ma y be necessar y t o a dj ust t he d ose(s) of a ge nts f or li pi d
c o ntr ol p ost ra n d o mizati o n – r efer t o A p pe n di x 1 1 f or sp o ns or -s u g geste d g ui da nce.
6. 5. 3. Me dic ati o ns f or C o ntr olli n g Bl o o d Press ure
Acr oss t he ma n y classes of a ge nts f or ma na ge me nt of h y perte nsi o n, partici pa nts are 
per mitte d t o be o n sta ble d oses of u p t o a m a xi m u m of 3 a ge nts f or B P c o ntr ol, f or
≥1 2 wee ks pri or t o S C R 1 a n d u ntil t he 1st o n- site f oll o w-u p/ Visit 2 0;

Starti n g at t he o n-site Visit 3/ R u n -In, d oses of me dicati o ns ca n be i ncrease d a n d 
a d diti o nal me dicati o ns ca n be a d de d t o a ma xi m u m of 3 i n or der t o c o ntr ol B P a n d 
meet criteria nee de d t o pr o gress t o ra n d o mizati o n - refer t o Secti o n 5. 2 (e xcl usi o n 
criteri o n 7 ) a n d Secti o n 5. 3 .
6. 5. 4. Ot her Acce pt a ble C o nc o mit a nt Me dic ati o ns
As m uc h as p ossi ble, p artici pa nts o n t he f oll o wi n g list of me dicati o ns m ust be o n sta ble 
d oses [ie, ≥1 2 wee ks pri or t o S C R 1 a n d u ntil t he 1st o n-site F oll o w- u p/ Visit 2 0]
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 7

Use of m ulti -vita mi ns is per mitte d t h o u g h th ose o n V it a mi n E m ust be o n sta ble d ose f or 
≥2 4 wee ks bef ore S C R 1;

Use of as piri n at d oses of ≤3 2 5 m g/ da y ;

Use of oral a ge nts t hat alter st o mac h p H – e g, a ntaci ds, hista mi ne- 2 rece pt or a nta g o nists, 
pr ot o n -p u m p i n hi bit ors;

Use of i n hale d a n d t o pical c ortic oster oi ds:

N O T E : Interc urre nt treat me nt wit h s y ste mic ster oi ds, d uri n g partici pati o n i n t he 
st u d y, ma y be per mitte d if treat me nt d oes/ will n ot e xcee d 1 4 d ays ;

T h y r oi d re place me nt t hera p y;

P ost me n o pa usal h or m o ne t hera p y;

A nti ps y c h otic me dicati o ns s uc h as ola nza pi ne, ris peri d o ne;

A nti de pressa nt me dicati o ns s uc h as tric yclic a ge nts, selecti ve ser ot o ni n re u pta ke 
i n hi bit ors a n d ser ot o ni n/ n ore pi ne p hri ne re u pta ke i n hi bit ors;

Selecte d (her bal ) s u p ple me nts (or a p pr o ve d a ge nts), bel o w , i n c o u ntries w here t he y are 
part of sta n dar d of care t o l o wer L F Ts ( b ase d o n li mite d/ we ak scie ntific evi de nce) –

Gl utat hi o ne;

Gl y c yrr hizic aci d;

P ol y e ne p h os p hati d ylc h oli ne;

Sil y mari n ;

Urs o de o x yc h olic aci d;

F or a d diti o nal g ui da nce, f or sites i n  
 o nly, refer t o A p pe n di x 8.

C hr o nic a n d i nter mitte nt use of N S AI Ds (s uc h as i b u pr ofe n, ket o pr ofe n, dicl ofe nac, 
na pr o xe n, i n d o met haci n, mel o xica m; a n d celec o xi b) is per mitte d;

I nter mitte nt use of aceta mi n o p he n/ paraceta m ol at d oses u p t o 2 gra ms per da y  
(f or e xa m ple: f or s h ort-ter m pai n ma na ge me nt) is dee me d acce pta ble;

Vacci nes, as per l ocal c o u ntr y /re gi o nal practice f or p o p ulati o n e nr olle d – i ncl u di n g 
i nfl ue nza vacci ne, C O VI D- 1 9 vacci ne; f or a d diti o nal g ui da nce re gar di n g a d mi nistrati o n 
of C O VI D -1 9 vacci nes, refer t o Secti o n 8. 2 . 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
6. 5. 5. Pr o hi bite d Me dic ati o ns
Acr oss t he a ge nts use f or gl yc e mic c o ntr ol, li pi d- m o dificati o n, a n d B P c o ntr ol, certai n 
me dicati o ns are n ot per mitte d – refer t o a b o ve Secti o n 6. 5. 1 t o Secti o n 6. 5. 3 .
Als o, use of dr u gs hist oricall y  ass ociate d wit h fatt y li ver are pr o hi bite d wit hi n a n y ≥4 wee ks 
i nter v al i n t he pre vi o us 1 2-m o nt hs pri or t o S C R 1 : 

Ex a m ples i ncl u de: e xe mesta ne, a mi o dar o ne, met h otre xate, s yste mic gl uc oc ortic oi ds 
(s uc h as pre d nis o ne, de xa met has o ne, tria mci n ol o ne, b u des o ni de, beta met has o ne), 
a na b olic ster oi ds, tetrac ycli nes, ta m o xife n, estr o ge ns at d oses greater t ha n t h ose use d
f or h or m o ne re place me nt, val pr oic aci d, ot her k n o w n he pat ot o xi ns;
I n a d diti o n, t he use of t he f oll o wi n g me dicati o ns wit hi n 1 2 wee ks pri or t o S C R 1 or li kel y t o 
nee d t hese, base d o n pri or me dical/ me dicati o n use hist or y , at a n y ti me u ntil 1 st o n- site 
F oll o w -u p / Visit 2 0 m ust n ot partici pate i n t his st u d y  –

C hr o nic use of i m m u n os u p pressa nts s uc h as c y cl os p ori ne, tacr oli m us, T N F -al p ha 
i n hi bit ors (e g, eta nerce pt, i nfli xi ma b, a dali m u ma b), I L- 6 rece pt or a nta g o nists (e g,
t ociliz u ma b, saril u ma b), J A K i n hi bit ors (e g, t ofaciti ni b);

P har mac ol o gical a ge nts wit h a p pr ove d i n dic ati o n f or wei g ht l oss s uc h as orlistat a n d 
si b utra mi ne;

O ver -t he-c o u nter a p petite- si m ula nt or a p petite- s u p pressa nt, as a d vertise d;

 wit h 
;

P ote nt i n d ucers a n d i n hi bit ors of  
 (refer t o A p pe n di x 8 ) i ncl u di n g b ut n ot 
li mite d t o t he f oll o wi n g:

I n d ucers – e g, rifam pi n, p he n y t oi n, car ba maze pi ne, St J o h n’s W ort, 
p he n o bar bital ;

I n hi bit ors – e g, ket oc o naz ole/itrac o naz ole, clarit hr o m y ci n, ma n y pr otease 
i n hi bit ors ( N O T E: partici pa nts w h o are HI V p ositi ve are n ot eli gi ble f or t his 
st u d y); 

 s u bstrates wit h 
 (e g, 
); 

B l o o d t hi n ner(s) – e g, cl o pi d o grel, a pi xa ba n, da bi gatra n, ri var o xa ba n, e d o xa ba n, 
f o n da pari n u x, he pari n, as well as Vita mi n K a nta g o nists (e g, warfari n );

C li nicall y si g nifica nt 
– e g, c ycl os p ori ne, ge mfi br ozil, rifa m pi n.
F or a d diti o nal g ui da nce, f or sites i n  
 o nly, refer t o A p pe n di x 8 .
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
6. 5. 6. Resc ue Me dici ne
T here is n o resc ue t hera p y t o re verse t he A Es (i ncl u di n g i de ntifie d a d verse dr u g reacti o ns) 
o bser ve d wit h a n y of t he st u d y  i nter ve nti o ns; sta n dar d me dical s u p p orti ve care m ust be 
pr o vi de d t o ma na ge t he A Es.
P artici p a nt wit h T 2 D M wit h re pe ate d fasti n g plas ma gl uc ose val ues > 2 7 0 m g/ d L 
( 1 5 m m ol/ L ) as rep orte d b y  t he s p o ns or-i de ntifie d ce ntral la b orat or y, at t w o se q ue ntial visits 
p ost ra n d o mizati o n, m ust ha ve bac k gr o u n d c o nc o mita nt me dicati o ns f or gl y ce mic c o ntr ol 
o pti mize d - starti n g wit h t he d ose of metf or mi n (f or t h ose o n t his a ge nt pri or t o 
ra n d o mizati o n) – refer t o Secti o n 6. 5. 1 a n d A p pe n di x 1 0 . T hese assess me nts ca n be a 
c o m bi nati o n of t w o sc he d ule d visits, or o ne sc he d ule d visit f oll o we d b y a n u n pla n ne d visit t o 
c o nfir m t he ele vate d res ult. 
, g ui da nce t o i n vesti gat ors i s offere d (refer t o 
A p pe n di x 1 1 a n d A p pe n di x 1 2 ) wit h re versal of effect t o war ds baseli ne e x pecte d/o bser ve d i n 
pre vi o us st u dies wit h 
 u p o n disc o nti n uati o n of st u d y i nter ve nti o n. 
6. 6. D ose M o dific ati o n 
D ose of d o u ble -bli n d , d o u ble-d u m m y st u d y i nter ve nti o n i n i n divi d u al partici pa nts i n t his 
st u d y is n ot per mitte d t o be m o difie d.
Be y o n d t he strate gic dec isi o n b y t he s p o ns or, via Pr ot oc ol A me n d me nt 1 , relate d t o t he 2 Q D 
d osi n g re gi me ns of D G A T 2i al o ne, t he decisi o n t o pa use or st o p d osi n g at a st u d y-le vel, f or 
1 or m ore ot her acti ve d ose(s) of D G A T 2i or D G A T 2i + A C Ci ma y  be c o nsi dere d base d o n 
rec o m me n dati o n fr o m t he E-D M C acc or di n g t o t heir re vie w of u n bli n de d, st u d y -le vel 
e mer gi n g, o bserve d safet y data – refer t o Secti o n 9. 6 . 
6. 7. I nter ve nti o n After t he E n d of t he St u d y
T his is t he first st u d y  t o e val uate t he efficac y of D G A T 2i a n d D G A T 2i + A C Ci . As s uc h, 
8 acti ve ar ms ( Ori gi nal Pr ot oc ol or 6 (Pr ot oc ol A me n d me nt 1 ) are bei n g i ncl u de d, t o e na ble 
i de ntificati o n of efficaci o us d ose(s) u p o n its’ c o m pleti o n ( n ot at start of st u d y ). He nce, 
 
 t o st u d y partici pa nts at t he e n d of t he st u dy.
7. DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L
7. 1. Disc o nti n u ati o n of St u d y I nter ve nti o n
I n rare i nsta nces, it ma y be necessar y f or a partici pa nt t o per ma ne ntly disc o nti n ue st u d y  
i nter ve nti o n ( defi niti ve disc o nti n uati o n). Reas o ns f or defi niti ve disc o nti n uati o n of st u d y 
i nter ve nti o n i ncl u de partici pa nts w h o meet prei de ntifie d t hres h ol ds f or i de ntifie d a d verse 
dr u g reacti o ns wit h A C Ci – refer t o A p pe n di x 1 1 a n d A p pe n di x 1 2 , as well as ot her a d verse 
e ve nts base d o n me dical j u d g me nt, or s o me ot her (a d mi nistrati ve) reas o n.
N ote t hat disc o nti n uati o n of st u d y i nter ve nti o n d oes n ot re prese nt wit h dra wal fr o m t he st u dy.
Partici pa nts ca n c o nti n ue i n t he st u d y a n d c o m plete all sc he d ule d visits, w hile off st u d y  
i nter ve nti o n. If st u d y i nter ve nti o n is defi niti vel y disc o nti n ue d, t he partici pa nt will re mai n i n 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 0
t he st u d y t o be e val uate d f or all acti vities – see t he S o A -Ta ble A 1 a n d S o A -Ta ble A 2 f or data 
t o be c ollecte d at t he ti me of disc o nti n uati o n of st u d y i nter ve nti o n a n d f oll o w-u p f or a n y  
f urt her e val uati o ns t hat nee d t o be c o m plete d.
I n t he e ve nt of disc o nti n uati o n of st u d y i nter ve nti o n, it m ust be d oc u me nte d o n t he 
a p pr o priate C R F/i n t he me dical rec or ds w het her t he partici pa nt is disc o nti n ui n g f urt her 
recei pt of st u dy i nter ve nti o n or als o fr o m st u d y  pr oce d ures, p osttreat me nt st u d y f oll o w- u p, 
a n d/ or f ut ure c ollecti o n of a d diti o nal i nf or mati o n.
7. 2. P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al Fr o m t he St u d y 
A partici pa nt ma y  wit h dra w fr o m t he st u d y at a ny ti me at his/ her o w n re q uest. Reas o ns f or 
disc o nti n uat i o n fr o m t he st u d y i ncl u de t he f oll o wi n g:

Ref use d f urt her f oll o w -u p;

L ost t o f oll o w - u p;

Deat h;

St u d y  ter mi nate d b y s p o ns or;

Discreti o n of t he i n vesti gat or or s p o ns or f or safety or be ha vi oral reas o ns, or t he 
i na bilit y of t he partici pa nt t o c o m pl y wit h t he p r ot oc ol-re q uire d sc he d ule of st u d y
visits or pr oce d ures at a gi ve n st u d y site. 
I n t his st u d y, a n y partici pa nt w h o disc o nti n ues partici pati o n after t he Pre Q visit b ut pri or t o 
r a n d o miz ati o n a n d a d mi nistr ati o n of t he 1 st d ose of d o u ble -bli n d, d o u ble -d u m my st u dy 
i nterve nti o n will ha ve n o a d diti o nal pr oce d ures c o m plete d.
T he earl y disc o nti n uati o n visit a p plies o nl y  t o partici pa nts w h o are e nr olle d/ra n d o mize d a n d 
t he n are pre mat urel y wit h dra w n fr o m t he st u d y. Partici pa nts s h o ul d be q uesti o ne d re gar di n g 
t heir reas o n f or wit h dra wal.
As s o o n as practicall y  p ossi ble after t he decisi o n t o wit h dra w fr o m t he st u d y, a n o n-site visit 
s h o ul d be c o nsi dere d –

Partici pa nts s h o ul d be q uesti o ne d re gar di n g t heir reas o n f or wit h dra wal;

See t he S o A -Ta ble A 1 a n d S o A -Ta ble A 2 f or assess me nts t o be c ollecte d at t he ti me 
of st u d y  disc o nti n uati o n a n d f oll o w-u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be 
c o m plete d.
If a partici pa nt wit h dra ws fr o m t he st u d y, he/s he ma y re q uest destr ucti o n of a n y re mai ni n g 
sa m ples ta ke n a n d n ot teste d, a n d t he i n vesti gat or m ust d oc u me nt a n y s uc h re q uests i n t he 
site stu d y  rec or ds a n d n otif y t he s p o ns or acc or di n gl y.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 1
If t he partici pa nt 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 - refer t o 
Secti o n 7. 2. 1 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 b e c ollecte d. T he s p o ns or ma y  retai n a n d c o nti n ue t o use a n y 
data c ollecte d bef ore s uc h wit h dra wal of c o nse nt.
Lac k of c o m pleti o n of all or a n y of t he wit h dra wal/earl y ter mi nati o n pr oce d ures will n ot be 
vie we d as pr ot oc ol de viati o ns s o l o n g as t he partici pa nt’s safet y was preser ve d.
7. 2. 1.
Wit h dr a w al of C o nse nt 
Partici pa nts w h o re q uest t o disc o nti n ue recei pt of st u d y  i nter ve nti o n will re mai n i n t he st u d y 
a n d m ust c o nti n ue t o be f oll o we d f or pr ot oc ol -s pecifie d f oll o w- u p pr oce d ures. T he o nly 
e xce pti o n t o t his is w he n a partici pa nt 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 partici pa nt t o pr o vi de t his 
i nf or mati o n. Partici pa nts 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 nsent fr o m f ut ure f oll o w - u p, w he ne ver p ossi ble. T he wit h dra wal of c o nse nt s h o ul d be 
e x plai ne 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 st u d y i nter ve nti o n or als o fr o m st u d y pr oce d ures an d/ or 
p osttreat me nt st u d y  f oll o w-u p a n d e ntere d o n t he a p pr o priate C R F pa ge. I n t he e ve nt t hat 
vital stat us ( w het her t he partici pa nt 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.
7. 3. L ost t o F oll o w -u p 
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he site f or a re q uire d 
st u d y visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as 
s o o n as p ossi ble a n d c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he 
assi g ne d visit sc he d ule a n d ascertai n w het her or n ot t he partici pa nt wis hes t o a n d/ or 
s h o ul d c o nti n ue i n t he st u d y;

Bef ore a partici pa nt is dee me d l ost t o f oll o w- u p, t he i n vesti gat or or desi g nee m ust 
ma ke e ver y  eff ort t o re gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne 
calls a n d, if necessar y, a certifie d letter t o t he partici pa nt’s last k n o w n maili n g 
a d dress or l ocal e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d;

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y. 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 2
8. S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
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) m ust o btai n si g ne d a n d 
date d I C Ds bef ore perf or mi n g a n y st u d y-s pecific pr oce d ures at Pre Q. I n a d diti o n, a se parate 
si g ne d/ date d I CD m ust be o btai ne d bef ore perf or mi n g a n y st u d y- s pecific pr oce d ures at 
S C R 1 . 
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A -Ta ble A 1 a n d S o A -Ta ble A 2 .
Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d.
Safet y  iss ues s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne w het her t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y  
i nter ve nti o n.
A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A -Ta ble A 1
a n d S o A -Ta ble A 2 , is esse ntial a n d re q uire d f or st u d y c o n d uct.
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y  criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble.
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat 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 ma y  be 
circ u msta nces o utsi de t he c o ntr ol of t he i n vesti gat or t hat ma y ma ke it u nfeasi ble t o perf or m 
t he test. In t hese cases, t he i n vesti gat or m ust 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 partici pa nt. W he n a pr ot oc ol- re q uire d test ca n n ot be perf orme d, t he 
i n vesti gat or will d oc u me nt t he reas o n f or t he misse d test a n d a ny 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 re q uire d 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 m ust be i nf or me d of t hese i nci de nts in a ti mel y  ma n ner.
F or sa m ples bei n g c ollecte 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.
T he t otal bl o o d sa m pli n g v ol u me f or i n di vi d ual partici pa nts i n t his st u d y  will ra n ge fr o m 
a p pr o xi matel y 
m L t o 
 m L, v ar y i n g b y c o u ntr y, a n d t u be sizes a vaila ble/ use d acr oss 
re gi o ns partici pati n g i n t his st u d y. A d diti o nal bl o o d sa m ples ma y be ta ke n f or safet y 
assess me nts at ti mes s pecifie d b y Pfizer, pr o vi de d t he t otal v ol u me ta ke n d uri n g t he st u d y 
d oes n ot e xcee d 
m L  d uri n g a ny peri o d of 6 0 c o nsec uti ve da ys.
8. 1. Effic ac y Assess me nts
8. 1. 1. C o n d uct of U ltr as o u n d-g ui de d , Perc ut a ne o us Li ver Bi o ps y
I n t his st u dy, ultras o u n d -g ui de d, perc uta ne o us bi o ps y  of t he ri g ht l o be of t he li ver will be 
u n derta ke n t wice, f oll o wi n g a fast of ≥4 -h o urs pl us w herever pr actic ally p ossi ble at t he sa me 
ti me of da y ( ± 2 h o urs) –
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 3

First , i n all partici pa nts w h o were dee me d t o be eli gi ble base d o n d o u ble-
c o nfir mati o n via n o n -i n vasi ve assess me nts bet wee n Pre Q a n d S C R 1, f or p ur p oses of 
deter mi ni n g eli gi bilit y  base d i n hist ol o gical e vi de nce of N A S H wit h F 2-F 3 fi br osis 
(a n d ser ve as baseli ne);

Partici pa nts wit h hist orical li ver bi o ps y  ≤1 2 wee ks pri or t o S C R 2 nee d n ot
u n der g o t he st u d y- re q uire d scree ni n g/ baseli ne li ver bi o ps y s o l o n g as m o u nte d, 
u nstai ne d tiss ue sli des are a vaila ble f or re vie w b y s p o ns or-i de ntifie d ce ntral 
pat h ol o gist (s);

Sec o n d , f or e val uati o n of treat me nt res p o nse, w he n a n y o ne of t he f oll o wi n g criteria 
are met –

A t ti me of decisi o n t o st o p st u d y i nter ve nti o n if ≥2 4 wee ks p ost Da y  1/ Visit 5;

At Wee k 4 8 / Visit 1 9 w hile off st u d y i nter ve nti o n b ut c o nti n ui n g sc he d ule d visits ;

A t Wee k 4 8/ Visit 1 9 ( wit hi n 2-da y s of last d ose of st u d y i nter ve nti o n).
I n li mite d c ases d ue t o e xcessi ve a b d o mi nal girt h (ie, waist circ u mfere nce) of a partici pa nt, 
c o n d uct of perc uta ne o us li ver bi o ps y  is per mitte d usi n g a n alter nati ve i ma gi n g tec h ni q ue 
(e g, c o m p ute d t o m o gra p h y), as per l ocal p olic y .
Bi o psies ma y  be perf or me d at t he st u d y site or t he partici pa nt ma y be referre d t o a 
Ra di ol o g y /Ima gi n g facilit y f or t he pr oce d ure t o be u n derta ke n b y a me dicall y-q ualifie d 
i n vesti gat or –

P artici pa nts m ust be pre pare d f or t he pr oce d ure t o be c o n d ucte d u n der sterile 
c o n diti o ns , u n der l ocal a nest hesia, wit h use of oral/i ntra ve n o us a n xi ol ytic per mitte d, 
as nee de d;

Bi o ps y  m ust be perf or me d, i de ally, usi n g a 1 6 - ga u ge nee dle;

A n 1 8 - ga u ge nee dle is acce pta ble if t his is part of sta n dar d practice f or t he 
i n vesti gat or(s) perf or mi n g t he li ver bi o psy;

Bi o ps y  nee dle s maller t ha n 1 8 ga u ge m ust n ot be use d as it si g nifica ntl y  
c o m pr o mises a bilit y t o gar ner acce pta ble tiss ue nee de d f or sta gi n g/sc ori n g b y t he 
s p o ns or-i de ntifie d ce ntral pat h ol o gist(s);

Pr o gressi o n of t he bi o ps y nee dle i nt o t he li ver ca ps ule m ust occ ur w hile t he 
partici pa nt is i nstr ucte d t o h ol d his/ her breat h;

Le n gt h of tiss ue sa m ple o btai ne d m ust be ≥1. 5 c m, wit h t he sa m ple c ut i nt o ≤1 0 
secti o ns, a n d eac h sa m ple 4- 5 µ m i n t hic k ness t o i m pr o ve hist ol o gical
gra di n g/sc ori n g ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 4

P ost pr oce d ure ultras o u n d s h o ul d be perf or me d t o e val uate f or a n y i m me diate 
p ost -bi o ps y  blee d;

Tiss ue sa m ple o btai ne d will be pr ocesse d / pre pare d usi n g sta n dar d met h o d ol o g y  a n d 
ma na ge d b y t he s p o ns or -i de ntifie d ce ntral la b orat or y;

C o m plet e details re gar di n g bi o ps y ac q uisiti o n will be pr o vi de d i n a st u d y-s pecific 
ma n ual s u p plie d b y  t he sp o ns or bef ore t he i nitiati o n of t his st u d y .
As part of u n dersta n di n g t he disease ( N A F L D/ N A S H) a n d t he st u d y i nter ve nti o ns, 
 
Partici pa nts will ha ve t he o pti o n t o o pt i n t o t his a d diti o nal 
researc h, u nless pr o hi bite d b y l ocal re g ulati o ns or E C decisi o n – refer t o Secti o n 8. 8. 1 a n d 
A p pe n di x 5 f or a d diti o nal details.
8. 1. 2. Li ver I m a gi n g A ssess me nts 
8. 1. 2. 1. Assess me nt of Li ver F at a n d Stiff ness – usi n g Fi br o Sc a n ®
I n t his st u dy, assess me nts of li ver fat a n d stiff ness usi n g Fi br o Sca n ® will occ ur at sc he d ule d 
visits o utli ne d i n t he S o A -Ta ble A 1 . T he res ults f or li ver fat ( via C A PT M ) i n d B/ m a n d li ver 
stiff ness ( via V C T E T M ) i n k Pa t o deter mi ne w het her a n i n di vi d ual partici pa nt q ualifies at 
Pre Q t o pr o gress t o Scree n 1 will be dis pla y e d o n t he Fi br o Sca n ® de vice at t he e n d of eac h 
assess me nt. Ac q uisiti o n res ults d o n ot nee d i n de pe n de nt o ver -rea di n g, b ut ste ps t o e ns ure 
t hat ac q uisiti o n was c o m plete a n d acc urate are re q uire d – per trai ni n g t o be offere d t o at le ast 
2 site st aff ( w h o m ay be s o n o gra p hers or c o m para ble) b y Ec h o Se ns a n d certifie d as 
o perat ors base d o n t his trai ni n g b y Ec h o Se ns, at t he start of t he st u d y. As m uc h as pr actic ally 
p ossi ble , atte m pts will be ma de t o e ns ure eac h i n di vi d ual partici pa nts’ assess me nt is 
perf or me d b y t he sa me site staff t hr o u g h o ut t he st u d y.
C o m plete details re gar di n g ac q uisiti o ns usi n g Fi br o Sca n ® t o assess C A PT M a n d V C T E T M will 
be pr o vi de d i n a Fi br o S ca n ® Ma n ual s u p plie d b y  t he sp o ns or bef ore i nitiati o n of t his st u d y . 
C o n d uct of assess me nts of li ver fat a n d stiff ness usi n g Fi br o Sca n ® m ust yiel d e val ua ble data 
as defi ne d b y c o m plia nce wit h t he q ualit y c o ntr ol ste ps o utli ne d i n t he s p o ns or-pr o vi de d 
Fi br o Sca n ® Ma n ual. Fi br o Sca n ® o ut p uts f or selecte d partici pa nts at a s u bset of n o mi nal 
ti me p oi nts will u n der g o re vie w a gai nst s p o ns or-defi ne d q ualit y  c o ntr ol ste ps b y t he S p o ns or.  
T he s u m mar y  of n u merical res ults (i ncl u di n g q ualit y-relate d o ut p uts) m ust be pri nte d a n d 
sa ve d by t he st u d y site ( or i ma gi n g facilit y, as a p plica ble) as part of eac h partici pa nt’s s o urc e 
d oc u me nts. I n a d diti o n, all i ma ges a n d o ut p ut re p orts ac q uire d m ust be sa ve d b y t he st u d y 
site u ntil t he c o ncl usi o n of t he st u d y.
8. 1. 2. 2. Assess me nt of Li ver F at Usi n g M RI- P D F F (I m a gi n g S u bst u d y)
At sc he d ule d visits (refer t o t he S o A -Ta ble A 1 ), li ver fat ( via M RI-P D F F) a n d t otal li ver 
v ol u me ( via M R v ol u me ac q uisiti o n pr ot oc ol ) will be assesse d , at selecte d sites i n 
N ort h A merica, o nly . All ot her c o u ntries partici pati n g i n t his st u d y will n ot be part of t he 
I ma gi n g S u bst u dy.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 5
Tra ns p ortati o n of t he partici pa nts t o t he I ma gi n g facilit y  d oes n ot nee d t o be s u per vise d b y 
t he site staff. Eac h assess me nt will re q uire t he partici pa nts t o be i n a s u pi ne p ositi o n i n t he 
c o nfi ne d s pace of t he M RI sca n ner f or a p pr o xi matel y 2 5 mi n utes wit h t he i ma ge ac q uisiti o n 
u n derta ke n f oll o wi n g a f ast (e xce pt w ater) of ≥4 -h o urs , a n d as m uc h as pr actic ally 
p ossi ble , at t he sa me ti me ( ± 2 h o urs) of t he da y  relati ve to assess me nt at Baseli ne (ie, 
bet wee n Visit 4/ Baseli ne a n d pri or t o 1 st d ose o n Da y  1/Visit 5 ).
Acr oss t he st u d y sites selecte d f or t his s u b -st u d y, t he s p o ns or-i de ntifie d ce ntral i ma gi n g 
ve n d or will trai n t he staff at t he i ma gi n g facilit y  o n t he M RI ac q uisiti o n pr ot oc ols, o n j ust-i n-
ti me re vie w of t he ac q uire d i ma ges f or assess me nt of i ma ges bei n g dee me d e val ua ble, a n d o n 
tra nsfer ( prefera bly electr o nicall y) of t he i ma ges t o t he s p o ns or -i de ntifie d ce ntral i ma gi n g 
ve n d or f or a nal ys is a n d q ua ntificati o n of liver fat. O nl y t he st aff me m bers at t he i m a gi n g 
f acilit y w h o are tr ai ne d b y t he s p o ns or-i de ntifie d ce ntr al i m a gi n g ve n d or are per mitte d 
t o ac q uire i m a ges i n t h ose w h o c o nse nt f or t his s u bst u d y, h o we ver i n rare/li mite d 
sit uati o ns, e xce pti o ns ma y be gra nte d wit h writte n a p pr o val of t he s p o ns or. C o m plete details 
o n t he M RI -P D F F ac q uisiti o n pr ot oc ol, deter mi nati o n of q ualit y  of i ma ges, a n d tra ns missi o n 
of data t o s p o ns or -i de ntifie d ce ntral i ma gi n g ve n d or will be pr o vi de d i n a n I ma gi n g Ma n ual 
pr o vi de d t o t he site s pri or t o t he start of t he st u dy.
At t he selecte d visits (refer t o t he S o A -Ta ble A 1 ) w he n li ver fat is assesse d via M RI -P D F F, 
 ma y be ac q uire d f or e x pl orat or y p ur p oses i ncl u di n g li ver v ol u me, 
, a n d 
 a n d 
 
, if a nalyz e d, will n ot be i ncl u de d i n t he cli nical st u d y  re p ort b ut will be 
s u m marize d via a sta n dal o ne re p ort.
M a n a ge me nt of I nci de nt al Fi n di n gs
A n i nci de ntal fi n di n g is o ne u n k n o w n t o t he partici pa nt t hat has p ote ntial healt h o r 
re pr o d ucti ve i m p orta nce, w hic h is disc o vere d u ne x pecte dl y i n t he c o urse of a researc h st u d y 
b ut is u nrelate d t o t he p ur p ose a n d be y o n d t he ai ms of t he st u d y .
T he i m a ges will be re vie we d b y  a s p o ns or-i de ntifie d ce ntral re vie w facilit y. T he p ur p ose of 
t his re vie w is t o e val uate i ma ges f or t he a m o u nt of fat i n t he li ver. Ce ntral i ma ge re vie w is 
n ot a c o m plete me dical re vie w of t he partici pa nt. If, d uri n g t he ce ntral re vie w pr ocess, a n 
u ne x pecte d o bser vati o n is i de ntifie d a n d t his fi n di n g c o ul d, i n t he o pi ni o n of t he ce ntral 
re vie wer, ha ve a si g nifica nt healt h or re pr o d ucti ve c o nse q ue nce, t his fi n di n g ma y be s hare d 
wit h t he st u d y  s p o ns or f or discl os ure t o t he PI. All f oll o w-u p testi n g a n d fi nal dia g n osis will 
be left t o t he discreti o n of t he me dical pr ofessi o n als at t he site or t h ose wit h a n e xisti n g 
p h y sicia n-partici pa nt relati o ns hi p. T he PI  will be res p o nsi ble f or re p orti n g a n y A Es i de ntifie d 
fr o m i nci de ntal fi n di n gs as descri be d i n t he A E re p orti n g secti o n. Ide ntificati o n of s uc h 
i nci de ntal fi n di n gs d uri n g the ce ntral re vie w pr ocess s h o ul d n ot be e x pecte d, a n d t he site 
mai ntai ns res p o nsi bilit y  f or perf or mi n g a ge neral safety re vie w of all i ma ges as per site 
pr ot oc ols.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 6
 
 
 
 
 data ac q uire d i n t his st u d y. A n y s uc h a nal ys es will n ot be 
i ncl u de d i n t he cli nical st u d y re p ort; a se parate s u p ple me ntal re p ort will be writte n t o ca pt ure 
t his w or k, if u n derta ke n. 
8. 1. 3. P atie nt -Re p orte d O utc o mes
All P R O assess me nts are i m ple me nte d usi n g s p o ns or -pr o vi de d e P R O de vice a n d c o m plete d 
b y  t he partici pa nts at h o me, or at a n o n -site visit, as per t he S o A -Ta ble A 1 a n d Ta ble 4.
T a ble 4.
P atie nt -Re p orte d O utc o me Me as ures Pl a n ne d i n St u d y C 2 5 4 1 0 1 3
M e as ure
Fre q ue nc y – refer t o S o A -T a ble A 1
N u m ber of 
q uesti o ns
Esti m ate d
C o m pleti o n 
ti me
Assess me nt
N A S H -C hec k
Visit 4/ Baseli ne 
Wee k 2 4/ Visit 1 3
Wee k 4 8/ Visit 1 9
3 1 
8 mi n utes
O n -site
N A S H S y m pt o m 
Diar y (a b d o mi nal 
pai n, bl oati n g, 
fati g ue, slee p, a n d 
da yti me 
slee pi ness)
O nce - a-d a y f or a 1 4 c o nsec utive d ay peri o d -
D uri n g t he i nter val bet wee n Visit 4/ 
Baseli ne a n d 1 -da y pri or t o Da y 1/ Visit 5
St arti n g at –
o
Wee k 1 2 / Visit 1 0a
o
Wee k 2 4 / Visit 1 3a
o
Wee k 3 6 / Visit 1 6a ( T)
Pri or t o Wee k 4 8 / Visit 1 9b
5 
2 mi n utes
At h o me , 
exce pt w he n 
n ote d as 
O n -site
N A S H P GI - S
T wice d uri n g a 1 4 -d ay peri o d -
D uri n g t he i nter val bet wee n Visit 4/ 
Baseli ne a n d 1 -da y pri or t o Da y 1/ Visit 5
St arti n g at –
o
Wee k 1 2/ Visit 1 0
a
o
Wee k 2 4/ Visit 1 3
a
o
Wee k 3 6/ Visit 1 6
a ( T)
Pri or t o Wee k 4 8/ Visit 1 9
b
2
3 mi n utes
N A S H P GI - C
O nce d uri n g a 1 4 -d ay peri o d -
St arti n g at –
o
Wee k 1 2/ Visit 1 0
a
o
Wee k 2 4/ Visit 1 3
a
o
Wee k 3 6/ Visit 1 6
a ( T)
Wee k 4 8/ Visit 1 9
– O n -site
2
P R O MI S Fati g ue
C ust o m 9-I t e m
Versi o n 
(“ Past 7 da ys” 
recall)
Visit 4/ Baseli ne ( c o m plete d O n-site)
Pl us, o nce d uri n g a 1 4 -d ay peri o d -
St arti n g at –
o
Wee k 1 2/ Visit 1 0
a
o
Wee k 2 4/ Visit 1 3
a
o
Wee k 3 6/ Visit 1 6
a ( T)
Wee k 4 8/ Visit 1 9
– O n -site
9
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 7
T a ble 4 .
P atie nt -Re p orte d O utc o me Me as ures Pl a n ne d i n St u d y C 2 5 4 1 0 1 3
M e as ure
Fre q ue nc y – refer t o S o A -T a ble A 1
N u m ber of 
q uesti o ns
Esti m ate d
C o m pleti o n 
ti me
Assess me nt
a.
Site staff re q uire d t o acti vate t he visit c o nfir mati o n o n site-s pecific s p o ns or-pr o vi de d e P R O de vice , as part of 
t hese o n-site/tele p h o ne visits i n or der t o acti vate partici pa nts a bilit y t o start c o m pleti n g t hese data c ollecti o ns 
o n p artici p a nt -s pecific s p o ns or-pr o vi de d de vice, at h o me
b.
At Wee k 4 6 (ie, 1 4 ± 4 da ys pri or t o t he o n -site visit f or Wee k 4 8/ Visit 1 9) site staff re q uire d t o acti vate t he 
visit c o nfir mati o n o n site-s pecific sp o ns or -pr o vi de d e P R O de vice i n or der t o acti vate partici pa nts a bilit y t o 
start c o mplet i n g t hese data c ollecti o ns o n p artici p a nt -s pecific s p o ns or-pr o vi de d de vice, at h o me; i n a d diti o n, 
site m ust call partici pa nts 1 4 ± 4 da ys pri or t o Wee k 4 8/ Visit 1 9 t o re mi n d t he m t o start c o m pleti n g t heir 
re q uired assess me nts
E ver y eff ort s h o ul d be ma de t o ha ve t he partici pa nt c o m plete all e P R O assess me nts; t h o u g h 
partial c o m pleti o n of e P R O assess me nts d oes n ot precl u de c o nti n uati o n of t he gi ve n visits or
partici pati o n i n t he st u d y .
A d diti o nal details re gar di n g e P R Os will be pr o vi de d i n a st u d y -s pecific e P R O trai ni n g 
ma n ual s u p plie d b y  t he sp o ns or bef ore i nitiati o n of t his st u d y .
8. 1. 3. 1. N A S H -C H E C K
T he N A S H -C H E C K is a N A S H -s pecific healt h-relate d q ualit y of life meas ure t hat was 
de vel o pe d bas e d o n q ualitati ve partici pa nt i n p ut ( A p pe n di x 9. 1 ). It c o nsists of 3 1 ite ms t hat 
meas ure 3 d o mai ns: s y m pt o ms ( 1 1 -p oi nt N R S), da y -t o-d a y  acti vities ( 5-p oi nt V R S), a n d 
e m oti o ns a n d lifest yle ( 4- poi nt V R S), o ver t he past 7 da y s.
8. 1. 3. 2. N A S H S y m pt o m Di ar y
T he N A S H S y m pt o m Diar y  is a daily, self -a d mi nistere d q uesti o n naire t hat meas ures 
s ym pt o ms of N A S H ( A p pe n di x 9. 2 ). T his meas ure was de vel o pe d b y Pfizer base d o n 
q ualitati ve partici pa nt i n p ut as well as re vie w of ot her data s o urces (ie, literat ure a n d ot her 
e xisti n g meas ures). T he meas ure c o nsists of a t otal of 5 ite ms t hat as k partici pa nts t o rate t he 
se verity of t heir a b d o mi nal s y m pt o m s ( pai n a n d bl oati n g [ 2 ite ms]), fati g ue ( 1 ite m), slee p 
dist ur ba nce ( 1 ite m), a n d da yti me slee pi ness ( 1 ite m), i n t he past 2 4-h o urs o n a n 1 1 -p oi nt 
N R S t hat ra n ges fr o m 0 t o 1 0.
8. 1. 3. 3. N A S H P atie nt’s Gl o b al I m pressi o n of Se verit y ( P GI -S)
T he N A S H P GI -S ( A p pe n di x 9. 3 ) c o nsist of t w o ite ms t hat as k partici pa nts t o e val uate t heir 
se verity of a b d o mi nal s y m pt o ms (a b d o mi nal pai n or bl oati n g) a n d fati g ue o ver t he past 7 
da y s o n a 5- p oi nt V R S t hat ra n ges fr o m “ N o ne” t o “ Ver y se vere”.
T h e P GI -S is rec o m me n de d b y  U S - F D A f or use as a n a nc h or meas ure t o ge nerate a n 
a p pr o priate t hres h ol d t hat re prese nts mea ni n gf ul wit hi n -partici pa nt c ha n ge i n t he tar get 
p o p ulati o n. 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 8
8. 1. 3. 4. N A S H P atie nt’s Gl o b al I m pressi o n of C h a n ge ( P GI -C)
T he N A S H P GI -C ( A p pe n di x 9. 4 ) c o nsist of t w o ite ms t hat as k partici pa nts t o rate t he 
o verall c ha n ge i n t heir se verit y  of a b d o mi nal sy m pt o ms (a b d o mi nal pai n or bl oati n g) a n d 
fati g ue si nce t he y starte d t he st u d y o n a 5-p oi nt V R S t hat ra n ges fr o m “ M uc h better” t o 
“ M uc h w orse”.
T he P GI -C is rec o m me n de d b y  U S - F D A f or use as a n a nc h or meas ure t o ge nerate a n 
a p pr o priate t hres h ol d t hat re prese nts mea ni n gf ul wit hi n -partici pa nt c ha n ge i n t he tar get
p o p ulati o n. 
8. 1. 3. 5. P R O MI S F ati g ue C ust o m 9 -Ite m Versi o n
T he P R O MI S Fati g ue C ust o m 9 -Ite m V ersi o n (A p pe n di x 9. 5 ) is a self-re p orte d meas ure t hat 
assesses a ra n ge of s ym pt o ms i n t he past 7 da ys fr o m mil d s u bjecti ve feeli n gs of tire d ness t o 
a n o ver w hel mi n g, de bilitati n g, a n d s ustai ne d se nse of e x ha usti o n t hat li kel y  decreases o ne’s 
a bilit y t o e xec ute daily acti vities a n d f u ncti o n n or mall y  i n fa mily or s ocial r oles.
T he s h ort f or m c o nsists of 9 ite ms t hat partici pa nts will be as ke d t o rate fr o m 1: “ Ne ver” t o 5: 
“ Al wa ys”. A gl o bal ra w sc ore ra n gi n g fr o m 9 t o 4 5 is calc ulate d a n d ca n be tra nslate d i nt o a 
T- sc ore ( Mea n = 5 0, S D = 1 0) usi n g t he a p plica ble sc ore c o n versi o n ta ble pr o vi de d i n t he 
P R O MI S User’s Ma n ual.
8. 2. S afet y Assess me nts
Pla n ne d ti me p oi nts f or all safet y  assess me nts are pr o vi de d i n t he S o A -Ta ble A 1 a n d 
S o A -Ta ble A 2 . U nsc he d ule d cli nical la b orat or y  meas ure me nts ma y be o btai ne d at a n y ti me 
d uri n g t he st u d y t o assess a n y percei ve d safet y iss ues.
C o nsi deri n g c o n d uct of t his st u d y  d uri n g t he o n g oi n g C O VI D-1 9 pa n de mic , t he f oll o wi n g 
g ui da nce is offere d f or partici pa nts recei vi n g C O VI D- 1 9 vacci nes w hic h ha ve te m p orar y
a ut h orizati o n or f ull a p pr o val, i n t he partici pati n g c o u ntries –
Sc o pe
Acti o n
C o nsi der ati o ns 
Partici pa nts p ost 
r a n d o miz ati o n w h o 
are c o nsi deri n g 
C O VI D -1 9 
vacci nati o n a
C O VI D -1 9 vacci ne a d mi nistrati o n(s), w here 
p ossi ble, as ke d t o occ ur at le ast 1 -wee k pr i or
t o sc he d ule d o n-site visit

1- wee k pri or t o o n -site visit 
f or St u d y C 2 5 4 1 0 1 3 t o all o w 
f or res ol uti o n of 
si g ns/s y m pt o ms p ost 
vacci nati o n (a n d he nce li mit 
i mpact o n fasti n g la b orat or y 
tests c ollecte d as part of 
st u d y C 2 5 4 1 0 1 3)

Lac k of a bilit y t o f oll o w 
sc he d uli n g g ui da nce will n ot 
be vie w e d as pr ot oc ol 
de viati o ns s o l o n g as 
partici pa nt’s safet y was 
p reser ve d 
Partici pa nts w h o 
re p ort S A R S -C O V- 2
p ositive res ult ( or 
Self -is olate at h o me u ntil

At le ast 1 0 d a ys si nce s y m pt o ms first 
a p peare d a n d
Pr o p osal n ot t o re-test a n d si m pl y 
self-is olate is i n li ne wit h 
g ui deli nes fr o m t he C D C i n t he 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 9
Sc o pe
Acti o n
C o nsi der ati o ns 
ha ve si g ns a n d 
s y m pt o ms of 
C O VI D -1 9) a

At le ast 2 4 h o urs wit h n o fe ver w it h o ut 
fe ver-re d uci n g me dicati o n a n d

Ot her s y m pt o ms of C O VI D -1 9 are 
i mpr o vi n g; t h o u g h l oss of taste a n d s mell 
ma y persist f or wee ks or m o nt hs after 
rec o ver y a n d nee d n ot dela y t he e n d of 
is olati o n

Sc he d ule d st u d y visits s h o ul d n ot occ ur
d uri n g t his i nter val

T hese visits ca n eit her occ ur -

o utsi de of wi n d o w  (str o n gl y 
a d v ocate d es peciall y f or visits 
p ost ra n d o mizati o n t o e ns ure 
c o nti n ue d safet y m o nit ori n g a n d 
a de q uate I P s u p pl y) 

or be s ki p pe d ( pr o vi de d t he 
partici pa nt ’s safet y is preser ve d)
U nite d States of A merica (as of 
0 7 Ja n uar y 2 0 2 1)
Partici pa nts w h o 
re p ort S A R S -C O V -2 
p ositive res ult a n d
were h os pitalize d f or 
a s h ort peri o d a
F or partici pa nts wit h se vere ill ness fr o m 
C O VI D -1 9 ( h os pital a d missi o n a n d nee d f or 
s u p ple me ntal o x y ge n), self-is olati o n f or l o n ger 
t h a n 1 0 d ays after s y m pt o ms first a p peare d 
( p ossi bl y u p t o 2 0 da ys) – i ncl u di n g nee d t o 
fi nis h peri o d of is olati o n at h o me ( p ost h os pital 
disc har ge) s h o ul d be c o nsi dere d

Sc he d ule d st u d y visits s h o ul d n ot occ ur
d uri n g t his i nter val

T hese visits ca n eit her occ ur -

o utsi de of wi n d o w  (str o n gl y 
a d v ocate d es peciall y f or visits 
p ost ra n d o mizati o n t o e ns ure 
c o nti n ue d safet y m o nit ori n g a n d 
a de q uate I P s u p pl y) 

or be s ki p pe d ( pr o vi de d t he 
partici pa nt ’s safet y is preser ve d)
Pr o p osal n ot t o re-test a n d 
si m pl y self-is olate is i n li ne wit h 
g ui deli nes fr o m t he C D C i n t he 
U nite d States of A merica (as of 
0 7 Ja n uar y 2 0 2 1)
a.
Details re gar di n g a d mi nistrati o n of vacci ne, a n y c o nc o mita nt me dicati o ns, a n y A Es are t o be ca pt ure d i n 
t he st u d y data base, per t he la n g ua ge i n t his pr ot oc ol a n d st u d y-s pecific C R F c o m pleti o n g ui deli nes
8. 2. 1. P h ysic al E x a mi n ati o ns
I n t his st u dy, p h y sical e xa mi nati o ns (i ncl u di n g partici pa nts’ hei g ht at selecte d visits) are t o 
be perf or me d at n o mi nal ti me p oi nts s pecifie d i n t he S o A -Ta ble A 1 .

A c o m plete p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he 
car di o vasc ular, res pirat or y, gastr oi ntesti nal, a n d ne ur ol o gical s ys te ms.

A brief p h y sical e xa mi nati on will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular sys te m, a n d a b d o me n (li ver a n d s plee n).
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 0
P h y sical e xa mi nati o n fi n di n gs c ollecte d d uri n g t he st u d y will be c o nsi dere d s o urce data a n d 
will n ot be re q uire d t o be re p orte d, u nless ot her wise n ote d. A n y u nt o war d p h ysical 
e xa mi nati o n fi n di n gs t hat are i de ntifie d d uri n g t he acti ve c ollecti o n peri o d a n d meet t he 
defi niti o n of a n A E o r S A E (A p pe n di x 3 ) m ust be re p orte d acc or di n g t o t he pr ocesses i n 
Secti o n 8. 3. 1 t o Secti o n 8. 3. 3 .
8. 2. 1. 1. Me as ure me nt of W aist Circ u mfere nce 
Waist circ u mfere nce will be meas ure d at t he n o mi nal ti me p oi nts s pecifie d i n t he 
S o A -Ta ble A 1 usi n g a fle xi ble a nt hr o p o metric ta pe a n d i deall y, re p orti n g t he meas ure me nt i n 
ce nti meters wit h acc urac y t o t he nearest 0. 1 ce nti meter ( or 1/ 1 6t h i nc h).
Meas ure me nt will be u n derta ke n as f oll o w s:

W hile partici pa nt is i n a sta n di n g p ositi o n wit h ar ms resti n g c o mf orta bl y at t he si de;

At t he e n d of a n or mal e x pirati o n ( w he n l u n gs are at t heir resi d ual ca pacit y ).
A n d t he meas ure me nt will c o nsi der t he f oll o wi n g a nat o mical feat ures as be nc h mar ks:

Cir c u mfere nce of t he narr o west part of t he t ors o as vie we d fr o m t he a nteri or as pect
or;

If t he narr o west part of t he t ors o ca n n ot be i de ntifie d, t he meas ure me nt m ust be ma de 
of t he s mallest h oriz o ntal circ u mfere nce i n t he area bet wee n t he ri bs a n d t he iliac 
crest.
8. 2. 2. B o d y Wei g ht
I n t his st u dy, assess me nt of b o d y wei g ht will occ ur at t he n o mi nal ti me p oi nts s pecifie d i n
t he S o A -Ta ble A 1 per t he f oll o wi n g s pecificati o ns:

Wei g ht will be rec or de d usi n g a scale place d o n a sta ble, flat s urface i n a
(se mi)-
pri vate area;

Sa me scale, as m uc h as pr actic ally p ossi ble , will be use d wit h t he scale re p orti n g
wei g ht i n kil o gra ms or p o u n ds, a n d acc urac y t o t he ne arest 0. 1 k g [ o r 0. 2 p o u n ds]
ie, t he de vice use d f or t his st u d y m ust be a ble t o disti n g uis h a differe nce bet wee n 
6 8. 4 k g a n d 6 8. 3 k g.

Meas ure me nt m ust be u n derta ke n a n d d oc u me nte d t o 1 deci mal place ;

At a p pr o xi matel y  t he sa me ti me of t he da y at eac h n o mi nal ti me p oi nt.
U n der sta n dar d c o n diti o ns (e g, partici pa nts m ust wear li g ht cl ot hi n g wit h c o nte nt of
t heir 
p oc kets e m ptie d or h os pital g o w n a n d n ot be weari n g s h oes or b u l k y l a yers of 
cl ot hi n g/jac kets).
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 1
8. 2. 3. Electr oc ar di o gr a ms
Sta n dar d 1 2 -lea d E C Gs utilizi n g li m b lea ds ( wit h a 1 0 sec o n d r hyt h m stri p) s h o ul d be 
c ollecte d at ti mes s pecifie d i n t he S o A -Ta ble A 1 usi n g a n E C G mac hi ne t hat a ut o maticall y  
calc ulates t he heart rate a n d meas ures P R, Q T, a n d Q Tc i nter vals a n d Q R S c o m ple x. 
Alter nati ve lea d place me nt met h o d ol o g y  usi n g t ors o lea ds (e g, Mas o n-Li kar) is n ot
rec o m me n de d gi ve n t he p ote ntial ris k of discre pa ncies wit h E C Gs ac q uire d usi n g sta n dar d 
li m b lea d place me nt. 

All sc he d ule d 1 2 -lea d E C Gs s h o ul d be perf or me d after t he partici pa nt has reste d 
q uietl y f or ≥1 0 -mi n utes i n a s u pi ne p ositi o n;

E C G val ues of p ote n tial cli nical c o ncer n are liste d i n A p pe n di x 7 .

St arti n g at Visit 4/ B aseli ne , if a mac hi ne -rea d Q Tc val ue is pr ol o n ge d, as defi ne d 
i n A p pe n di x 7 , re peat meas ure me nts ma y n ot be necessar y  if a q ualifie d 
p h y sicia n’s i nter pretati o n deter mi nes t hat t he Q Tc val ues are i n t he acce pta ble 
ra n ge;

Assess me nt of w het her pr ol o n ge d Q Tc i nter val meets criteria as defi ne d i n 
A p pe n di x 7 , m ust assess Q Tc i nter v al usi n g o nly t he Fri dericia’s c orrecti o n 
(ie, Q Tc F) eit her as re p orte d b y t he 1 2-lea d E C G mac hi ne or Q Tc F deri ve d 
usi n g sp o ns or -pr o vi de d t o ol a n d re p orte d Q T a n d R R i nter vals .

I n s o me cases, it ma y be a p pr o priate t o re peat a b n or mal 1 2-lea d E C Gs t o r ule o ut 
i m pr o per lea d place me nt as c o ntri b uti n g t o t he E C G a b n or malit y; as m uc h as 
pr actic ally, p ossi ble, it is i m p orta nt t hat lea ds be place d i n t he sa me p ositi o ns eac h 
ti me i n or der t o ac hie ve precise E C G rec or di n gs.
8. 2. 4. Vit al Si g ns
I n t his st u dy, assess me nt of vital si g ns (i ncl u di n g seate d bl o o d press ure, a n d p ulse rate) will
occ ur at t he n o mi nal ti me p oi nts s pecifie d i n t he S o A -Ta ble A 1 per t he f oll o wi n g 
s pecificati o ns :

At t he Pre Q visit, t he partici pa nts’ ar m circ u mfere nce s h o ul d be meas ure d (usi n g a 
fle xi ble a nt hr o p o metric ta pe) at t he mi d p oi nt of t he le n gt h of t he u p per ar m a n d t he
a p pr o priate c uff selecte d a n d use d t hr o u g h o ut t he st u d y t o meas ure B P/ p ulse rate via 
a n a ut o mate d de vice usi n g a n oscill o metric met h o d ( n ot a usc ultati o n):

Partici pa nts wit h ar m circ u mfere nce greater t ha n t he lar gest c uff size a vaila ble at
eac h site are n ot eli gi ble.

Si n gle se ate d bl o o d press ure/ p ulse rate will be meas ure d wit h t he partici pa nt’s ar m
s u p p orte d at t he le vel of t he heart, a n d rec or de d t o t he nearest m m H g, f oll o wi n g a
rest of ≥ 5 -mi n utes ;
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 2

Sa me ar m ( prefera bl y  t he d o mi na nt ar m) will be use d f or bl o o d press ure/ p ulse rate
assess me nt t hr o u g h o ut t he st u d y.
8. 2. 5. Cli nic al S afet y L a b or at or y Assess me nts 
See A p pe n di x 2 f or t he list of cli nical safety la b orat or y  tests t o be perf or me d a n d t he 
S o A -Ta ble A 2 f or t he ti mi n g a n d fre q ue nc y. All pr ot oc ol-re q uire d la b orat or y assess me nts, as 
defi ne d i n A p pe n di x 2 , m ust be c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he 
S o A -Ta ble A 2 . U nsc he d ule d cli nical la b orat or y meas ure me nts ma y be o btai ne d at a n y ti me 
d uri n g t he st u d y t o assess a n y percei ve d safet y iss ues. 
T he i n vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt this re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F. 
Cli nicall y  si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h 
t he u n derlyi n g disease, u nless j u d ge d b y  t he i n vestigat or t o be m ore se vere t ha n e x pecte d f or 
t he partici pa nt's c o n diti o n.
All la b orat or y  tests wit h val ues c o nsi dere d cli nicall y si g nifica ntly a b n or mal d uri n g 
partici pati o n i n t he st u d y  or wit hi n 2 8 d a ys after t he last d ose of st u d y i nter ve nti o n s h o ul d be 
re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger c o nsi dere d cli nicall y 
si g nifica nt by t he i n vesti gat or or me dical m o nit or.
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d ge d reas o na ble b y 
t he i n vesti gat or, t he eti ol o g y s h o ul d be i de ntifie d, a n d t he s p o ns or n otifie d.
See A p pe n di x 6 f or s u g geste d acti o ns a n d f oll o w- u p assess me nts i n t he e ve nt of p ote ntial 
dr u g -i n d uce d li ver i nj ur y.
8. 2. 6. Pre g n a nc y Testi n g
Pre g na nc y  tests ma y be uri ne a n d/or ser u m tests b ut m ust ha ve a se nsiti vit y of at le ast 
2 5 mI U/ m L . P re g na nc y tests will be perf or me d i n W O C B P at t he ti mes liste d i n t he 
S o A -Ta ble A 2 F oll o wi n g a ne gati ve pre g na nc y  test res ult at scree ni n g, a p pr o priate 
c o ntrace pti o n m ust be c o m me nce d ( or c o nti n ue d) a n d a sec o n d ne gati ve pre g na nc y  test res ult 
will be re q uire d at t he baseli ne visit pri or t he partici pa nt’s recei vi n g t he st u d y  i nter ve nti o n. 
Pre g na nc y  tests will als o be d o ne w he ne ver 1 me nstr ual c ycle 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) a n d at t he e n d of t he 
st u d y. Pre gna nc y  tests ma y als o be re peate d if re q ueste d b y IR Bs/ E Cs or if re q uire d b y l ocal 
re g ulati o ns. If a uri ne test ca n n ot be c o nfir me d as ne gati ve (e g, a n a m bi g u o us res ult), a ser u m 
pre g na nc y  test is re q uire d. In s uc h cases, t he partici pa nt m ust be e xcl u de d i f t he ser u m 
pre g na nc y  res ult is p ositi ve.
8. 2. 7. Alc o h ol I nt a ke Assess me nt
I n t his st u dy, t he i ntervie w-b ase d A U DI T q uesti o n naire 1 8 will be c o m plete d b y  me d ic ally 
q u alifie d site st aff base d o n res p o nses offere d b y t he partici pa nts – at t he visits o utli ne d i n 
t he S o A -Ta ble A 1 . Trai ni n g f or t he site staff c o m pleti n g t his q uesti o n naire will be offere d b y  
t he s p o ns or as part of t he pr ot oc ol-s pecific trai ni n g a hea d of t he i nitiati o n of t he st u d y.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 3
8. 2. 8. Tri g gere d re q uire me nts a n d I n di vi d u al P artici p a nt st o p pi n g r ules
8. 2. 8. 1. P ote nti al C ases of H y pertri gl yceri de mi a
I n t he c urre nt st u d y, fasti n g ser u m tri glyc eri des as re p orte d b y t he s p o ns or -i de ntifie d ce ntral 
la b orat or y, wit h or wit h o ut a n y acc o m pa n yi n g si g ns/s ym pt o ms, will be assesse d vers us t he 
t hres h ol d o utli ne d i n A p pe n di x 1 1 . 
I n di vi d ual partici pa nts wit h c o nsiste ntly i ncre asi n g fasti n g ser u m tri glyc eri des o ver ti me 
ulti matel y  reac hi n g t he t hres h ol d o f ≥8 0 0 m g/ d L ( 9 m m ol/ L ) as o utli ne d i n A p pe n di x 1 1
s h o ul d st o p d osi n g wit h st u d y i nter ve nti o n a n d a n A E of h ypertri gl yc eri de mia ca pt ure d.
W he n c o nsi deri n g a dj ust me nt of d ose(s) of bac k gr o u n d li pi d -m o dif y i n g a ge nts i n or der t o 
ma na ge ele vati n g fasti n g ser u m tri gl yc eri de res ults, i n vesti gat ors m ust c o nsi der t he g ui da nce 
offere d i n Secti o n 6. 5. 2 relate d t o d oses of certai n li pi d-m o dif y i n g a ge nts a n d ta ke acti o n 
o nl y  w he n it has bee n esta blis he d t hat o bser ve d res ult is n ot d ue t o lac k of c o m plia nce wit h 
d osi n g of st u d y i nter ve nti o n a n d/ or bac k gr o u n d li pi d -m o dif y i n g a ge nts.
8. 2. 8. 2. P ote nti al C ases of T hr o m b oc yt o pe ni a
I n t he c urre nt st u d y, platelet c o u nt as re p orte d b y t he s p o ns or-i de ntifie d ce ntral la b orat or y, 
wit h or wit h o ut a n y  acc o m pa n yi n g si g ns/s ym pt o ms, will be assesse d vers us t he t hres h ol d 
o utli ne d i n A p pe n di x 1 2 .

I n partici pa nts o bserve d t o ha ve platelet c o u nt bel o w t he L L N s h o ul d ha ve a n 
u n pla n ne d visit occ ur as s o o n as pr actic ally p ossi ble t o –

I n q uire a b o ut a d verse e ve nts via ope n -e n de d i n q uir y; 

C o nfir m via o pe n -e n de d i n q uir y t hat partici pa nt has bee n f oll o wi n g d osi n g 
i nstr ucti o ns as i nte n de d (a n d o utli ni n g i n t he d osi n g i nstr ucti o ns) a n d t hat t here is 
n o case of me dicati o n err or;

A n d c ollect bl o o d sa m ple t o per mit safet y- relate d la b orat or y assess me nts i ncl u de d 
he mat ol o g y  pa nel assess me nt b y t he s p o ns or-i de ntifie d ce ntral la b orat or y.
Partici pa nts w h o ha ve bee n f oll o wi n g d osi n g i nstr ucti o ns a n d i n w h o m c o nsiste nt decli ne
over ti me ulti matel y  reac hi n g t he t hres h ol d of < 7 5, 0 0 0/ m m3 i n platelet c o u nt has bee n 
o bser ve d as o utli ne d i n A p pe n di x 1 2 s h o ul d st o p d osi n g wit h st u d y i nter ve nti o n a n d a n A E 
of t hr o m b oc y t o pe nia ca pt ure d.
8. 3. A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o ns of a n A E a n d a n S A E ca n be f o u n d i n A p pe n di x 3 .
A Es will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or 
t he partici pa nt's le gally a ut h orize d re prese ntati ve).
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 4
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble t o 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 a ssess w het her t he 
e ve nt meets t he criteria f or classificati o n as a n S A E or ca use d t he partici pa nt t o disc o nti n ue 
t he st u d y i nter ve nti o n - refer t o Secti o n 7. 1 . 
Eac h partici pa nt will be q uesti o ne d a b o ut t he occ urre nce of A Es i n a n o nlea di n g ma n ner.
I n a d diti o n, t he i n vesti gat or ma y be re q ueste d b y Pfizer Safety 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.
8. 3. 1. Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d 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 partici pa nt be gi ns fr o m t he ti me t he partici pa nt pr o vi des i nf or me d c o nse nt, 
w hic h is o btai ne d bef ore t he partici pa nt’s partici pati o n i n t he st u d y  (ie, bef ore u n der g oi n g 
a n y st u d y-relate d pr oce d ure a n d/ or recei vi n g st u d y i nter ve nti o n), t hr o u g h a n d i ncl u di n g a 
mi ni m u m of 2 8 c ale n d ar d ays , e xce pt as i n dicate d bel o w, after t he last a d mi nistrati o n of t he 
st u d y i nter ve nti o n or u ntil st u d y  c o m pleti o n or wit h dra wal, w hic he ver is l o n ger. 
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 A E or S A E or its se q uelae res ol ve or sta bilize at a le vel acce pta b le t o t he 
i n vesti gat or a n d Pfizer c o nc urs wit h t hat assess me nt.
F or partici pa nts 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.
If t he partici pa nt 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 t he c ollecti o n of 
f ut ure i nf or mati o n, t he acti ve c ollecti o n peri o d e n ds w he n c o nse nt is wit h dra w n.
If a partici pa nt defi niti vel y disc o nti n ues or te m p oraril y disc o nti n ues st u d y i nter ve nti o n 
beca use of a n A E or S A E, t he A E or S A E m ust be rec or de d o n t he C R F a n d t he S A E 
re p orte d usi n g t he C T S A E Re p ort F or m.
I n vesti gat ors are n ot o bli gate d t o acti vely see k A Es or S A Es after t he partici pa nt has 
c o ncl u de d st u d y partici pati o n . H o we ver, if t he i n vesti gat or lear ns of a ny S A E, i ncl u di n g a 
deat h, at a n y ti me after a partici pa nt has c o m plete d t he st u d y , a n d he/s he c o nsi ders t he e ve nt 
t o be reas o na bl y relate d t o t he st u d y i nter ve nti o n, t he i n vesti gat or m ust pr o m ptl y re p ort t he 
S A E t o Pfizer usi n g t he C T S A E Re p ort F or m.
8. 3. 1. 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 partici pa nt d uri n g t he acti ve c ollecti o n peri o d as descri be d i n 
Secti o n 8. 3. 1 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 im me diatel y  u p o n 
a ware ness a n d u n der n o circ u msta nce s h o ul d t his e xcee d 2 4 h o urs, as i n dicate d i n 
A p pe n di x 3 . T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 
2 4 h o urs of it bei n g a vaila ble.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 5
8. 3. 1. 2. Rec or di n g N o nseri o us A Es a n d S A Es o n t he C R F
All n o nseri o us A Es a n d S A Es occ urri n g i n a partici pa nt d uri n g t he acti ve c ollecti o n peri o d as 
descri be d i n Secti o n 8. 3. 1 are rec or de d o n t he C R F. A Es a n d S A Es t hat be gi n after o btai ni n g 
i nf or me d c o nse nt b ut bef ore t he start of st u dy i nter ve nti o n will be rec or de d o n t he Me dical 
Hist or y / C urre nt Me dical C o n diti ons secti o n of t he C R F, n ot t he A E secti o n. A Es a n d S A Es 
t hat be gi n after t he start of st u d y i nter ve nti o n are rec or de d o n t he A E secti o n of t he C R F.
T he i n vesti gat or is t o rec or d o n t he C R F all directl y  o bser ve d a n d all s p o nta ne o usl y re p orte d 
A Es a n d S A Es re p orte d b y t he partici pa nt.
8. 3. 2. Met h o d of Detecti n g A Es a n d S A Es
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y  of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 3 .
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d 
n o nlea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nces.
8. 3. 3. F oll o w - u p of A Es a n d S A Es
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. F or eac h e ve nt, t he i n vesti gat or m ust p urs ue a n d 
o btai n a de q uate i nf or mati o n u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, 
or t he partici pa nt is l ost t o f oll o w-u p (as defi ne d i n Secti o n 7. 3 ).
I n ge neral, f oll o w- u p i nf or mati o n will i ncl u de a descri pti o n of t he e ve nt i n s ufficie nt detail 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 oss i ble ca usalit y. A ny 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 n d ill nesses, m ust be pr o vi de d. I n t he case of a partici pa nt deat h, a s u m 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. 
F ur t her i nf or mati o n o n f oll o w-u p pr oce d ures is gi ve n i n A p pe n di x 3 .
8. 3. 4. Re g ul at or y Re p orti n g Re q uire me nts f or S A Es
Pr o m pt n otificati o n b y  t he i n vesti gat or t o t he s p o ns or of a n S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of a 
st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.
T he s p o ns or has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safety of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T he 
s p o ns or will c o m pl y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts relati n g t o safety 
re p orti n g t o t he re g ulat or y a ut h ority, I RBs/ E Cs , a n d i n vesti gat ors.
I n vesti gat or safet y re p orts m ust be pre pare d f or S U S A Rs acc or di n g t o l ocal re g ulat or y  
re q uire me nts a n d s p o ns or p olic y a n d f or war de d t o i n vesti gat ors as necessar y.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6
A n i n vesti gat or w h o recei ves S U S A Rs or ot her s pecific safet y i nf or mati o n (e g, s u m mar y or 
listi n g of S A Es) fr o m t he s p o ns or will re vie w a n d t he n file it al o n g wit h t he S R S D(s) f or t he 
st u d y a n d will n otif y t he I R B/ E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
8. 3. 5. E x p os ure 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 st u d y  i nter ve nti o n 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 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. 3. 5. 1. E x p os ure D uri n g Pre g n a nc y
A n E D P occ urs if: 

A fe male partici pa nt is f o u n d t o be pre g na nt w hile recei vi n g or after disc o nti n ui n g 
st u d y i nter ve nti o n.

A fe male is f o u n d t o be pre g na nt w hile bei n g e x p ose d or ha vi n g bee n e x p ose d t o 
st u d y i nter ve nti o n d ue t o e n vir o n me ntal e x p os ure. Bel o w are e xa m ples of 
e n vir o n me ntal e x p os ure d uri n g pre g na nc y :

A fe male fa mil y  me m ber or healt hcare pr o vi der re p orts t hat s he is pre g na nt after 
ha vi n g bee n e x p ose d t o t he st u d y  i nter ve nti o n b y i n halati o n or s ki n c o ntact.

A male fa mil y me m ber or healt hcare pr o vi der w h o has bee n e x p ose d t o t he st u d y 
i nter ve nti o n b y i n halati o n or s ki n c o ntact t hen e x p oses his fe male part ner pri or t o 
or ar o u n d t he ti me of c o nce pti o n.
T he i n vesti gat or m ust re p ort E D P 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, irres pecti ve of w het her a n S A E has occ urre d. T he i nitial 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 mi nati o n of pre g na nc y). 

If E D P occ urs i n a partici pa nt or a partici pa nt’s part ner, 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 or m, re gar dless of w het her a n S A E has occ urre d. Details of t he 
pre g na nc y  will be c ollecte d after t he start of st u d y i nter ve nti o n a n d u ntil at le ast 2 8
d ays after t he last d ose of st u d y  i nter ve nti o n.

If E D P occ urs i n t he setti n g of e n vir o n me ntal e x p os ure, t he i n vesti gat or m ust re p ort 
i nf or mati o n t o Pfizer Safet y usi n g t he C T S A E Re p ort F or m a n d E D P S u p ple me ntal 
F or m. Si nce t he e x p os ure i nf or mati o n d oes n ot pertai n t o t he partici pa nt e nr olle d i n 
t he st u d y, t he i nf or mati o n is n ot rec orde d o n a C R F; h o we ver, a c o p y  of t he 
c o m 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 file.
F oll o w -u p 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 otif y Pfizer Safety of t he o utc o me as a 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 7
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 h o ul d be s pecifie d a n d, if cli nicall 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 are 
re p orte d).
A b n or mal pre g na nc y  o utc o mes are c o nsi dere d S A Es. 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 
d e 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 nate d fet us, a n 
i ntra uteri ne fetal de mise, or a ne o natal deat h, t he i n 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 Safet y  as S A Es f oll o ws: 

S p o nta ne o us a b orti o n i ncl u di n g miscarria ge a n d misse d a b orti o n;

Ne o natal deat hs t hat occ ur wit hi 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 st u d y i nter ve nti o n. 
A d diti 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 ut c 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 
preter m i nfa nts t o i de ntif y de vel o p me ntal dela y s). In t he case of pater nal e x p os ure, t he 
i n vesti gat or will pr o vi de t he partici pa nt 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 me nts t hat 
t he partici pa nt was gi ve n t he Pre g na nt Part ner Release of I nf or mati o n F or m t o pr o vi de t o his 
part ner.
8. 3. 5. 2. E x p os ure D uri n g Bre astfee di n g
A n e x p os ure d uri n g breastfee di n g occ urs if:

A fe male partici pa nt is f o u n d t o be breastfee di n g w hile recei vi n g or after 
disc o nti n ui n g st u d y  i nter ve nti o n.

A fe male is f o u n d t o be breastfee di n g w hile bei n g e x p ose d or ha vi n g bee n e x p ose d t o 
st u d y i nter ve nti o n (ie, e n vir o n me ntal e x p os ure). A n e xa m ple of e n vir o n me ntal 
e x p os ure d uri n g breastfee di n g is a fe male fa mil y  me m ber or healt hcare pr o vi der w h o 
re p orts t hat s he is breastfee di n g after ha vi n g bee n e x p ose d t o t he st u d y i nter ve nti o n 
b y  i n halati o n or s ki n c o ntact. 
T he i n vesti gat or m ust re p ort e x p os ure d ur i n g breastfee di n g 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, irres pecti ve of w het her a n S A E has occ urre d. T he 
i nf or mati o n m ust be re p orte d usi n g t he C T S A E Re p ort F or m. W he n e x p os ure d uri n g 
breastfee di n g occ urs i n t he setti n g of e n vi r o n me ntal e x p os ure, t he e x p os ure i nf or mati o n d oes 
n ot pertai n t o t he partici pa nt e nr olle d i n t he st u d y , s o t he i nf or mati o n is n ot rec or de d o n a 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 8
C R F. H o we ver, a c o p y of t he c o m 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 file.
A n e x p os ur e 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 or d wit h 
a ut h orize d use. H o we ver, if t he i nfa nt e x perie nces a n S A E ass ociate d wit h s uc h a dr u g, 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. 3. 5. 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 a pers o n recei ves u n pla n ne d direct c o ntact wit h t he 
st u d y i nter ve nti o n, w hic h ma y or ma y n ot lea d t o t he occ urre nce of a n A E. S uc h pers o ns ma y 
i ncl u de healt hcare pr o vi ders, fa mily me m bers, a n d ot her r oles t hat are i n v ol ve d i n t he trial 
partici pa nt’s care.
T he i n vesti gat or m ust re p ort occ u pati o nal e x p os ure 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, re gar dless of w het her t here is a n ass ociate d S A E. T he i nf or mati o n 
m ust be re p orte d usi n g t he C T S A E Re p ort F or m. Si nce t he i nf or mati o n d oes n ot pertai n t o a 
partici pa nt 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 o m 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 file.
I n t his st u dy, 
 are t he 
 

I ncrease i n f asti n g
 – refer t o 
A p pe n di x 1 1 – i deall y via d o u ble-c o nfir mati o n pr o vi de d partici pa nt is as y m pt o matic;

R e d ucti o n i n 
– refer t o A p pe n di x 1 2 – i deall y via 
d o u ble -c o nfir mati o n pr o vi de d partici pa nt is as y m pt o matic.
All 
 m ust be re p orte d as a n A E or S A E f oll o wi n g t he pr oce d ures descri be d i n 
Secti o ns 8. 3. 1 t hr o u g h 8. 3. 4 . A n 
 is t o be rec or de d as a n A E or S A E o n t he C R F. I n 
a d diti o n, a n 
 t hat is als o a n S A E m ust be re p orte d usi n g t he C T S A E Re p ort F or m.
8. 3. 7. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult fro m t he a d mi nistrati o n or c o ns u m pti o n of t he st u d y  
i nter ve nti o n b y t he wr o n g partici pa nt, 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.
E x p os ures t o t he st u d y  i nter ve nti o n u n der st u d y ma y occ ur i n cli nical trial setti n gs, s uc h as 
me dicati o n err ors.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 9
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
Me dicati o n err 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
Me dicati o n err ors i ncl u de:

Me dicati o n err ors i n v ol vi n g partici pa nt e x p os ure t o t he st u d y  i nter ve nti o n;

P ote ntial me dicati o n err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o 
or d o n ot i n v ol ve t he st u d y  partici pa nt.
S uc h me dicati o n err ors occ urri 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 wit hi n 2 4 h o urs .
W het her or n ot t he me dicati o n err or is acc o m pa nie d b y  a n A E, as deter mi ne d b y t he 
i n vesti gat or, t he me dicati o n err or is rec or de d o n 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 nseri o us, are rec or de d o n t he A E pa ge of t he 
C R F. 
Me 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 urs o n a C T S A E Re p ort 
F or m o nl y w he n ass oci ate d wit h a n S A E .
8. 4. Tre at me nt of O ver d ose
F or t his st u d y , a n y d ose of D G A T 2i greater t ha n 
m g, or a n y d ose of A C Ci greater t ha n 
m g, wit hi n a 2 4 - h o ur ti me peri o d will be c o nsi dere d a n o ver d ose.
S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose. H o we ver, i n t he e ve nt of a n 
o ver d ose, t he i n vesti gat or s h o ul d:
1.
C o ntact t he me dical m o nit or wit hi n 2 4 h o urs .
2.
Cl osel y  m o nit or t he partici pa nt f or a ny A Es/ S A Es a n d la b orat or y  a b n or malities f or at 
least 5 half-li ves or 2 8 cale n dar da ys after t he o ver d ose of st u d y i nter ve nti o n.
3.
O btai n a bl o o d sa m ple f or P K a nal ys is as s o o n as pr actic ally p ossi ble ;
4.
D oc u me nt t he q ua ntit y of t he e xcess d oses as well as t he d urati o n of t he o ver d ose i n 
t he C R F.
5.
O ver d ose is re p orta ble t o Safet y  o nl y w he n ass oci ate d wit h a n S A E.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 0
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y  t he i n vesti gat or i n 
c o ns ultati o n wit h t he me dical m o nit or base d o n t he cli nical e val uati o n of t he partici pa nt. 
8. 5. P h ar m ac o ki netics 
I n t his st u dy, bl o o d sa m ples ( a p pr o xi matel y 5 m L eac h) t o pr o vi de s ufficie nt 
f or 
p har mac o ki netic a nal ys is will be c ollecte d i nt o a p pr o priately la bele d t u bes c o ntai ni n g 
K 2 -E D T A, at ti mes defi ne d i n t he S o A -Ta ble A 2 . T he date/ti me of t he bl o o d dra w a n d t he 
date/ti me of t he pre vi o us t w o d oses of d o u ble -bli n d , d o u ble-d u m m y st u d y i nter ve nti o n pri or 
t o e ac h of t he bl o o d dra ws relate d t o P K ( b ot h pre- a n d p ost - d ose sa m ples) s h o ul d be n ote d 
i n a d osi n g diar y ( or si milar) b y t he partici pa nts a n d ca pt ure d i n t he e C R F.

T he P K sa m ples m ust be pr ocesse d a n d s hi p pe d as i n dicate d i n t he st u d y-s pecific 
la b orat or y ma n ual pr o vi de d t o t he site, pri or t o i nitiati o n of st u d y, t o mai ntai n sa m ple 
i nte grity:

A n y  de viati o ns fr o m t he P K sa m ple ha n dli n g pr oce d ure (e g, sa m ple c ollecti o n 
a n d pr ocessi n g ste ps, i nteri m st ora ge or s hi p pi n g c o n diti o ns) , i ncl u di n g a ny 
acti o ns ta ke n, m ust 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 de viati o n fr o m t he s pecifie d sa m ple ha n dli n g pr oce d ure 
resulti n g i n c o m pr o mise d sa m ple i nte grit y  will be c o nsi dere d a pr ot oc ol 
de viati o n;

A ny of t he f oll o wi n g err ors i n sc he d ule d c ollecti o n of bl o o d sa m ples f or P K (refer 
t o S o A -Ta ble A 2 ) will be ca pt ure d as pr ot oc ol de viati o ns e ve n if res ults are 
dee me d t o be e val ua ble –

P re d ose c ollecti o n (ie, Ctr o u g h) o btai ne d p ost d ose ;

P ost d ose P K sa m ple n ot c ollecte d wit h i n c ollecti o n wi n d o w f oll o wi n g 
m or ni n g d ose ;

P K sa m ple ( pre - or p ost - d ose) n ot c ollecte d.

As part of u n dersta n di n g t he p har mac o ki netics of t he st u d y  i nter ve nti o n, sa m ples ma y 
be use d f or 
 
. T hese data will n ot be i ncl u de d 
i n t he cli nical re p ort;

Sa m ples will be a nal y ze d f or D G A T 2i a n d/ or A C Ci usi n g a vali date d a nal ytical 
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.
8. 6. P h ar m ac o d y n a mics
P har mac o d y na mic para meters are n ot e val uate d i n t his st u d y .
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 1
H o we ver, r efer t o Secti o n 8. 2 f or details re gar di n g t he pla n ne d safety- relate d assess me nts 
a n d Secti o n 8. 8 f or c ollecti o ns relate d t o e x pl orat or y bi o mar kers, pla n ne d i n t his st u d y. 
A 
 will be c ollecte d i nt o plastic 
K 2-E D T A t u bes, as defi ne d i n t he S o A -Ta ble A 2 .
 sa m ples will be a nal yze d f or t he 
p ur p ose of assessi n g t he i m pact of 
 
 
. As part of t hese 
a nal ys es, 
 
A d diti o nall y , t hese sa m ples ma y als o be use d f or 
 
Sa m ples will be retai ne d f or a peri o d of u p t o 3 ye ars after 
re g ul at or y a p pr o v al.
I n t he e ve nt of 
, a re place me nt  
 bl o o d sa m ple ma y be re q ueste d 
fr o m t he partici pa nt.
See A p pe n di x 5 f or i nf or mati o n re gar di n g  
 researc h. Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt of t hese sa m ples ca n be f o u n d i n s p o ns or -i de ntifie d st u d y-s pecific 
ce ntral la b orat or y ma n ual.
T he 
 m ust be pr ocesse d a n d s hi p pe d as i n dicate d i n t he i nstr ucti o ns pr o vi de d t o 
t he i n vesti gat or site, t o mai ntai n sa m ple i nte grit y. A n y de viati o ns fr o m t he 
 
ste ps, i ncl u di n g a ny acti o ns ta ke n, m ust 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 sp o ns or ma y  ma ke a deter mi nati o n as t o w het her sa m ple i nte grity has 
bee n c o m pr o mise d. A n y sa m ple dee me d o utsi de of esta blis he d sta bilit y, or of q uesti o na ble 
i nte grity, will be c o nsi dere d a pr ot oc ol de viati o n.
As part of f urt her u n dersta n di n g t he bi ol o gical res p o nse t o st u d y  i nter ve nti o n, sa m ples ma y 
be use d f or 
 
 
 a n d will n ot be i ncl u de d i n t he 
cli nical st u d y re p ort. 
A 
 will be c ollecte d as l ocal 
re g ulati o ns a n d I R Bs/ E Cs all o w - as defi ne d i n t he S o A -Ta ble A 2 . 
 ma y be use d f or researc h relate d t o t he st u d y i nter ve nti o n(s) a n d 
N A F L D/ N A S H.
 
 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 2
T he 
 d oes n ot re q uire t he c ollecti o n of a ny f urt her sa m ples.
See A p pe n di x 5 f or i nf or mati o n re gar di n g 
. Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt of t hese sam ples ca n be f o u n d i n s p o ns or-i de ntifie d st u d y-s pecific 
ce ntral la b orat or y ma n ual.
8. 8. Bi o m ar kers
C ollecti o n of sa m ples f or bi o mar ker researc h is part of t his st u d y .
Bl o o d , ser u m, plas ma, a n d li ver bi o ps y tiss ue sa m ples f or e x pl orat or y/tertiar y e n d p oi nt
bi o mar ker s, incl u di n g N A S H -relate d bi o mar kers, p ote ntial mec ha nis m-relate d para meters, 
meta b olic para meters , a n d t o ai de i n u n dersta n di n g t he st u d y i nter ve nti o ns, will be c ollecte d 
at t he n o mi nal ti me p oi nts defi ne d i n t he S o A -Ta ble A 2 .

T hese sa m ples m ust be pr ocesse d a n d s hi p pe d as i n dicate d i n t he st u d y -s pecific 
la b orat or y ma n ual pr o vi de d b y  t he sp o ns or t o t he site, pri or t o i nitiati o n of st u d y, t o 
mai ntai n sa m ple i nte grit y:

A n y  de viati o ns fr o m t he sa m ple ha n dli n g pr oce d ure (e g, sa m ple c ollecti o n a n d 
pr ocessi n g ste ps, i nteri m st ora ge or s hi p pi n g c o n diti o ns), 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 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 grity has bee n 
c o m pr o mise d. A n y de viati o n fr o m t he s pecifie d sa m ple ha n dli n g pr oce d ure 
res ulti n g i n c o m pr o mise d sa m ple i nte grit y will be c o nsi dere d a pr ot oc ol 
de viati o n;

A n y  sc he d ule d c ollecti o n pri or t o ne xt d ose of d o u ble -bli n d , d o u ble-d u m m y st u d y 
i nter ve nti o n, if u n derta ke n p ost d ose, will be ca pt ure d as a pr ot oc ol de viati o n e ve n 
if res ults are dee me d e val ua ble;

Sa m ples will be a nal y ze d usi n g a vali date d a nal yt ical met h o d ( w hic h nee d n ot meet 
G L P sta n dar ds, es peciall y f or t hese e x pl orat or y e n d p oi nts) b ut i n all cases, t he 
met h o d will be i n c o m plia nce wit h Pfizer sta n dar d o perati n g pr oce d ures.
I n a d diti o n, as part of f urt her u n dersta n di n g t he bi ol o gical res p o nse t o st u d y i nter ve nti o n, 
sa m ples ma y be use d f or e val uati o n of ot her relate d bi o mar kers as well as de vel o p me nt a n d 
vali dati o n of bi oa nal yt ical met h o ds. T hese data will be use d f or i nter nal e x pl orat or y p ur p oses 
a n d will n ot be i ncl u de d i n t he cli nical st u d y  re p ort.
 
 
 
 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 3
 
 
 
 
 
See A p pe n di x 5 f or i nf or mati o n re gar di n g 
. Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt of t hese sa m ples ca n be f o u n d i n s p o ns or -i de ntifie d st u d y-s pecific 
ce ntral la b orat or y ma n ual. 
8. 1 0. He alt h Ec o n o mics
Healt h ec o n o mics/ me dical res o urce utilizati o n a n d healt h ec o n o mics para meters are n ot 
e val uate d i n t his st u d y.
9. S T A TI S TI C A L C O N SI D E R A TI O N S
Detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nal ys es of t he data c ollecte 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 S A P, w hic h will be mai ntai ne d by 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 pri mar y  e n dp oi nt defi niti o ns or t heir a nal ys es will als o be reflecte d i n a 
pr ot oc ol a me n d me nt.
9. 1. Esti m a n ds a n d St atistic al H y p ot heses
9. 1. 1. Esti m a n ds
F or t he pri mar y  o bjecti ve of t he st u d y, t he pri mar y esti ma n d (Esti m a n d 1. 1 ) will use a 
c o m p osite esti ma n d strate g y, i n partici pa nts wit h bi o ps y-c o nfir me d N A S H a n d fi br osis, as 
assesse d b y t he s p o ns or -i de ntifie d ce ntral pat h ol o gist(s), t o esti mate t he treat me nt effect of 
D G A T 2i d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o 
place b o, a n d c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he 
pr o p orti o n of ‘cli nical res p o n ders’, defi ne d as partici pa nts ac hie vi n g ce ntrall y  a dj u dicate d: 
res ol uti o n of N A S H wit h o ut w orse ni n g of fi br osis or i m pr o ve me nt i n fi br osis b y ≥1 sta ge 
wit h o ut w ors e ni n g of N A S H, or b ot h, at Wee k 4 8 a n d treati n g all cases of wit h dra wal fr o m 
treat me nt f or lac k of efficac y or t olerati o n as n o n-res p o n ders. All treat me nt effect c o ntrasts 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 4
will be o btai ne d t hr o u g h fitti n g t he Ba y esia n d ose -res p o nse a n d/ or e x p os ure-res p o nse m o dels 
wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n m o dels.
A sec o n dar y  esti ma n d t o assess t he pri mary o bjecti ve will be:

Esti m a n d 1. 2 : Usi n g a h y p ot hetical esti ma n d strate g y, i n partici pa nts wit h bi o ps y-
c o nfir me d N A S H a n d fi br osis, as assesse d b y t he s p o ns or-i de ntifie d ce ntral 
pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i d oses a d mi nistere d al o ne a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of esti mati n g t he pr o p orti o n of 
'cli nical res p o n ders', defi ne d as partici pa nts ac hie vi n g ce ntrally a dj u dicate d: res ol uti o n of 
N A S H wit h o ut w orse ni n g of fi br osis or i m pr o ve me nt i n fi br osis b y  ≥1 sta ge wit h o ut 
w orse ni n g of N A S H, or b ot h, at Wee k 4 8, ass u mi n g all partic i pa nts ha d re mai ne d i n t he 
trial a n d recei ve d treat me nt as pla n ne d wit h o ut wit h dra wal u p t o 4 8 Wee ks. E n d p oi nt 
data c ollecte d after treat me nt wit h dra wal will be ce ns ore d. All treat me nt effect c o ntrasts 
will be o btai ne d t hr o u g h fitti n g t he Ba y esia n d ose -res p o nse a n d/ or e x p os ure-res p o nse 
m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n m o dels.
Sec o n dar y  esti ma n ds t o assess sec o n dar y o bjecti ves will be:

Esti m a n d 2. 1 : Usi n g a c o m p osite esti ma n d strate g y, i n partici pa nts wit h bi o ps y-
c o nfir me d NA S H a n d fi br osis, as assesse d b y t he s p o ns or -i de ntifie d ce ntral 
pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i d oses a d mi nistere d al o ne a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of ‘cli nical 
res p o n ders’, defi ne d as partici pa nts ac hie vi n g ce ntrall y a dj u dicate d res ol uti o n of N A S H 
wit h o ut w orse ni n g of fi br osis, at Wee k 4 8 a n d treati n g all cases of wit h dra wal fr o m 
treat me nt f or lac k of efficac y or t olerati o n as n o n-res p o n ders. All treat me nt effect 
c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba yesia n d ose- res p o nse a n d/ or e x p os ure-
res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n m o dels.

Esti m a n d 2. 2 : Usi n g a c o m p osite esti ma n d strate g y, i n partici pa nts wit h bi o ps y-
c o nfir me d N A S H a n d fi br osis, as assesse d b y t he s p o ns or -i de ntifie d ce ntral 
pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i d oses a d mi nistere d al o ne a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of ‘cli nical 
res p o n ders’, defi ne d as partici pa nts ac hie vi n g ce ntrall y a dj u dicate d i m pr o ve me nt i n 
fi br osis b y ≥1 sta ge wit h o ut w orse ni n g of N A S H, at Wee k 4 8 a n d treati n g all cases of 
wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n as n o n-res p o n ders. All 
treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba yesia n d ose -res p o nse 
a n d/ or e x p os ure- res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n 
m o dels.

Esti m a n d 2. 3 : Usi n g a c o m p osite esti ma n d strate g y, i n partici pa nts wit h bi o ps y -
c o nfir me d N A S H a n d fi br osis, as assesse d b y t he s p o ns or -i de ntifie d ce ntral 
pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i d oses a d mi nistere d al o n e a n d 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 5
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of ‘cli nical 
res p o n ders’, defi ne d as partici pa nts ac hie vi n g ce ntrall y a dj u dicate d i m pr o ve me nt i n 
fi br osis b y ≥2 sta ges wit h o ut w orse ni n g of N A S H, or b ot h, at Wee k 4 8 a n d treati n g all 
cases of wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n as n o n-res p o n ders. 
All treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba y esia n d ose-res p onse 
a n d/ or e x p os ure-res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n 
m o dels.

Esti m a n d 2. 4 : Usi n g a c o m p osite esti ma n d strate g y, i n partici pa nts wit h bi o ps y -
c o nfir me d N A S H a n d fi br osis, as assesse d b y t he s p o ns or -i de ntifie d ce ntral 
pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i d oses a d mi nistere d al o ne a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he pr o p orti o n of ‘cli nical 
res p o n ders’, define d as partici pa nts ac hie vi n g ce ntrall y a dj u dicate d i m pr o ve me nt of 
≥2 p oi nts o n T otal N A F L D Acti vit y  Sc ore ( N A S) at Wee k 4 8 a n d treati n g all cases of 
wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n as n o n -res p o n ders. All 
treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba y esia n d ose -res p o nse 
a n d/ or e x p os ure-res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n 
m o dels.

Esti m a n d 2. 5 : Usi n g a h y p ot hetical esti ma n d strate g y, i n partici pa nts wit h bi o ps y -
c o nfir me d N A S H a n d fi br osis, as assesse d b y t he s p o ns or -i de ntifie d ce ntral 
pat h ol o gist(s ), esti mate t he treat me nt effect of D G A T 2i d oses a d mi nistere d al o ne a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he p o p ulati o n le vel a vera ge 
perce nta ge c ha n ge fr o m baseli ne i n li ver fat (assesse d via M RI -P D F F) at Wee k 4 8 , 
ass u mi n g all partici pa nts ha d re mai ne d i n t he trial a n d recei ve d treat me nt as pla n ne d 
wit h o ut wit h dra wal u p t o 4 8 wee ks. E n d p oi nt data c ollecte d after treat me nt wit h dra wal 
will be ce ns ore d. All treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he 
Ba yesia n d ose -res p o nse a n d/ or e x p os ure-res p o nse m o dels, or A N C O V A m o dels .
9. 1. 2. H y p ot hesis Tests
F or t his st u d y t here are n o f or mal h y p ot hesis tests pla n ne d.
9. 2. S a m ple Size Deter mi n ati o n
T he sa m ple size esti mati o n f or t his st u d y is dri ve n b y t he c haracterizati o n of d ose res p o nse 
a n d treat me nt effect usi n g a Ba yesia n E ma x st u d y desi g n a n d m o delli n g a p pr oac h, w hic h will 
utilize wea kl y  i nf or mati ve pri ors f or m o del para meters a n d will pr o vi de t he a bilit y t o ma ke 
m ore precise c o m paris o ns bet wee n treat me nt ar ms. T he sa m ple size calc ulati o n is base d o n 
t he pri mar y efficac y e n d p oi nt, t he pr o p orti o n of partici pa nts wit h i m pr o ve me nt i n fi br osis 
wit h o ut w orse ni n g of N A S H or N A S H res ol uti o n wit h o ut w orse ni n g of fi br osis, or b ot h 
i m pr o ve me nt i n fi br osis a n d N A S H res ol uti o n at Wee k 4 8. 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 6
T he D G A T 2i E D 5 0 f or t he hist ol o gical -base d pri mar y  e n d p oi nt has bee n ass u me d t o be 
sli g htl y hi g her t ha n t he pr ojecte d E C 5 0 f or re d ucti o n i n li ver fat w hic h was esti mate d fr o m a 
preli mi nar y  p o p ulati o n p har mac o ki netic m o del base d o n pre vi o us cli nical st u dies wit h 
D G A T 2i. T heref ore, t he D G A T 2i E D 5 0 was esti mate d t o be a p pr o xi matel y  3 0 m g BI D a n d 
t he place b o res p o n der rate ( E0) was esti mate d t o be 1 6 %. It is esti mate d t hat a t otal sa m ple 
size of 3 5 0 partici pa nts ( 5 0 ra n d o mize d partici pa nts per ar m) will gi ve acce pta ble 
pr o ba bilities t o ma ke decisi o ns a b o ut t he d ose res p o nse i n a N A S H p o p ulati o n base d o n 
si m ulati o n st u dies. At t he t he oretical Ema x of 0. 6 (ie, a 6 0 % res p o n der rate), t here w o ul d be 
e n o u g h precisi o n t o s h o w a greater t ha n 2 4 % differe nce i n t he pri mar y  e n d p oi nt res p o n der
rate bet wee n place b o a n d t he sec o n d hi g hest BI D d ose of D G A T 2i (ie, 1 5 0 m g BI D) wit h a 
pr o ba bili t y of at least 8 9 %.
I n a d diti o n, t his sa m ple size will pr o vi de a de q uate precisi o n t o assess w het her 
D G A T 2i + A C Ci pr o vi des a hi g her res p o n der rate t ha n D G A T 2i m o n ot hera p y wit h a 
pr o ba bilit y  of 8 2 % if t he tr ue effect size is at least 6 %.
9. 3. A n al ysis Sets
F or p ur p oses of a nal y sis, t he f oll o wi n g a nalys is sets are defi ne d:
P atie nts A n al ysis Set
Descri pti o n
E nr olle d 
All partici pa nts w h o si g n t he Pre Q I C D
Ra n d o ml y assi g ne d t o 
i n vesti gati o nal pr o d uct
All ra n d o mize d partici pa nts
E val ua ble
Defi ne d acc or di n g t o t he F ull A nal ysis Set:
All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose of i n vesti gati o nal 
pr o d uct w h o ha ve pr o vi de d baseli ne data f or t he pri mar y e n d p oi nt (i.e. 
baseli ne bi o ps y data). Partici pa nts will be a nal yze d acc or di n g t o t he 
treat me nt gr o u p t hey are ra n d o mize d t o.

T he o nl y e xce pti o n t o t his is f or partici pa nts ra n d o mize d bef ore 
Pr ot oc ol A me n d me nt 1 is e nacte d w h o are ra n d o mize d t o eit her of 
t he 2 Q D d osi n g re gi me ns of D G A T 2i al o ne, w h o s witc h t o t he 
c orres p o n di n g BI D d osi n g re gi me n of D G A T 2i al o ne , a n d will be 
a nal yze d u n der t hat treat me nt gr o u p .
Safet y
All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose of i n vesti gati o nal 
pr o d uct. Partici pa nts will be a nal yze d acc or di n g t o t he treat m e nt t he y 
act uall y recei ve d.

T he o nl y e xce pti o n t o t his is f or partici pa nts ra n d o mize d bef ore 
P r ot oc ol A me n d m e nt 1 is e nacte d wh o are ra n d o mize d t o eit her of 
t he 2 Q D d osi n g re gi me ns of D G A T 2i al o ne, w h o s witc h t o t he 
c orres p o n di n g BI D d osi n g re gi me n of D G A T 2i al o ne, a n d will be 
a nal yze d u n der t hat treat me nt gr o u p .
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 7
Defi ne d A n al ysis D at a Set 
( at t he d at a le vel) – e n d p oi nt 
s pecific
Descri pti o n
All bi o psy -derive d e n d p oi nts
Bi o ps y -base d C o m p osite 
Esti ma n d
If a partici pa nt disc o nti n ues treat me nt or fr o m t he st u d y d ue t o lac k of 
efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve Wee k 4 8 
Bi o ps y data, t he y will be c o nsi dere d t o be a n o n -res p o n der.
Bi o ps y -base d H y p ot hetica l
Esti ma n d
A n y a vaila ble bi o ps y data f or all partici pa nts c ollecte d bef ore or at t he 
ti me of treat me nt wit h dra wal will be i ncl u de d i n t he a nal ysis, e ve n if 
t he y ha ve wit h dra w n fr o m treat me nt f or lac k of efficac y or t olerati o n. 
E n d p oi nt data c ollecte d after treat me nt wit h dra w al will be ce ns ore d.
All M RI -P D F F -deri ve d e n d p oi nts (i n I m a gi n g S u bst u dy)
M RI -base d H y p ot hetical
Esti ma n d
A n y a vaila ble M RI data f or all partici pa nts c ollecte d bef ore or at t he 
ti me of treat me nt wit h dra wal will be i ncl u de d i n t he a nal ysis, e ve n if 
t he y ha ve wit h dra w n fr o m treat me nt f or lac k of efficac y or t olerati o n. 
E n d p oi nt data c ollecte d after treat me nt wit h dra w al will be ce ns ore d .
9. 4. St atistic al A n al yses
T he S A P will be de vel o pe d a n d fi nalize d bef ore a n y a n al y ses are perf or me d a n d will 
descri be t he a nal ys es a n d pr oce d ures f or acc o u nti n g f or missi n g, u n use d, a n d s p uri o us data. 
T his secti o n is a s u m mar y of t he pla n ne d statistical a nal y ses of t he pri mar y a n d sec o n dar y 
e n d p oi nts of t he st u d y.
9. 4. 1. Ge ner al C o nsi der at i o ns
F or t he assess me nt of d ose -res p o nse, t he f oll o wi n g BI D treat me nt gr o u ps (at a mi ni m u m) 
will be i ncl u de d i n a Ba yesia n E ma x d ose -res p o nse m o del:

Place b o

D G A T 2i 2 5 m g BI D 

D G A T 2i 7 5 m g BI D – i ncl u di n g t h ose ra n d o mize d t o 1 5 0 m g Q D – refer t o Ta ble 3

D G A T 2i 1 5 0 m g BI D – i ncl u di n g t h ose ra n d o mize d t o 3 0 0 m g Q D – refer t o Ta ble 3

D G A T 2i 3 0 0 m g BI D
Ot her treat me nt gr o u ps will be a nal yz e d t o assess t he c o m paris o ns as s h o w n bel o w:

D G A T 2i 1 5 0 m g BI D + A C Ci 5 m g BI D vs D G A T 2i 1 5 0 m g BI D

D G A T 2i 3 0 0 m g BI D + A C Ci 1 0 m g BI D vs D G A T 2i 3 0 0 m g BI D
9. 4. 2. Pri m ar y E n d p oi nt(s)
T he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of N A S H wit h o ut w orse ni n g of fi br osis 
or i m pr o ve me nt i n fi br osis b y  ≥1 sta ge wit h o ut w orse ni n g of N A S H, or b ot h, base d o n 
assess me nt b y s p o ns or-i de ntifie d ce ntral pat h ol o gist(s) at Wee k 4 8 a n d treati n g all cases of 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 8
wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n as n o n-res p o n ders, will be 
a nal yz e d b y fitti n g a Ba yesia n Ema x d ose -res p o nse m o del. T his m o del will be utilize d t o 
c haracterize t he d ose res p o nse acr oss all D G A T 2i BI D treat me nt gr o u ps, t o esti mate t he 
pr o p orti o n of res p o n ders (a n d 9 5 % CI ) f or eac h d ose st u die d, a n d t o esti mate t he place b o-
a dj uste d pr o p orti o n of res p o n ders f or eac h d ose (a n d 9 5 % CI). If a n E ma x d ose -res p o nse 
m o del ca n n ot be fitte d t o t he data, t he n ot her m o dels t hat all o w d ose res p o nse t o be esti mate d 
will be fitte d, ie, li near, l o g -li near or e x p o ne ntial. N o a dj ust me nt f or m ulti ple c o m paris o ns 
will be ma de. 
T he Ba y esia n esti mati o n of t he E ma x d ose -res p o nse m o del uses pri or distri b uti o ns o n t he 
place b o res p o nse ( E 0), d ose t hat pr o d uces half ma xi mal dr u g effect ( E D5 0) a n d Ema x
para meters . T he s pecificati o n of t he Ema x m o del a n d t he pri or distri b uti o ns f or s o me of its 
para meters are base d o n t hree meta -a nal yses of cli nical d ose res p o nse fr o m m ore t ha n 1 0 0 
c o m p o u n ds 2 7 ,2 8 ,2 9. T he c urre nt ass u me d val ue f or E D 5 0 is 3 0 m g BI D, w hic h is base d o n 
e x p os ure -res p o nse a nalyses of D G A T 2i f or li ver fat (Secti o n 4. 3 ), utilizi n g data fr o m 
pre vi o us cli nical st u dies wit h D G A T 2i a n d ass u mi n g a tra nslati o n t o a sli g hter hi g her E D 5 0
f or a hist ol o gical e n d p oi nt. T he s u bsta ntial u ncertai nt y  i n E D5 0 val ues was assesse d i n t he 
meta -a nal ys es of cli nical d ose res p o nse st u dies 2 9. T heref ore, base d o n t he meta-a nal ys es, a 
scale d t- distri b uti o n ( wit h 5 de grees of free d o m) is pla n ne d t o be use d t hat is f oc use d o n t he 
i nitial pr ojecte d E D5 0= 3 0 m g BI D, wit h a scale para meter of 0. 6. A n or mal pri or distri b uti o n 
f or t he l o git of t he place b o res p o nse ce ntere d at l o git ( 0. 1 6) wit h a pri or sta n dar d de viati o n of 
2. 0 (l o gistic scale) is pla n ne d t o be use d, w hic h yi el ds a wea k diff use pri or distri b uti o n f or 
t he place b o res p o nse. A n or mal pri or distri b uti o n f or t he E ma x para meter will als o be use d, 
ce ntere d o n t he a ntici pate d E ma x ( 0. 6) o n t he l o gistic scale. T his pri or distri b uti o n will als o be 
diff use o n t he l o gistic scale wit h a pri or sta n dar d de viati o n of 2. 0.
T he c o m paris o ns of t he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of N A S H wit h o ut 
w orse ni n g of fi br osis or i m pr o ve me nt i n fi br osis b y ≥1 sta ge wit h o ut w orse ni n g of N A S H, or 
b ot h, base d o n assess me nt b y  s p o ns or-i de ntifie d ce ntral pat h ol o gist(s) at Wee k 4 8 a n d 
treati n g all cases of wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n as n o n-
res p o n ders, f or D G A T 2i + A C Ci BI D vs place b o a n d vs t he c orres p o n di n g D G A T 2i BI D 
m o n ot hera p y d ose will be a nal yz e d usi n g a l o gistic re gressi o n m o del t o esti mate t he 
pr o p orti o n of res p o n ders i n eac h treat me nt gr o u p a n d o d ds rati o (a n d c orres p o n di n g 9 5 % CI ) 
f or eac h treat me nt c o m paris o n.
I n or der t o esti mate t he h y p ot hetical sec o n dar y esti ma n d, t he pri mar y e n d p oi nt will als o be 
a nal yz e d t o assess treat me nt differe nces , ass u mi n g all partici pa nts ha d re mai ne d i n t he trial 
a n d recei ve d treat me nt as pla n ne d wit h o ut wit h dra wal u p t o Wee k 4 8 . All treat me nt effect 
c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba yesia n d ose- res p o nse a n d/ or e x p os ure-
res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n m o dels. T his esti ma n d 
assesses t he treat me nt effect i n a n alter nati ve, h y p ot hetical setti n g of a d here nce t o t heir 
treat me nt as pla n ne d.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 9
9. 4. 3. Sec o n d ar y E n d p oi nt(s)
Bi n ar y (res p o n de r) e n d p oi nts
T he pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of N A S H wit h o ut w orse ni n g of fi br osis, 
base d o n assess me nt b y s p o ns or -i de ntifie d ce ntral pat h ol o gist(s) at Wee k 4 8 a n d treati n g all 
cases of wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n as n o n-res p o n ders, will 
be a nal yz e d b y fitti n g a Ba y esia n E ma x d ose -res p o nse m o del. T his m o del will be utilize d t o 
c haracterize t he d ose res p o nse acr oss all BI D treat me nt gr o u ps, t o esti mate t he pr o p orti o n of 
res p o n ders (a n d 9 5 % CI ) f or eac h BI D d ose st u die d, a n d t o esti mate t he place b o- a dj uste d 
pr o p orti o n of res p o n ders f or eac h d ose (a n d 9 5 % CI ). If t he Ema x d ose -res p o nse m o del ca n n ot 
be fitte d t o t he data, t he n ot her m o dels t hat all o w d ose res p o nse t o be esti mate d will be fitte d, 
ie, li near, l og-li near or e x p o ne ntial. N o a dj ust me nt f or m ulti ple c o m paris o ns will be ma de. 
Si milar a nal y ses will be perf or me d f or t he f oll o wi n g sec o n dar y e n d p oi nts:

Pr o p orti o n of partici pa nts wit h i m pr o ve me nt i n fi br osis b y  ≥1 sta ge wit h o ut w orse ni n g of 
N A S H, base d o n assess me nt b y s p o ns or-i de ntifie d ce ntral pat h ol o gist(s) at Wee k 4 8

Pr o p orti o n of partici pa nts wit h i m pr o ve me nt i n fi br osis b y  ≥2 sta ges wit h o ut w orse ni n g 
of N A S H, base d o n assess me nt b y  s p o ns or-i de ntifie d ce ntral pat h ol o gist(s) at Wee k 4 8

Pr o p orti o n of pa rtici pa nts wit h i m pr o ve me nt of ≥2 p oi nts o n T otal N A S, base d o n 
assess me nt b y s p o ns or-i de ntifie d ce ntral pat h ol o gist(s) at Wee k 4 8
T he c o m paris o n of t he pr o p orti o n of res p o n ders f or eac h of t he bi nar y  sec o n dar y e n d p oi nts 
f or D G A T 2i + A C Ci BI D d oses vs place b o as well as v ers us t he c orres p o n di n g D G A T 2i BI D 
m o n ot hera p y d oses will be a nal yz e d a n usi n g l o gistic re gressi o n m o dels t o esti mate t he 
pr o p orti o n of res p o n ders i n eac h treat me nt gr o u p a n d o d ds rati o (a n d c orres p o n di n g 9 5 % CI ) 
f or eac h treat me nt c o m paris o n. F or c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs 
c orres p o n di n g D G A T 2i BI D m o n ot hera p y d oses c orres p o n di n g 5 0 % CI  will als o be 
pr o vi de d. N o a dj ust me nt f or m ulti ple c o m paris o ns will be ma de.
C o nti n u o us e n d p oi nts
T he c o nti n u o us e n d p oi nt, pe rce nta ge c ha n ge fr o m baseli ne i n li ver fat (assesse d via 
M RI -P D F F) at Wee k 4 8, will be a nal yz e d usi n g a Ba yesia n E ma x d ose -res p o nse m o del f or t he 
D G A T 2i BI D d oses. 
T he c o m paris o n of t he perce nta ge c ha n ge fr o m baseli ne i n li ver fat (assesse d via M RI -P D F F) 
at Wee k 4 8 f or D G A T 2i + A C Ci BI D vs place b o a n d vs t he c orres p o n di n g D G A T 2i BI D 
m o n ot hera p y d ose will be a nal yz e d usi n g a n A N C O V A perf or me d o n l o g -tra nsf or me d 
relati ve c ha n ge fr o m baseli ne wit h treat me nt ( w here relati ve c ha n ge fr o m baseli ne = p ost 
baseli ne val ue/ baseli ne val ue) a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors, a n d l o g-
tra nsf or me d baseli ne li ver fat val ue as a c o variate. Esti mates of t he mea n relati ve c ha n ges f or 
eac h treat me nt c o m paris o n a n d t he c orres p o n di n g 9 5 % CI  will be o btai ne d fr o m t he m o del. 
T he mea n relati ve c ha n ges a n d t heir CIs will be e x p o ne ntiate d a n d perce nt c ha n ge will t he n 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 0
be deter mi ne d as f oll o ws: Perce nt c ha n ge = 1 0 0 * ( Relati ve C ha n ge - 1). F or c o m paris o ns of 
D G A T 2i + A C Ci BI D vs t he c orres p o n di n g D G A T 2i BI D m o n ot hera p y d ose t he 
c orres p o n di n g 5 0 % CI  will als o be pr o vi de d. N o a dj ust me nt f or m ulti ple c o m paris o ns will be 
ma de. 
Descri pti ve s u m maries of t he o bser ve d val ues a n d perce nt c ha n ge fr o m baseli ne i n li ver fat 
f or eac h treat me nt gr o u p will als o be pr o d uce d.
9. 4. 4. Terti ar y/ E x pl or at or y E n d p oi nt(s)
T he f oll o wi n g tertiar y/e x pl orat or y e n d p oi nts will be a nal yz e d usi n g si milar met h o ds t o t hose 
pla n ne d f or ot her si milar sec o n dar y  e n d p oi nts: 

Pr o p orti o n of partici pa nts wit h w orse ni n g of fi br osis b y  ≥1 sta ge , o n li ver bi o ps y, as 
assesse d b y  s p o ns or i de ntifie d ce ntral pat h ol o gist(s), at Wee k 4 8

P r o p orti o n of partici pa nts wit h w orse ni n g of ≥2 p oi nts i n T otal N A S o n li ver bi o ps y, as 
assesse d b y  s p o ns or i de ntifie d ce ntral pat h ol o gist(s), at Wee k 4 8
A d diti o nal e x pl orat or y  a nal yses will be perf or me d o n t hese e n d p oi nts if warra nte d, si milar t o 
t h ose descri be d f or ot her sec o n dar y bi nar y (res p o n der) e n d p oi nts.
9. 4. 5. P h ar m ac o ki netic A n al ysis
 c o nce ntrati o n data f or D G A T 2i a n d A C Ci (A C Ci c o nce ntrati o ns f or Treat me nt s H 
a n d I o nl y – refer t o Ta ble 3 ) will be liste d b y C o h ort . 
I n a d diti o n, as per mitte d b y data a n d deter mi ne d b y t he s p o ns or, 
 
 c o nce ntrati o ns of D G A T 2i a n d/ or A C Ci a n d effect o n pri mar y  
( bi o ps y), sec o n dar y a n d tertiar y e n d p oi nts ma y be c haracterize d 
 
 T he o bjecti ves of s uc h a n a nalys is, if c o n d ucte d, w o ul d ai m t o c haracterize 
 a n d e x pl ore p ote ntial c o variates (e g, a ge, race, ge n der, a n d 
b o d y  wei g ht, etc) i nfl ue nci n g t he o bser ve d P K a n d/ or res p o nse t o D G A T 2i a n d/ or A C Ci. T he 
 a n d/ or  
 a nal yses, if c o n d ucte d, will be re p orte d se paratel y fr o m t he 
mai n cli nical st u d y  re p ort.
9. 4. 6. Ot her S afet y A n al yses
All safet y a nal ys es will be perf or me d o n t he safet y p o p ulati o n. T hese will be prese nte d i n 
ta b ular a n d/ or gra p hical f or mat a n d s u m marize d descri pti vely a n d will f oll o w Pfizer 
sta n dar ds as a p pr o priate.
T he Me d D R A will be use d t o classif y  all A Es wit h res pect t o s ys te m or ga n class a n d 
preferre d ter m. S u m maries of A Es will i ncl u de treat me nt- e mer ge nt A Es acc or di n g t o 
treat me nt gr o u p. 
F urt her m ore, a 3 -tier a p pr oac h will be use d t o s u m marize A Es. Tier-1 c o nsists of pre -
s pecifie d a d verse e ve nts of i nterest a n d will i ncl u de A Es or c ollecti o ns of A Es relate d t o 
i de ntifie d a d verse dr u g reacti o ns i n t his pr o gra m relate d t o eit her D G A T 2i or A C Ci. W here 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 1
a vaila ble, sta n dar d Me d D R A q ueries will be use d t o p o ol differe nt A E ter ms t hat are relate d 
t o t he Tier- 1 A Es. T he precise A E ter ms t hat will c o ntri b ute t o t he Tier-1 e n d p oi nts will be
deter mi ne d pri or t o u n bli n di n g. F or t hese e ve nts, t he perce nta ge of partici pa nts wit h i nci de nt 
A E, t he ris k differe nce, its 9 5 % CI , a n d p-val ue will be pr o vi de d. T he CI  s a n d p-val ues are 
n ot a dj uste d f or m ulti plicit y  a n d are pr o vi de d f or scree ni n g p ur p oses o nly. Tier -2 A Es are 
t h ose t hat are n ot Tier-1, b ut are c o m m o n, occ urri n g i n at least 4 partici pa nts i n a n y treat me nt 
ar m. T he c ut- off of at least 4 e ve nts was c h ose n beca use t he 9 5 % CI f or t he bet wee n-gr o u p 
differe nce i n perce nt i nci de nce will al wa ys i ncl u de zer o w he n treat me nt gr o u ps of e q ual size 
eac h ha ve less t ha n 4 e ve nts a n d s o a d ds little t o t he i nter pretati o n of p ote ntiall y  mea ni n gf ul 
differe nces. F or t hese e ve nts, t he perce nta ge of partici pa nts wit h i nci de nt A E, t he ris k 
differe nce a n d its 9 5 % CI will be pr o vi de d. T he CI s are f or esti mati o n p ur p oses o nl y. Tier- 3 
A Es are all ot her A Es ( neit her Tier -1 n or Tier -2). F or Tier -3 A Es, o nl y wit hi n -gr o u p 
i nci de nce pr o p orti o ns will be ta b ulate d.
9. 4. 6. 1. Vit al Si g ns A n al yses
C ha n ges fr o m baseli ne i n s y st olic bl o o d press ure, diast olic bl o o d press ure a n d p ulse rate will 
be s u m marize d b y  treat me nt a n d ti me. T he n u m ber ( %) of partici pa nts wit h ma xi m u m 
i ncreases fr o m baseli ne will be ta b ulate d b y treat me nt as defi ne d i n t he S A P. N u m bers a n d 
perce nta ges of partici pa nts meeti n g t he cate g orical criteria will be pr o vi de d a n d i n di vi d ual 
val ues liste d i n t he st u d y  re p ort. N o f or mal i nfere ntial statistics will be a p plie d t o t he vital 
si g ns data.
9. 4. 6. 2. Electr oc ar di o gr a m A n al yses
C ha n ges fr o m baseli ne f or t he E C G para meters Q T i nter val, heart rate, Q Tc F i nter val, P R 
i nter val, a n d Q R S i nter val will be s u m marize d b y treat me nt a n d ti me. F or p ur p oses of 
re p orti n g st u d y-le vel res ults, Q Tc F i nter val will be deri ve d usi n g Fri dericia’s heart rate 
c orrecti o n f or m ula a p plie d t o data base d Q T i nter val, a n d R R i nter val. T he n u m ber ( %) of 
partici pa nts wit h ma xi m u m i ncreases fr o m baseli ne will be ta b ulate d b y treat me nt as defi ne d 
i n t he S A P. N u m bers a n d perce nta ges of partici pa nts meeti n g t he cate g orical criteria 
s u m marize d i n Ta ble 5 will be pr o vi de d a n d i n di vi d ual val ues liste d i n t he st u d y  re p ort. N o 
f or mal i nfere ntial statistics will be a p plie d t o t he E C G data.
T a ble 5 .
S afet y -Rel ate d Assess me nt of Q T a n d Q Tc F I nter v al
De gree of Pr ol o n g ati o n
Q Tc F I nter v al Pr ol o n g ati o n ( msec)
U nc orrecte d Q T 
I nter v al ( msec)
Mil d ( msec)
M o der ate 
( msec)
Se vere ( m sec)
A bs ol ute val ue
> 4 5 0 -4 8 0
> 4 8 0 -5 0 0
> 5 0 0
> 5 0 0
I ncrease fr o m baseli ne
3 0 -6 0
> 6 0
9. 4. 7. Ot her A n al yse(s ) 
Be y o n d t he o bjecti ves, esti ma n ds, a n d e n d p oi nts o utli ne d i n Secti o n 3 , t his st u d y will als o 
e val uate t he o bjecti ves/e n d p oi nts s u m marize d i n Ta ble 6 .
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 2
T a ble 6.
A d diti o n al Terti ar y/ E x pl or at or y O bjecti ves a n d E n d p oi nts
O bjecti ves
Esti m a n ds
E n d p oi nts
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n liver f at
Perce nt c ha n ge i n li ver fat (assesse d via M RI-
P D F F i n I ma gi n g s u bst u d y p o p ulati o n), o ver ti me 
u p t o Wee k 4 8
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n liver v ol u me, 
Perce nt c ha n ge i n li ver v ol u me , 
 
(assesse d via M RI i n I ma gi n g s u bst u d y 
p o p ulati o n), o ver ti me u p t o Wee k 4 8
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n liver f at
Perce nt c ha n ge fr o m baseli ne i n li ver fat as 
assesse d via C A P T M meas ure b y Fi br o Sca n ® , 
(e ntire st u d y p o p ulati o n), o ver ti me u p t o Wee k 4 8
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n liver stiff ness
Perce nt c ha n ge fr o m baseli ne i n li ver stiff ness 
(assesse d via V C T E T M us i n g Fi br o Sca n® (e ntire 
st u d y p o p ulati o n), o ver ti me u p t o Wee k 4 8
T o e val uate t he effect of a ra n ge of D G A T 2i d oses
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n liver f u ncti o n tests: A L T, A S T, A L P, G G T
Perce nt c ha n ge fr o m baseli ne i n A L T, A S T, A L P 
a n d G G T o ver ti me u p t o Wee k 4 8
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n bi o m ar kers of p h ar m ac ol o gy a n d/ or dise ase 
st ate – over ti me
Perce nt c ha n ge fr o m baseli ne, o verti me u p t o 
Wee k
4 8 i n 

P C S K 9

C K 1 8 -M 3 0 a n d C K 1 8 -M 6 5, 

P r o C 3 a n d Pr o C 6 

E L F test 

hs -C R P
T o e val uate t he effect o n ot her p ote ntiall y mec ha nis m -
relate d para meters a n d meta b olic para meters, over ti me ,
wit h a ra n ge of D G A T 2i d oses a d mi nistere d al o ne, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci , c o m pare d t o 
place b o, a n d t he c oa d mi nistrati o n of D G A T 2i + A C Ci
relati ve t o D G A T 2i al o ne, i n all partici pa nts i n t he st u d y
Perce nt c ha n ge fr o m baseli ne, o verti me u p t o
Wee k
4 8 , f or:

P ote ntiall y mec ha nis m -relate d para meters 
A p oli p o pr otei n A 1, B (t otal), B 1 0 0, B 4 8, C 3, E

Meta b olic para meters i ncl u di n g -
−
H b A 1 C
−
Fasti n g li pi d pa nel (t otal c h olester ol, direct
L D L -C, H D L -C, tri gl yceri des, direct 
V L D L)
−
A di p o necti n
−
B o d y wei g ht
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n p ar a meters of glyce mic c o ntr ol i n a d ults wit h
T 2 D M, o nly
Perce nt c ha n ge fr o m baseli ne, o ver ti me u p t o 
Wee k 4 8 , i n:

H b A 1 C

F P G

F PI

H O M A -I R
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
Occ urre nce of a n y o ne of t he f oll o wi n g o ver ti me 
u p t o Wee k 4 8: 

all-ca use m ortalit y
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 3
T a ble 6.
A d diti o n al Terti ar y/ E x pl or at or y O bjecti ves a n d E n d p oi nts
O bjecti ves
Esti m a n ds
E n d p oi nts
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, over ti me o n t he i nci de nce of he p atic o utc o mes

he patic dec o m pe nsati o n e ve nts ( ie, he patic 
e nce p hal o pat h y, variceal blee di n g,

de vel o p me nt of ascites re q uiri n g treat me nt)

hist ol o gical pr o gressi o n t o cirr h osis 

i ncrease of M E L D-N a sc ore fr o m ≤1 2 t o ≥1 5 
i n dicati n g listi n g f or li ver tra ns plant
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, overti me o n t he i nci de nce of c ar di ov asc ul ar 
o utc o mes
Occ urre nce of m or bi dit y a n d m ortalit y a n d C V 
e n d p oi nts ( M A C E) o ver ti me u p t o Wee k 4 8
T o e val uate t he effect of a ra n ge of D G A T 2i d oses 
a d mi nistere d al o ne, a n d c oa d mi nistrati o n of 
D G A T 2i + A C Ci , c o m pare d t o place b o, a n d t he 
c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o D G A T 2i 
al o ne, o n vari o us patie nt re p orte d o utc o mes 
C ha n ge fr o m baseli ne, o ver ti me, o n t he f oll o wi n g 
e n d p oi nts 
a b d o mi nal pai n a n d bl oati n g q uesti o ns fr o m t he 
N A S H S y m pt o m Diar y 
fati g ue, slee p dist ur ba nce, a n d da yti me 
slee pi ness q uesti o ns fr o m t he N A S H S y m pt o m 
Diar y 
fati g ue as meas ure d b y P R O MI S Fati g ue C ust o m 
9-I te m V ersi o n q uesti o n naire
H R Q o L s u b -scale sc ores as meas ure d b y 
N A S H -C hec k
N A S H P G I- S
I n a d diti o n, s u m mar y of a bs ol ute sc ore, b y ti me, of 
N A S H P G I- S
N A S H P G I-C
T o e na ble t he e x pl orat or y researc h t hr o u g h c ollecti o n of 
, u nless pr o hi bite d b y l ocal 
re g ulati o ns or et hics c o m mittee decisi o n
 
t o per mit 
retr os pecti ve a nal ysis of 
 
 
T hese res ults ma y or ma y n ot be ge nerate d i n t he 
c o nte xt of t he prese nt st u d y
C o nti n u o us e n d p oi nts o ver ti me
A M M R M will be use d f or t he a nal ys is of c o nti n u o us e n d p oi nts wit h m ore t ha n o ne p ost-
baseli ne c ollecti o n ti me p oi nt. All o bser ve d data c ollecte d d uri n g t he p ost - baseli ne treat ment 
peri o d will be utilize d. T he M M R M a nal y sis will be perf or me d wit h treat me nt, st u d y wee k 
( n o mi nal ti me p oi nt) a n d treat me nt -b y -st u d y wee k i nteracti o n as fi xe d effects, a n d baseli ne 
val ue of t he a nal ys is e n d p oi nt. If t he e n d p oi nt bei n g a nalyz e d is l o g-tra nsf or me d, t he baseli ne 
val ue of t he a nal ys is e n d p oi nt will als o be l o g-tra nsf or me d. Re peate d meas ures m o del wit h 
u nstr uct ure d c orrelati o n matri x will be utilize d. If t his d oes n ot c o n ver ge t he n c o m p o u n d 
s ym metr y  str uct ure will be c o nsi dere d. A d diti o nall y, the n u m ber of c o variates ma y  be 
re d uce d t o i m pr o ve m o del fit. Esti mates of treat me nt effects will be assesse d usi n g L S Ms 
a n d CIs at eac h ti me p oi nt. LS M differe nce f or eac h c o m paris o n al o n g wit h t he 
c orres p o n di n g 9 5 % CI will be pr o vi de d. If t here are maj or de viati o ns fr o m t he statistical 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 4
ass u m pti o ns u n derl yi n g t his m o del t he n alter nati ve tra nsf or mati o ns (e g, l o g) or n o n-
para metric a nal ys es ma y be prese nte d.
E ve nt -b ase d e n d p oi nts
T he occ urre nce of he patic e ve nts, a n d m or bi dit y a n d m ortalit y a n d C V e n d p oi nts ( M A C E) 
o ver ti me u p t o Wee k 4 8 will be s u m marize d descri pti vel y  b y treat me nt gr o u p.
9. 5. I nteri m A n al yses
I nteri m a nalys es will be perf or me d t o assess s afety, at a mi ni m u m, after a p pr o xi matel y 3 3%, 
6 7 %, a n d 1 0 0 % of pla n ne d t otal sa m ple size (i n P r ot oc ol A me n d me nt 1) , has bee n 
ra n d o mize d i n t he st u d y. As s uc h, t he 1 st tri g ger f or safety re vie w re mai ns at a p pr o xi matel y 
t he sa me n u m ber ra n d o mize d as O ri gi nal P r ot oc ol (a p pr o xi matel y 2 5 % ra n d o mize d ie, 
1 1 2/ 4 5 0 vs 1 1 5/ 3 5 0 = 3 3 % i n Pr ot oc ol A me n d me nt 1 ). I nteri m a nal ys is res ults ma y be use d 
f or i nter nal b usi ness decisi o ns re gar di n g f ut ure st u d y pla n ni n g, c o n d ucti n g a sa m ple size 
re-esti mati o n, or a da pti n g t he safet y-relate d e n d p oi nts i n t he st u d y after t he i nteri m a nal ys is, 
or earl y u n bli n di n g t o facilitate P o p ulati o n P K/ P D m o del de vel o p me nt . Bef ore a ny i nteri m 
a nal ys is is i nsti gate d, t he details of t he o bjecti ves, decisi o n criteria, disse mi nati o n pl a n, a n d 
met h o d of mai ntai ni n g t he st u d y  bli n d as per Pfizer’s S O Ps will be d oc u me nte d a n d 
a p pr o ve d i n a n E- D M C c harter. I n a d diti o n, t he a nal y sis details will be d oc u me nte d a n d 
a p pr o ve d i n a n i nteri m a nal y sis S A P or fi nal S A P.
9. 6. D at a M o nit ori n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee
T his st u d y  will use a n E-D M C, A dj u dicati o n C o m mittee, a n d a steeri n g c o m mittee.

T he E- D M C is i n de pe n de nt of t he st u d y tea m a n d i ncl u des o nl y e xter nal me m bers 
(c o nsisti n g of at least 1 car di ol o gist, 1 e n d ocri n ol o gist, 1 gastr oe nter ol o gist or 
he pat ol o gist, a n d 1 statisticia n ). T he E -D M C c harter descri bes t he r ole of t he E -D M C
i n m ore detail.

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 safet y of 
partici pa nts i n t he st u d y  acc or di n g t o t he 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 t he a p pr o priate 
Pfizer p ers o n nel 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 nalys es of safet y data, t o re g ulat or y a ut h orities, 
as a p pr o priate. 

A n i n de pe n de nt A dj u dic ati o n C o m mittee c o nsisti n g of e xter nal e x perts perf or mi n g 
b li n de d re vie w of all p ote ntial e ve nts hi g hli g hte d bel o w a n d f urt her s pecifie d i n t he 
A dj u dicati o n C o m mittee C harter, t o c o nfir m t hat t he data s u p p ort t he e n d p oi nt 
desi g nati o n –

Fatal e ve nts: L i ver-relate d deat h, car di o vasc ular deat h, or ot her deat h;

H e patic e ve nts: i ncl u di n g b ut n ot li mite d t o he patic dec o m pe nsati o n e ve nts [ie, 
he patic e nce p hal o pat h y, h os pitalizati o n f or variceal blee di n g, de vel o p me nt of 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 5
ascites re q uiri n g treat me nt ], hist ol o gical pr o gressi o n t o cirr h osis , i ncrease of 
M E L D- Na sc ore fr o m ≤1 2 t o ≥1 5 i n dicati n g listi n g f or li ver tra ns pla nt, H C C, 
dr u g -i n d uce d li ver i nj ur y;

C ar di o vasc ular e ve nts : i ncl u di n g b ut n ot li mite d t o maj or a d verse car di o vasc ular 
e ve nts – ie, n o nfatal m y ocar dial i nfarcti o n, n o nfatal str o ke, car di o vasc ular deat h ;
pl us , h os pitalizati o n f or u nsta ble a n gi na – ie, heart fail ure, tra nsie nt isc he mic 
attac k, re vasc ularizati o n .

A bli n de d Steeri n g C o m mittee c o m prisi n g of b ot h e xter nal a n d i nter nal (ie, Pfizer) 
me dical /cli nical re prese ntati ves fr o m eac h c o u ntr y/re gi o n of st u d y  o perati o ns w h o 
will o versee recr uit me nt, rete nti o n, a n d q ualit y iss ues wit hi n t he c o u ntr y /re gi o n.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 6
1 0. S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L C O N SI D E R A T I O N S
1 0. 1. A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
1 0. 1. 1. Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui deli nes;

A p plica ble I C H G C P g ui deli nes;

A p plica ble la ws a n d re g ulati o ns, i ncl u di n g a p plica ble pri vac y  la ws.
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C D, S R S D(s), a n d ot her rele va nt d oc u me nts (e g, 
a d vertise me nts) m ust be re vie we d a n d a p pr o ve d b y t he s p o ns or a n d s u b mitte d t o a n I R B/ E C 
b y  the i n vesti gat or a n d re vie we d a n d a p pr o ve d b y t he IR B/ E C bef ore t he st u d y  is i nitiate d.
A n y  a me n d me nts t o t he pr ot oc ol will re q uire I R B/ E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y  t o eli mi nate a n i m me diate 
hazar d t o st u d y  partici pa nts.
T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y  t o t he I R B/ E C a n n uall y or 
m ore fre q ue ntl y  i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures 
esta blis he d b y t he I R B/ E C;

N otif y i n g t he I R B/ E C of S A Es or ot her si g nifica nt safety fi n di n gs as re q uire d b y 
I RB/ E C pr oce d ures;

Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o 
re q uire me nts of 2 1 C F R, I C H g ui deli nes, t he I RB/ E C, E ur o pe a n re g ulati o n 5 3 6/ 2 0 1 4 
f or cli nical st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns.
1 0. 1. 1. 1. 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 I C H G C P
I n t he e ve nt of a ny 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 a n d ris ks of t he st u d y 
i nter ve nti o n, Pfizer s h o ul d be i nf or me d i m me diatel y. 
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 by t he i n vesti gat or t o pr otect t he st u d y partici pa nts a gai nst a n y 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.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 7
1 0. 1. 2. Fi n a nci al Discl os ure
I n vesti gat ors a n d s u bi n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure st ate me nts t o t he a p pr o priate re g ulat or y  a ut h orities. In vesti gat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 ye ar after c o m pleti o n of t he st u d y .
1 0. 1. 3. I nf or me d C o nse nt Pr ocess
T he i n vesti gat or or his / her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
partici pa nt a n d a ns wer all q uesti o ns re gar di n g t he st u d y . T he partici pa nt s h o ul d be gi ve n 
s ufficie nt ti me a n d o p p ort u nit y t o as k q uesti o ns a n d t o deci de w het her or n ot t o partici pate i n 
t he trial.
Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y . Partici pa nts will be 
re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts of 2 1 C F R 5 0, 
l ocal re g ulati o ns, I C H g ui deli nes, HIP A A re q uire me nts, w here a p plica bl e, a n d t he I R B/ E C 
or st u d y  ce nter.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  partici pa nt is f ull y 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 relate d 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 
partici pa nt’s pers o nal data. 
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d data will be use d b y t he 
s p o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici pa nt.
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he s p o ns or, b y 
a p pr o priate I RB/ E C me m bers, a n d b y i ns pec t ors fr o m re g ulat or y a ut h orities.
T he i n vesti gat or f urt her m ust e ns ure t hat eac h st u d y  partici pa nt 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 pers o nal dat a.
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. 
T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t h e I C D.
Partici pa nts m ust be rec o nse nte d t o t he m ost c urre nt versi o n of t he I C D(s) d uri n g t heir 
partici pati o n i n t he st u d y .
A c o p y of t he I C D(s) m ust be pr o vi de d t o t he partici pa nt. Partici pa nts w h o are rescree ne d are 
re q uire d t o si g n a ne w I C D.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 8
U nless pr o hi bite d b y l ocal re q uire me nts or I R B/ E C decisi o n, t he I C D will c o ntai n a se parate 
secti o n t hat a d dresses t he use of sa m ples f or o pti o nal a d diti o nal researc h. T he o pti o nal 
a d diti o nal researc h d oes n ot re q uire t he c ollecti o n of a n y f urt her sa m ples. T he i n vesti gat or or 
a ut h orize d desi g nee will e x plai n t o eac h partici pa nt t he o bjecti ves of t he a d diti o nal researc h. 
Partici pa nts will be t ol d t hat t he y  are free t o ref use t o partici pate a n d ma y wit h dra w t heir 
c o nse nt at a n y ti me a n d f or a n y reas o n d uri n g t he st ora ge peri o d. 
A se parate si g nat ure will be re q uire d t o d oc u me nt a partici pa nt's a gree me nt t o all o w 
s peci me ns t o be use d f or a d diti o nal researc h. Partici pa nts w h o decli ne t o partici pate i n t his 
o pti o nal a d diti o nal researc h will n ot pr o vi de t his se parate si g nat ure.
1 0. 1. 4. D at a Pr otecti o n
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 partici pa nt data.
Partici pa nts’ pers o nal data will be st ore d at t h e 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 otecte 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 ha 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 site will be res p o nsi ble f or 
deter mi ni n g w het 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 oti ficati 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 partici pa nts wit h re gar d t o t he pr ocessi n g of pers o nal 
data, partici pa nts will be assi g ne d a si n gle, partici pa nt -s pecific n u merical c o de. A n y 
partici pa nt rec or ds or data sets t hat are tra n sferre d t o t he s p o ns or will c o ntai n t he n u merical 
c o de; partici pa nt na mes will n ot be tra nsferre d. All ot her i de ntifia ble data tra nsferre d t o t he 
s p o ns or will be i de ntifie d b y t his si n gle, partici pa nt-s pecific c o de. T he st u d y site will 
mai ntai n a c o nfi de nt ial list of partici pa nts w h o partici pate d i n t he st u d y, li n ki n g eac h 
partici pa nt’s n u merical c o de t o his or her act ual i de ntit y  a n d me dical rec or d i de ntificati o n. I n 
case of data tra nsfer, t he s p o ns or will pr otect t he c o nfi de ntialit y  of partici pa nts’ pers onal 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.
1 0. 1. 5. Disse mi n ati o n of Cli nic al St u d y D at a
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical st u d y 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 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 wit h a p plica ble l ocal 
la ws/re g ulati o ns. I n a d diti o n, Pfizer re p orts st u d y res ults o utsi de of t he re q uire me nts of l ocal 
la ws/re g ulati o ns p urs ua nt t o its S O Ps.
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.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 9
w w w.cli nicaltrials. g o v
Pfizer p osts c li nical trial 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 safet y a n d/ or efficac y of a 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. T hese res ults are 
s u b mitte d f or p osti n g i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y U S la w.
E u dra C T
Pfizer p osts cli nical trial res ults o n E u dra C T f or Pfizer -s p o ns ore d i nter ve nti o nal st u dies i n 
acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y  E U re q uire me nts.
w w w. pfizer.c o m
Pfizer p osts p u blic discl os ure s y n o pses ( C S R s y n o pses i n w hic h a n y data t hat c o ul d be use d 
t o i de ntif y i n di vi d ual partici pa nts ha ve 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 ti me t he c orres p o n di n g st u d y res ults are 
p oste d t o w w w.cli nicaltrials. g o v.
D oc u me nts wit hi n mar keti n g a ut h orizati o n pac ka ges/s u b missi o ns
Pfizer c o m plies wit h t he E ur o pea n U ni o n P olic y  0 0 7 0, t he pr oacti ve p u blicati o n of cli nical 
data t o t he E M A we bsite. Cli nical dat a, u n der P hase 1 of t his p olic y , i ncl u des cli nical 
o ver vie ws, cli nical s u m maries, C S Rs, a n d a p pe n dices c o ntai ni n g t he pr ot oc ol a n d pr ot oc ol 
a me n d me nts, sa m ple C R Fs, a n d statistical met h o ds. Cli nical data, u n der P hase 2 of t his 
p olic y , i ncl u des t he p u blis hin g of i n di vi d ual partici pa nt data. P olic y  0 0 7 0 a p plies t o ne w 
mar keti n g a ut h orizati o n a p plicati o ns s u b mitte d via t he ce ntralize d pr oce d ure si nce 
0 1 Ja n uar y 2 0 1 5 a n d a p plicati o ns f or li ne e xte nsi o ns a n d f or ne w i n dicati o ns s u b mitte d via 
t he ce ntralize d pr oce d ure si nce 0 1 J ul y 2 0 1 5.
Data S hari n g
Pfizer pr o vi des researc hers sec ure access t o patie nt- le vel data or f ull C S Rs f or t he p ur p oses 
of “ b o na -fi de scie ntific researc h” t hat c o ntri b utes t o t he scie ntific u n dersta n di n g of t he 
disease, tar get, or c o m p o u n d class. Pfizer will ma ke a vaila ble data fr o m t hese trials 
2 4 m o nt hs after st u d y  c o m pleti o n. Patie nt-le vel data will be a n o ny m ize d i n acc or da nce wit h 
a p plica ble pri vac y la ws a n d re g ulati o ns. C S Rs will ha ve pers o nall y i de ntifia ble i nf or mati o n 
re dacte d.
Data re q u ests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal yses. Researc h tea ms m ust i ncl u de a bi ostatisticia n. Data will n ot 
be pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals 
re q uesti n g access f or c o m mercial/c o m petiti ve or le gal p ur p oses.
1 0. 1. 6. D at a Q u alit y Ass ur a nce
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o t he s p o ns or or desi g nee electr o nicall y (e g, la b orat or y data). T he i n vesti gat or is 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 0
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or 
electr o nicall y si g ni n g t he C R F.
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F.
T he i n vesti gat or m ust e ns ure t hat t he C R Fs 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 f or m a n d are pass w or d pr otecte d t o pre ve nt access b y u na ut h orize d t hir d parties.
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori ng, a u dits, I R B/ E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts. T his 
verificati o n ma y  als o occ ur after st u d y c o m pleti o n. 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 vaila ble d uri n g t he m o nit 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.
M o nit ori n g details descri bi n g strate g y  (e g, ris k-base d i nitiati ves i n o perati o ns a n d q ualit y  
s uc h as ris k ma na ge me nt a n d miti gati o n strate gies a n d a nal yt ical ris k-base d m o nit ori n g), 
met h o ds, res p o nsi bilities, a n d re q uire me nts, i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n -site m o nit ori n g), are pr o vi de d i n t he st u d y 
m o nit ori n g pla n.
T he s p o ns or or de si g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y, i ncl u di n g 
q ualit y  c hec ki n g of t he data.
St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nt o t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y  is 
bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y  a p pr o ve d pr ot oc ol a n d a n y ot her st u d y 
a gree me nts, I C H G C P, a n d all a p plica ble re g u lat or y re q uire me nts.
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Ds, pertai ni n g t o t he c o n d uct of t his st u d y  m ust 
be retai ne d b y t he i n vesti gat or f or 1 5 ye ars after st u d y c o m pleti o n u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti on peri o d. N o rec or ds ma y  be destr o ye d d uri n g 
t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he s p o ns or. N o rec or ds ma y be 
tra nsferre d t o a n ot her l ocati o n or party wit h o ut writte n n otificati o n t o t he s p o ns or. T he 
i n vesti gat or m ust e ns ure t hat t he recor ds c o nti n ue t o be st ore d sec urel y f or as l o n g as t he y are 
mai ntai ne d.
W he n partici pa nt data are t o be delete d, t he i n vesti gat or will e ns ure t hat all c o pies of s uc h 
data are pr o m ptl y  a n d irre v oca bly delete d fr o m all s yste ms.
T he i n vesti gat or(s) will n otif y t he s p o ns or 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 otificati o 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 t he s p o ns or 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 
t he sp o ns or or its 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 a n 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 partici pa nt's me dical rec or ds. T he i n vesti gat or w ill pr o m ptl y 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 1
pr o vi de c o pies of t he i ns pecti o n fi n di n gs t o t he s p o ns or or its a ge nt. Bef ore res p o nse 
s u b missi 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 t he s p o ns or 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.
1 0. 1. 7. S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or site.
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are fr o m s o urce d oc u me nts m ust be 
c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n 
t he st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
Defi niti o n of w hat c o nstit utes s o urce data ca n be f o u n d i n t he cli nical m o nit ori n g pla n.
Descri pti o n of t he use of c o m p uterize d s y ste m is d oc u me nte d i n t he Data Ma na ge me nt Pla n.
1 0. 1. 8. St u d y a n d Site St art a n d Cl os ure
T he st u d y  start date is t he date o n w hic h t he cli nical st u d y will be o pe n f or recr uit me nt of 
partici pa nts.
T he first act of recr uit me nt is t he date of t he first partici pa nt’s first visit a n d will be t he st u d y  
start date.
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y 
ti me f or a ny reas o n at t he s ole discreti o n of t he s p o ns or. St u d y  sites will be cl ose d u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d d oc u me nts a n d st u d y 
s u p plies ha ve bee n c ollecte d a n d a st u dy- site cl os ure visit has bee n perf or me d.
T he i n vesti gat or ma y  i nitiate st u d y-site cl os ure at a n y ti me u p o n n otificati o n t o t he sp o ns or if 
re q ueste d t o d o s o by t he res p o nsi ble I R B/ E C or if s uc h ter mi nati o n is re q uire d t o pr otect t he 
healt h of st u d y  participa nts.
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he s p o ns or ma y i ncl u de b ut are n ot li mite d 
t o:

Fail ure of t he i n vesti gat or t o c o m pl y  wit h t he pr ot oc ol, t he re q uire me nts of t he 
I RB/ E C or l ocal healt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g ui deli nes;

I na de q uate recr uit me nt of partici pa nts b y  t he i n vesti gat or;

Disc o nti n uati o n of f urt her st u d y  i nter ve nti o n de vel o p me nt.
If t he st u dy is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
i n vesti gat ors, t he E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y C R O(s) use d i n t he st u d y of 
t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 2
re q uire me nts. T he i n vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt a n d s h o ul d ass ure 
a p pr o priate partici pa nt t h era p y a n d/ or f oll o w - u p.
St u d y  ter mi nati o n is als o pr o vi de d f or i n t he cli nical st u d y a gree me nt. If t here is a n y c o nflict 
bet wee n t he c o ntract a n d t his pr ot oc ol, t he c o ntract will c o ntr ol as t o ter mi nati o n ri g hts.
1 0. 1. 9. P u blic ati o n P olic y
T he res ults fr o m t his st u d y are e n visi o ne d t o be prese nte d, se parately, at scie ntific meeti n gs –
as deter mi ne d j oi ntly b y  t he sp o ns or a n d me m ber(s) of t he Steeri n g C o m mittee . Be y o n d t his, 
the res ults of t his st u d y  ma y be p u blis he d or prese nte d at scie ntific meeti n gs by t he
i n vesti gat or after p u blicati o n of t he o verall st u d y res ults or 1 year after t he e n d of t he st u d y 
( or st u d y ter mi nati o n), w hic he ver c o mes first. 
T he i n vesti gat or a grees t o refer t o t he pri mar y  p u blicati o n i n a n y s u bse q ue nt p u blicati o ns 
s uc h as sec o n dar y ma n uscri pts a n d s u b mits all ma n uscri pts or a bstracts t o t he s p o ns or 
3 0 da y s bef ore s u b missi o n. T his all o ws t he s p o ns or t o pr otect pr o prietar y i nf or mati o n a n d t o 
pr o vi de c o m me nts a n d t he i n vesti 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 n y  st u d y- or Pfizer 
i nter ve nti o n-relate d i nf or mati o n necessar y f or t he a p pr o priate scie ntific prese ntati o n or 
u n dersta n di n g of t he st u d y  res ults.
F or all p u blicati o ns relati n g t o t he st u d y, t he i n vesti gat or 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 t h ose 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.
T he s p o ns or will c o m pl y  wit h t he re q uire me nts f or p u blicati o n of t he o verall st u d y res ults 
c o veri n g all i n vesti gat or sites. I n acc or da nce wit h sta n dar d e dit orial a n d et hical practice, t he 
s p o ns or will s u p p ort p u blicati o n of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as 
i n di vi d ual site data. In t his case, a c o or di nati n g i n vesti ga t or will be desi g nate d b y m ut ual 
a gree me nt. A ut h ors hi p of p u blicati o ns f or t he o verall st u d y  res ults will be deter mi ne d b y 
m ut ual a gree me nt a n d i n li ne wit h I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors 
a ut h ors hi p re q uire me nts. If p u blicati o n is a d dre sse d i n t he cli nical st u d y a gree me nt, t he 
p u blicati o n p olic y  set o ut i n t his secti o n will n ot a p pl y.
1 0. 1. 1 0. 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 pers o 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 s u p p orti n g st u d y d oc u me ntati o n. 
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, partici pa nts are pr o vi de d wit h a c o ntact car d at t he ti me of i nf or me d 
c o nse nt. 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 st u d y i nter ve nti o n i de ntifiers, 
partici pa nt 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 n ot 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 partici pa nt’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 he y are see ki n g a d vice o n me dical q uesti o ns or pr o ble ms; h o we ver, it 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 3
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 esta bli s 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 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 partici pa nt directl y, a n d if a partici pa nt 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.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 4
1 0. 2. A p pe n di x 2: Cli nic al L a b or at or y Tests
T a ble 7 .
Pr ot oc ol -Re q uire d S afet y -Rel ate d L a b or at or y Assess me nts a n d 
E x pl or at or y Bi o m ar kers i n St u d y C 2 5 4 1 0 1 3
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
−H e m o gl o bi n
−H e m at o crit
−R B C c o u nt
−R eti c ul o c yt e c o u nt ( A bs)
−M C V
−M C H
−M C H C
−Pl at el et c o u nt
−W B C c o u nt
−T ot al n e utr o p hils ( A bs)
−E osi n o p hils ( A bs)
−M o n o c yt es ( A bs)
−B as o p hils ( A bs)
−L y m p h o c yt es ( A bs)
−B U N
−Creati ni n e
−Pl as m a gl uc ose
−C al ci u m
−S o di u m
−P ot assi u m
−C hl ori d e
−T ot al C O 2 ( Bicar b o nate)
−A S T ( S G O T)
−A L T ( S G P T)
−Al k ali n e p h os p hatase
−G G T
−T ot al Bilir u bi n
−Dir e ct (c o nj u gate d)
bilir u bi n
−I n dir e ct ( u nc o nj u gate d)
bilir u bi n
−T ot al bile aci ds
−Cr e ati n e Ki nase
−Uri c aci d
−Al b u mi n
−T ot al pr ot ei n
−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
−Ur o bili n o ge n
−Uri ne bilir u bi n
−Micr osc o p y a
−C ystati n - C ( a n d e G F R 
usi n g C K D -E PI -C ystati n -
C)
−Pl as m a a P T T, P T, I N R
−S er u m F S H b
−S er u m a n d uri n e 
pr e g n a n c y t est 
(S e cti o n 8. 2. 6 )
−Uri ne dr u g test c
−1- a ntitr y psi n d
−C er ul o pl as mi n d
−S er ol o g y d : H Bs A g, 
H C V A b ( a n d if p ositi v e, 
r efl e x H C V R N A), HI V
−% C D T e
−H b A 1 C
−F asti n g s er u m Li pi d 
P a n el f
−A di p o n e cti n
A d diti o n al e x pl or at or y bi o m ar ker assess m e nts g i ncl u de:
−S er u m a p oli p o pr otei ns A 1, B(t otal), B 1 0 0, B 4 8, C 3, E a n d direct V L D L
−Pl as m a I ns uli n
−hs -C R P
−C K 1 8 -M 3 0, C K 1 8 -M 6 5
−Pr o C 3 a n d Pr o C 6
−Pl as m a P C S K 9
−E L F Test
A d diti o n al Tests – n ee de d f or i nsta nces of s us pecte d H y’s la w – refer t o A p pe n di x 6
a.
O nl y if uri ne di pstic k is p ositi ve f or bl o o d, pr otei n, nitrites or le u k oc yte esterase
b.
I n fe males, at Pre Q, a n d S C R 1, o nly
c.
At Pre Q, S C R 1, a n d Visit 4/ Baseli ne , o nly ; mi ni m u m re q uire me nt f or uri ne dr u g test i ncl u de c ocai ne,
o piates/ o pi oi ds, be nz o diaze pi nes a n d a m p heta mi nes ; t his test n ot per mitte d t o be re peate d at sc he d ule d visits .
d.
At Pre Q, a n d S C R 1, o nly
e.
At Pre Q, S C R 1, Visit 4/ Baseli ne, Da y 1/ Visit 5, Wee k 4 8/ Visit 1 9, a n d w he n st u d y i nter ve nti o n is pre mat urel y st o p pe d
( wit h partici pa nt re mai ni n g i n st u d y or per ma ne ntl y wit h dra w n)
f.
I ncl u des tri gl yceri des, H D L -C, direct L D L - C, a n d t otal c h olester ol
g.
At selecte d visits starti n g fr o m Visit 4/ Baseli ne t h o u g h 1 st o n -site F oll o w-u p/ Visit 2 0 , i ncl usi ve, per S o A -Ta ble A 2
F or list of ter ms c orres p o n di n g t o t he a b bre viati o ns use d herei n, refer t o A p pe n di x 1 3
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 5
Ta ble 7 deli neates t he pr ot oc ol -ma n date d safet y- relate d la b orat or y tests a n d e x pl orat or y 
bi o mar kers. T he re q uire d bl o o d a n d uri ne c ollecti o ns will be perf or me d at ti mes defi ne d i n 
t he S o A -Ta ble A 2 .
A d diti o nal la b orat or y  res ults ma y be re p orte d o n t hese sa m ples as a res ult of t he met h o d of 
a nal ys is or t he t ype of a nal y zer use d b y t he s p o ns or-i de ntifie d ce ntral la b orat or y(ies), or as 
deri ve d fr o m calc ulate d val ues. T hese a d diti o nal tests w o ul d n ot re q uire a d diti o nal c ollecti o n 
of bl o o d. U nsc he d ule d cli nical la b orat or y  meas ure me nts ma y be o btai ne d at a n y ti me d uri n g 
t he st u d y t o assess an y  percei ve d safet y iss ues.
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safety re p ort.
La b orat or y /a nalyt e res ults t hat c o ul d u n bli n d t he st u d y  will n ot be re p orte d t o i n vesti gat or 
sites or ot her bli n de d pers o n nel u ntil t he st u d y has bee n u nbli n de d.
: D ue t o c urre nt restricti o ns t o s hi p h u ma n ge netic sa m ples o utsi de of 
, 
a n d as t he s p o ns or’s dili ge nce di d n ot i de ntif y  a c o m para ble assa y i n  
 t o t he o ne 
pla n ne d f or use i n t he st u d y , t he f oll o wi n g will a p pl y  t o all partici pa nts c o nse nte d i n 
–

sa m ples f or a nal yzi n g Pr o C 3 a n d Pr o C 6 will n ot be c ollecte d ;

assess me nt of direct V L D L  will be re m ove d fr o m t he fasti n g li pi d pa nel a nalys is;

s u m marizati o n of t hese para meters will n ot i ncl u de a ny data fr o m partici pa nts 
c o nse nte d a n d ra n d o mize d i n 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 6
1 0. 3. A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
1 0. 3. 1. Defi niti o n of A E
A E Defi niti o n

A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y 
partici pa nt, te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her or n ot 
c o nsi dere d relate d t o t he st u d y  i nter ve nti o n.

N O T E: A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or dis ease ( ne w or e xacer bate d) 
te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n.
E ve nts Meeti n g
t he A E Defi niti o n

A n y  a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) 
or ot her safet y assess me nts (e g, E C G, ra di ol o gical sca ns, vital si g n meas ure me nts), 
i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d cli nically si g nifica nt i n t he 
me dical a n d scie ntific j u d g me nt of t he i n vesti gat or A n y a b n or mal la b orat or y test 
res ults t hat meet a ny of t he c o n diti o ns bel o w m ust be rec o r de d as a n A E:

Is ass ociate d wit h acc o m pa n yi n g sy m pt o ms.

Re q uires a d diti o nal dia g n ostic testi n g or me dical/s ur gical i nter ve nti o n.

Lea 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 nt, or ot her t hera p y.

E xacer bati o n of a c hr o nic or i nter mitte nt pree xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n.

Ne w c o n diti o ns detecte d or dia g n ose d after st u d y i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt bef ore t he start of t he st u d y.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y
i nter ve nti o n or a c o nc o mita nt me dicati o n. O ver d ose per se will n ot be re p orte d as 
a n A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble 
s uici dal/self- har mi n g i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of 
se q uelae.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 7
E ve nts N O T Meeti n g t he A E Defi niti o n

A n y  cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safety 
assess me nts w hic h are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y  t he 
i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n.

T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of 
t he disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he 
partici pa nt’s c o n diti o n.

Me dical or s ur gical pr oce d ure (e g, e n d osc o p y, a p pe n dect o m y ): t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is t he A E.

Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).

A ntici pate d da y -t o-d a y  fl uct uati o ns of pree xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n. 
1 0. 3. 2. Defi niti o n of S A E
If a n e ve nt is n ot a n A E per defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us 
c o n diti o ns are met (e g, h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y , deat h 
d ue t o pr o gressi o n of disease).
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
T he ter m “life -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. I t d oes n ot refer t o a n e ve nt t hat 
h y p ot heticall y  mi g ht ha ve ca use d deat h if it were m ore se vere.
c.
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n
I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ys icia n’s office or 
o ut patie nt setti n g. C o m plic ati o ns t hat occ ur d uri n g h os pitalizati o n are Ae s. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was necessar y, t he A E 
s h o ul d be c o nsi dere d seri o us.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 8
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
H os pitalizati o n f or electi ve treat me nt of a pree xisti n g c o n diti o n t hat di d n ot w orse n fr o m 
baseli ne is n ot c o nsi dere d a n A E.
d.
Res ults i n persiste nt dis a bilit y/i nc a p acit y

T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal life f u ncti o ns.

T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, 
i nfl ue nza, a n d acci de ntal tra u ma (e g, s prai ne d a n kle) w hic h ma y i nterfere wit h or 
pre ve nt e ver y d a y  life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n.
e.
Is a c o n ge nit al a n o m al y/ birt h defect
f.
Ot her sit u ati o ns:

Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 
re p orti n g is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat 
ma y  n ot be i m me diately l ife-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut 
ma y  je o par dize t he partici pa nt or ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts 
s h o ul d us uall y be c o nsi dere d seri o us.

E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt 
i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t h at d o n ot res ult i n h os pitalizati 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.

S us pecte d tra ns missi o n via a Pfizer pr o d uct of a n i nfecti o us a ge nt, pat h o ge nic or 
n o n - pat h o ge nic, is c o nsi dere d seri o us. T he e ve nt ma y  be s us pecte d fr o m cli nical 
s ym pt o ms or la b orat or y  fi n di n gs i n dicati n g a n i nfecti o n i n a partici pa nt e x p ose d t o 
a Pfizer pr o d uct. T he ter ms “s us pecte d tra ns missi o n” a n d “tra ns missi o n” are 
c o nsi dere d s y n o n y m o us. T hese cases are c o nsi dere d u ne x pecte d a n d ha n dle d as 
seri o us e x pe dite d cases b y phar mac o vi gila nce pers o n nel. S uc h cases are als o 
c o nsi dere d f or re p orti n g as pr o d uct defects, if a p pr o priate.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 9
1 0. 3. 3. Rec or di n g/ Re p orti n g a n d F oll o w -u p of A E s a n d/ or S A Es
A E a n d S A E Rec or di n g/ Re p orti n g
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 a d verse e ve nts o n t he C R F 
a n d f or re p orti n g seri o us a d verse e ve nts o n t he C T 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 y pes of e ve nts: ( 1) S A Es; ( 2) n o nseri o us a d verse 
e ve nts (A Es ); a n d ( 3) e x p os ure t o t he st u d y i nter ve nti on 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. 
It s h o ul d be n ote d t hat t he C T S A E Re p ort F or m f or re p orti n g of S A E i nf 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 E s 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 ot h 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 orti n g of S A E i nf or mati o n .
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 nseri o us A E
All
N o ne
E x p os ure t o t he st u d y 
i nter ve nti o n 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 A Es/ S A Es ass ociate d 
wit h e x p os ure d uri n g 
pre g na nc y or breastfee di n g

Occ u pati o nal e x p os ure is 
n ot rec or de d.
N ote : I ncl u de all S A Es 
ass ociate d wit h e x p os ure d uri n g 
pre g na nc y or breastfee di n g. 
I ncl u de all A Es/ S A Es ass ociate d 
wit h occ u pati o nal e x p os ure.

W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all 
d oc u me ntati o n (e g, h os pital pr o gress n otes, la b orat or y  re p orts, a n d dia g n ostic 
re p orts) relate d t o t he e ve nt.

T he i n vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he C R F.

It is n ot acce pta bl e f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt’s 
me dical rec or ds t o Pfizer Safet y  i n lie u of c o m pleti o n of t he C T S A E Re p ort 
F or m/ A E/ S A E C R F pa ge.

T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are 
re q ueste d by Pfize r Safet y. In t his case, all partici pa nt i de ntifiers, wit h t he 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 0
A E a n d S A E Rec or di n g/ Re p orti n g
e xce pti o n of t he partici pa nt n u m ber, will be re dacte d o n t he c o pies of t he me dical 
rec or ds bef ore s u b missi o n t o Pfizer Safet y.

T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s ym pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis ( n ot 
t he i n di vi d ual si g ns/s ym pt o ms) will be d oc u me nte d as t he A E/ S A E.
Assess me nt of I nte nsit y
T he i n vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h A E a n d S A E re p orte d 
d uri n g t he st u d y a n d assi g n it t o 1 of t he f oll o wi n g cate g ories: 

Mil d:
A n e ve nt t hat is easil y  t olerate d b y t he partici pa nt, ca usi n g mi ni mal 
disc o mf ort a n d n ot i nterferi n g wit h e ver y d a y  acti vities.

M o der ate:
A n e ve nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or mal 
e ver yd a y  acti vities.

Severe: A n e ve nt t hat pre ve nts n or mal e ver y d a y  acti vities. A n A E t hat is assesse d 
as se vere s h o ul d n ot be c o nf use d wit h a n S A E. Se vere is a cate g or y  utilize d f or 
rati n g t he i nte nsity of a n e ve nt; a n d b ot h A es a n d S A Es ca n be assesse d as se vere.
A n e ve nt is defi ne d as “seri o us” w he n it meets at least 1 of t he pre defi ne d o utc o mes as 
descri be d i n t he defi niti o n of a n S A E, N O T w he n it is rate d as se vere.
Assess me nt of C a us alit y

T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n 
a n d eac h occ urre nce of eac h A E/ S A E.

A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot 
be r ule d o ut.

T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t h e relati o ns hi p.

Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her 
ris k fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y i nter ve nti o n 
a d mi nistrati o n, will be c o nsi dere d a n d i n vesti gate d.

T he i n vesti gat or wi ll als o c o ns ult t he I B a n d/ or pr o d uct i nf or mati o n, f or mar kete d 
pr o d ucts, i n his/ her assess me nt.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 1
Assess me nt of C a us alit y

F or eac h A E/ S A E, t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he 
has re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y .

T here ma y be sit uati o ns i n w hic h a n S A E has occ urre d, a n d t he i n vesti gat or has 
mi ni mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he s p o ns or. H o we ver, it is 
ver y i m p ort a nt t h at t he i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y 
f or e ver y e ve nt bef ore t he i niti al tr a ns missi o n of t he S A E d at a t o t he s p o ns or.

T he i n vesti gat or ma y  c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w- u p 
i nf or mati o n a n d se n d a n S A E f oll o w-u p re p ort wit h t he u p date d ca usalit y  
assess me nt.

T he ca usalit y  assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y  
re p orti n g re q uire me nts.

If t he i n vesti gat or d oes n ot k n o w w het her or n ot t he st u d y i nter ve nti o n 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 st u d y  i nter ve nti o n” f or re p orti n g 
p ur p oses, as defi ne d b y  t he s p o ns or. 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 a n 
assess me nt i n t he de dicate d secti 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.
F oll o w -u p of A E s a n d S A Es

T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y  i n dicate d or as re q ueste d b y t he 
s p o ns or t o el uci date t he nat ure a n d/ or ca usality of t he A E or S A E as f ull y as 
p ossi ble. T his m a y i ncl u de a d diti o nal la b orat or y tests or i n vesti gati o ns, 
hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt hcare pr o vi ders.

If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d 
f oll o w- u p peri o d, t he i n vesti gat or will pr o vi de Pfizer Safety wit h a c o p y of a n y 
p ost m orte m fi n di n gs i ncl u di n g hist o pat h ol o g y .

Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y  c o m plete d C R F.

T he i n vesti gat or will s u b mit a n y  u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs 
of recei p t of t he i nf or mati o n.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 2
1 0. 3. 4. Re p orti n g of S A Es
S A E Re p orti n g t o Pfizer S afet y vi a C T S A E Re p ort F or m

Facsi mile tra ns missi o n of t he C T S A E Re p ort F or m is t he preferre d met h o d t o 
tra ns mit t his i nf or mati o n t o Pfizer Safet y.

I n circ u msta nces w he n t he facsi mile is n ot w or ki n g, n otificati o n b y  tele p h o ne is 
acce pta ble wit h a c o p y of t he C T S A E Re p ort F or m se nt b y  o ver ni g ht mail or 
c o urier ser vice.

I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o 
c o m plete a n d si g n t he C T S A E Re p ort F or m pa ges wit hi n t he desi g nate d re p orti n g 
ti me fra mes.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 3
1 0. 4. A p pe n di x 4: C o ntr ace pti ve G ui d a nce 
1 0. 4. 1. M ale P artici p a nt Re pr o d ucti ve I ncl usi o n Criteri a
N o c o ntrace pti o n met h o ds are re q uire d f or male partici pa nts i n t his st u d y , 
 
F or  
 o nly : alt h o u g h n o c o ntrace pti o n met h o ds are re q uire d f or male partici pa nts i n t he 
ot her c o u ntries/re gi o ns , base d o n a s pecific re q uire me nt fr o m t he re g ulat or y a ut h orit y i n 
, male partici pa nts are eli gi ble t o partici pate if t he y  a gree t o t he f oll o wi n g re q uire me nts 
d uri n g t he i nter ve nti o n peri o d a n d f or at least 2 8 da ys after t he last d ose of st u d y 
i nter ve nti o n, w hic h c orres p o n ds t o t he ti me nee de d t o eli mi nate re pr o d ucti ve safety ris k of 
t he st u d y i nter ve nti o n: 

Refrai n fr o m d o nat i n g s per m

P L U S eit her –

Be a bsti ne nt fr o m heter ose x ual i nterc o urse wit h a fe male of c hil d beari n g 
p ote ntial as t heir preferre d a n d us ual lifest y le (a bsti ne nt o n a l o n g ter m 
a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt .
O R

M ust a gree t o use a male c o n d o m w he n e n ga gi n g i n a n y acti vit y t hat 
all o ws f or passa ge of ejac ulate t o a n ot her pers o n.

Ot her secti o ns of t he pr ot oc ol rele va nt t o t he re q uire me nt f or c o ntrace pti o n i n 
male partici pa nts i ncl u de Secti o n 4. 2. 1 a n d Secti o n 5. 4. 1 a n d c o nsi dere d t o be 
u p date d i n acc or da nce wit h te xt hi g hli g hte d a b o ve.

A n E D P als o occ urs if a male partici pa nt w h o is recei vi n g or has disc o nti n ue d 
st u d y i nter ve nti o n e x p oses a fe male part ner pri or t o or ar o u n d t he ti me of 
c o nce pti o n – refer t o Secti o n 8. 3. 5 .
1 0. 4. 2. Fe m ale P artici p a nt Re pr o d ucti ve I ncl usi o n Criteri a
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt or breastfee di n g, a n d at 
least 1 of t he f oll o wi n g c o n diti o ns a p plies:

Is n ot a W O C B P (see defi niti o ns bel o w i n Secti o n 1 0. 4. 3 ).
O R

Is a W O C B P a n d usi n g a c o ntrace pti ve met h o d t hat is hi g hl y effecti ve ( wit h a 
fail ure rate of < 1 % per year), prefer a bly wit h l o w user de pe n de nc y , as descri be d 
bel o w d uri n g t he i nter ve nti o n peri o d a n d f or at le ast 2 8 d ays after t he last d ose of 
st u d y i nter ve nti o n, w hic h c orres p o n d s t o t he ti me nee de d t o eli mi nate a n y 
re pr o d ucti ve safety ris k of t he st u d y i nter ve nti o n(s). T he i n vesti gat or s h o ul d 
e val uate t he effecti ve ness of t he c o ntrace pti ve met h o d i n relati o ns hi p t o t he first 
d ose of st u d y  i nter ve nti o n.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 4
T he i n vesti gat or is res p o ns i ble f or re vie w of me dical hist or y, me nstr ual hist or y, a n d rece nt 
se x ual acti vit y t o decrease t he ris k f or i ncl usi o n of a w o ma n wit h a n early u n detecte d 
pre g na nc y . 
1 0. 4. 3. W o m a n of C hil d be ari n g P ote nti al
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal 
u nless per ma ne ntl y sterile (see bel o w).
If fertilit y is u nclear (e g, a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot 
be c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, a d diti o nal e val uati o n s h o ul d be 
c o nsi dere d.
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P:
1.
Pre me narc hal. 
2.
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:

D oc u me nte d h ys terect o m y;

D oc u me nte d bilateral sal pi n gect o m y ;

D oc u me nte d bilateral o o p h orect o m y.
F or i n di vi d uals wit h per ma ne nt i nfertilit y d ue t o a n alter nate me dical ca use ot her t ha n t he 
a b o ve, (e g, m ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y), i n vesti gat or discreti o n s h o ul d be 
a p plie d t o deter mi ni n g st u d y e ntr y.
N O T E: D oc u me ntati o n f or a n y of t he a b o ve cate g ories ca n c o me fr o m t h e site 
pers o n nel’s re vie w of t he partici pa nt’s me dical rec or ds, me dical e xa mi nati o n, or me dical 
hist or y  i nter vie w. T he met h o d of d oc u me ntati o n s h o ul d be rec or de d i n t he partici pa nt’s 
me dical rec or d f or t he st u d y .
3.
P ost me n o pa usal fe male:

A p ost me n o pa usal sta te is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use. I n a d diti o n, a

H i g h F S H le vel i n t he p ost me n o pa usal ra n ge m ust be use d t o c o nfir m a 
p ost me n o pa usal state i n w o me n u n der 6 0 ye ars of a ge a n d n ot usi n g h or m o nal 
c o ntrace pti o n or HR T. 

Fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o 
use o ne of t he n o n -estr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds 
if t he y wis h t o c o nti n ue t heir H R T d uri n g t he st u d y. Ot her wise, t he y m ust 
disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y  
e nr oll me nt.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 5
1 0. 4. 4. C o ntr ace pti o n Met h o ds
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal a vaila bilit y /re g ulati o ns 
re gar di n g t he use of c o ntrace pti ve met h o ds f or t h ose partici pati n g i n cli nical trials.
1.
I m pla nta ble pr o gest o ge n-o nl y  h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n.
2.
I ntra uteri ne de vice.
3.
I ntra uteri ne h or m o ne-releasi n g sys te m.
4.
Bilateral t u bal occl usi o n.
5.
Vasect o mize d part ner:

Vasect o mize d part ner is a hi g hl y effecti ve c o nt race pti ve met h o d pr o vi de d t hat t he 
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 a n d t he 
a bse nce of s per m has bee n c o nfir me d. If n ot, a n a d diti o nal hi g hl y  effecti ve 
met h o d of c o ntrace pti o n s h o ul d be use d. T he s per mat o ge nesis c y cle is 
a p pr o xi matel y 9 0 da ys.
6.
C o m bi ne d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n:

Oral;

I ntra va gi nal;

Tra ns der mal .
7.
Pr o gest o ge n - o nly h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n:

Oral;

I njecta ble.
8.
Se x ual a bsti ne nce:

Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y  if defi ne d as 
refrai ni n g fr o m heter ose x ual i nterc o urse 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  i nter ve nti o n. T he relia bilit y of se x ual a bsti ne nce nee ds t o be 
e val uate d i n relati o n t o t he d urati o n of t he st u d y a n d t he preferre d a n d us ual 
lifest yle of t he partici pa nt.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 6
I n a d diti o n, o ne of t he f oll o wi n g effecti ve b arrier met h o ds m ust als o be use d w he n 
o pti o n 6 or 7 are c h ose n a b o ve:

Male or fe male c o n d o m wit h or wit h o ut s per mici de;

Cer vical ca p, dia p hra g m, or s p o n ge wit h s per mici de;

A c o m bi nati o n of male c o n d o m wit h eit her cer vical ca p, dia p hra g m, or s p o n ge wit h 
s per mici de ( d o u ble-barrier met h o ds).
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 7
1 0. 5. A p pe n di x 5: 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 8
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 9
1 0. 6. A p pe n di x 6: Li ver S afet y: S u g geste d Acti o ns a n d F oll o w -u p Assess me nts
P ote nti al C ases 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 n o 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 partici pa nts, 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 partici pa nts 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 DI LI. 
Partici pa nts w h o e x perie nce a tra nsa mi nase ele vati o n a b o ve 3 × 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 A S T a n d/ or A L T prece de T Bili ele vati o ns 
( > 2 × U L N) b y s e veral da ys or wee ks. T he i ncrease i n T Bili t y picall 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 orat or y sa m ple). I n rare i nsta nces, b y t he ti me T Bili ele vati o ns are detecte 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 Bili t hat meet t he 
criteria o utli ne d bel o w are c o nsi dere d p ote ntial DI LI (assesse d per H y ’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 ote ntial DI LI case de pe n ds o n t he 
partici pa nt’s i n di vi d ual baseli ne val ues a n d u n derl yi n g c o n di ti o ns. Partici pa nts 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 
( Hy’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:

Partici pa nts wit h A S T/ A L T a n d T Bili baseli n e 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 LT 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 hatase val ue 
< 2 × U L N or n ot a vaila ble.

F or partici pa nts wit h baseli ne A S T O R A L T O R T Bi li 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 baseli ne:

Pree xisti n g A S T or A L T baseli ne val ues a b 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 ncrease d fr o m 
baseli ne val ue b y a n a m o u nt of at least 1 × U L N o r 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 t o 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. 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 0
T he par tici pa nt 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 res ults. T his e val uati o n s h o ul d 
i ncl u de 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 on t o re peati n g meas ure me nts of A S T a n d A L T a n d T Bili f or s us pecte d cases of 
H y ’s la w, a d diti o nal la b orat or y tests s h o ul d i ncl u de al b u mi n, C K, direct a n d i n direct 
bilir u bi n, G G T, P T/I N R, t otal bile aci ds, a n d al kali ne p h os p hatase. 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 n g, as nee de d, f or f urt her c o nte m p ora ne o us a nalys 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/ paraceta m ol (eit her b y itself or as a c of or m ulate 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 pers o n, s ur ger y , bl o o d tra nsf usi o n, hist or y of li ver 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 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) a n d c ollecti o n of 
ser u m sa m ples f or aceta mi n o p he n/ paraceta m ol dr u g a n d/ or pr otei n a d d uct le vels ma y  be 
warra nte d. 
All cases de m o nstrate d o n re peat testi n g 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 L F T a b n or malities has yet bee n f o u n d. S uc h p ote nti al DI LI ( H y’s l a w) 
c ases 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 nfir me d case o nly after all res ult s 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.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 1
1 0. 7. A p pe n di x 7: E C G Fi n di n gs of P ote nti al Cli nic al C o ncer n
E C G Fi n di n gs T h at M a y
Q u alif y as A d verse E ve nts

Mar ke d si n us bra d y car dia (rate < 4 0 b p m) lasti n g mi n utes.

Ne w P R i nter val pr ol o n gati o n > 2 8 0 msec.

Ne w pr ol o n gati o n of Q Tc F t o > 4 8 0 msec (a bs o l ute) or b y ≥6 0 msec fr o m baseli ne.

Ne w -o nset atrial fl utter or fi brillati o n, wit h c o ntr olle d ve ntric ular res p o nse rate: ie, 
rate < 1 2 0 b p m.

Ne w -o nset t y pe I sec o n d-de gree ( W e nc ke bac h) A V bl oc k of > 3 0 sec o n ds’ 
d urati o n.

Fre q ue nt P V Cs, tri plets, or s h ort i nter vals ( < 3 0 sec o n ds) of c o nsec uti ve ve ntric ular 
c o m ple xes.
E C G Fi n di n gs T h at M a y
Q u alif y as Seri o us A d verse E ve nts

Q Tc F pr ol o n gati o n > 5 0 0 msec.

Ne w S T - T c ha n ges s u g gesti ve of m y ocar dial isc he mia.

Ne w - o nset left b u n dle bra nc h bl oc k ( Q R S > 1 2 0 msec).

Ne w -o nset ri g ht b u n dle bra nc h bl oc k ( Q R S > 1 2 0 msec).

S y m pt o matic bra d y car dia. 

As y st ole:

I n a wa ke, sy m pt o m -free patie nts i n si n us r h yt h m, wit h d oc u me nte d peri o ds of 
as yst ole ≥3. 0 sec o n ds or a n y  esca pe rate < 4 0 b p m, or wit h a n esca pe r h yt h m 
t hat is bel o w t he A V n o de; 

I n a wa ke, sy m pt o m -free patie nts wit h atrial fi brillati o n a n d bra dyc ar dia wit h 1 
or m ore pa uses of at least 5 sec o n ds or l o n ger; 

Atrial fl utter or fi brillati o n, wit h ra pi d ve ntric ular res p o nse rate:
ra pi d = rate 
> 1 2 0 b p m.

S ustai ne d s u pra ve ntric ular tac h yc ar dia (rate > 1 2 0 b p m) (“s ustai ne d” = s h ort 
d urati o n wit h rele va nt s y m pt o ms or lasti n g > 1 mi n ute).
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 2

Ve ntric ular r h yt h ms > 3 0 sec o n ds’ d urati o n, i ncl u di n g i di o ve ntric ular r h y t h m (H R
< 4 0 b p m), accelerate d i di o ve ntric ular r h yt h m ( H R 4 0 b p m t o < 1 0 0 b p m), a n d 
m o n o m or p hic/ p ol y m or p hic
ve ntric ular tac h yc ar dia ( H R > 1 0 0 b p m (s uc h as 
t orsa des de p oi ntes)).

T yp e II sec o n d-de gree ( M o bitz II) A V bl oc k.

C o m plete (t hir d- de gree) heart bl oc k.
E C G Fi n di n gs T h at Q u alif y as Seri o us A d verse E ve nts

C ha n ge i n patter n s u g gesti ve of ne w m y ocar dial i nfarcti o n. 

S ustai ne d ve ntric ular tac h y arr h yt h mias ( > 3 0 sec o n ds’ d urati o n).

Sec o n d - or t hir d -de gree A V bl oc k re q uiri n g pace ma ker place me nt.

As y st olic pa uses re q uiri n g pace ma ker place me nt.

Atrial fl utter or fi brillati o n wit h ra pi d ve ntric ular res p o nse re q uiri n g car di o versi o n.

Ve ntric ular fi brillati o n/fl utter.

At t he discreti o n of t he i n vesti gat or, a n y  arr h yt h mia classifie d as a n a d verse 
e x perie nce.
T he e n u merate d list of maj or e ve nts of p ote ntial cli nical c o ncer n are rec o m me n de d as “alerts” or 
n otificati o ns fr o m t he c ore E C G la b orat or y t o t he i n vesti gat or a n d Pfizer st u d y tea m, a n d n ot t o be 
c o nsi dere d as all -i ncl usi ve of w hat t o be re p orte d as A Es/ S A Es.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 3
1 0. 8. A p pe n di x 
 I n hi bit ors a n d I n d ucers
T his list is n ot c o nsi dere d as e x ha usti ve. A n y  q uesti o ns re gar di n g use of  
 i n hi bit ors 
a n d i n d ucers s h o ul d be directe d t o t he sp o ns or st u d y  tea m.
 I n hi bit ors
 I n d ucers
HI V a nti vir als
HI V a nti vir als
I n di na vir
Ne vira pi ne
Nelfi na vir
Miscell a ne o us
Rit o na vir
Bar bit urates
Sa q ui na vir
Car ba maze pi ne
B oce pre vir
Gl uc oc ortic oi ds (s yste mic)
L o pi na vir/rit o na vir
O xcar baze pi ne
A m pre na vir
P he n o bar bital
Ataza na vir
P he n yt oi n
Tela pre vir
Rifa b uti n
Dar u na vir/rit o na vir
Rifa m pi n
F osa m pre na vir
St. J o h n's w or t3
Ti pri na vir/rit o na vir
Tr o glitaz o ne
A nti bi otics
Nafcilli n
Clarit hr o m yci n
A vasi mi b e 4
Tr olea n d o m yci n
E nzal uta mi de
Telit hr o m yci n
Mit ota ne
A nti -i nfecti ve
Itrac o naz ole
Ket oc o naz ole
P osac o naz ole
V oric o naz ole
Miscell a ne o us
Nefaz o d o ne
Gra pefr uit j uice 1
C o ni va pta n
Mi befra di l2
I delalisi b
1.
T he effect of gra pefr uit j uice varies wi del y a mo n g bra n ds a n d is c o nce ntrati o n-, d ose -, a n d pre parati o n -
de pe n de nt. St u dies ha ve s h o w n t hat it ca n b e classifie d as a “
i n hi bit or” w he n a certai n
pre parati o n was use d (e g, hi g h d ose, d o u ble stre n gt h) or as a “ m o derate C Y P 3 A i n hi bit or” w he n a n ot her
pre parati o n was use d (e g, l o w d ose, si n gle stre n gt h).
2.
Wit h dra w n
fr o m t he U nite d States mar ket.
3.
T he effect of St. J o h n’s w ort varies wi del y a n d is pre parati o n -de pe n de nt.
4.
N ot a mar kete d dr u g.
Refere nce: U. S. F o o d a n d Dr u g A d mi nistrati o n. Dr u g De vel o p me nt a n d Dr u g I nteracti o ns: 
Ta ble of S u bstrates, I nhi bit ors a n d I nd ucers, a vaila ble at:
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nter
acti o ns La beli n g/ uc m 0 9 3 6 6 4. ht m
F or 
 o nly: I n res p o nse t o t he u ni q uel y dis pr o p orti o nate use of her bal pre parati o ns, 
al o n g wit h u ni q ue c o nc o mita nt me dicati o ns o nl y  a vaila ble i n  
, i n t he p o p ulati o n bei n g 
e nr olle d i n t his st u d y, t he f oll o wi n g clarificati o ns re gar di n g t he use of her bal pre parati o ns
a n d 
-s pecific c o nc o mita nt me dicati o ns, is offere d; t hese c ha n ges are g ui de d b y a 
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 4
c o m pre he nsi ve re vie w of t he a vaila ble/accessi ble literat ure re gar di n g eac h of t he her bal 
c o m p o ne nts -
N O T E: T he cate g ories me nti o ne d a b o ve is c o m pre he nsi ve, b ut t he s pecific her bal pre parati o ns/ me dicati o ns 
is n ot all i ncl usi ve an d e xa m ple of a ge nts offere d are ill ustrati ve – t hese ma y or ma y n ot be a vaila ble i n 
T he S p o ns or s h o ul d be c o ns ulte d i n deter mi ni n g w het her or n ot it is per mitte d t o use s pecific her bal 
pre parati o n/c o nc o mita nt me dicati o n n ot i ncl u de d herei n .
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 5
1 0. 9. A p pe n di x 9: P atie nt -Re p orte d O utc o mes
1 0. 9. 1. N A S H C H E C K
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 6
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 7
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 8
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 9
1 0. 9. 2. N A S H S y m pt o m Di ar y
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 0
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 1
1 0. 9. 3. N A S H P GI - S
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 2
1 0. 9. 4. N A S H P GI - C
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 3
1 0. 9. 5. P R O MI S F A TI G U E C ust o m 9 -Ite m V ersi o n
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 4
1 0. 1 0. A p pe n di x 1 0: G ui d a nce t o I n vesti g at ors – M a n a ge me nt of I n di vi d u al 
P artici p a nts Gl yce mic C o ntr ol – i ncl u di n g Metf or mi n D ose St arti n g at R u n-I n/ Visit 3
I n p artici p a nts i n w h o m metf or mi n d ose is a dj uste d at R u n-I n/ Visit 3, bl o o d c ollecti o ns at 
Wee k 2/ Visit 6 , Wee k 6 / Visit 8, a n d Wee k 1 2/ Visit 1 0 ca n i ncl u de assess me nt of 
F P G ± H b A 1 C ( be yo n d at t he ti me p oi nts liste d i n S o A -Ta ble A 2 ), t o ai de e val uati o n per 
g ui da nce a b o ve.
I s P arti ci p a nt wit h T 2 D M 
o n M etf or mi n at S C R 1 ? 
I s T D D > 1 g m p er d a y ?
N o
Y e s

St arti n g at Vi sit 3/ R u n -I n, p arti ci p a nt 
m u st a gr e e t o dr o p T D D b y o n e -
t hir d or o n e -h alf , g ui d e d b y a v ail a bl e 
t a bl et str e n gt h s
I s F a sti n g Pl a s m a Gl u c o s e ≥ 2 7 0 m g/ d L  [1 5 m m ol/ L ] at a n y vi sit b et w e e n W e e k 2/ Vi sit 6
a n d W e e k 6/ Vi sit 8 , i n cl u si v e, a s a s s e s s e d vi a S p o n s or-i d e ntifi e d c e ntr al l a b or at or y ?
N o
Y e s

P arti ci p a nt t o b e S cr e e n F ail e d 

A n d m etf or mi n d o s e r et ur n e d t o 
b e s a m e a s pri or t o Vi sit 3/ R u n -I n
At B a s eli n e/ Vi sit 4, i s F P G r e s ult 
≤ 2 7 0 m g/ d L ( 1 5 m m ol/ L) ?
Y e s
N o
N o
Y e s

If o n m etf or mi n, i n cr e a s e d o s e t o m at c h T D D pri or t o R u n-I n/ Vi sit 3

If n ot o n m etf or mi n , c o nti n u e t o n e xt S c h e d ul e d Vi sit
I s F a sti n g Pl a s m a Gl u c o s e ≥ 2 4 0 m g/ d L [1 3. 3 m m ol/ L ] at W e e k 8/ Vi sit 9
or
W e e k 1 2/ Vi sit 1 0 , a s a s s e s s e d vi a S p o n s or-i d e ntifi e d c e ntr al l a b or at or y ?
N o
Y e s

If o n m etf or mi n, i n cr e a s e d o s e t o m at c h T D D pri or t o R u n-I n/ Vi sit 3

If n ot o n m etf or mi n , i n cr e a s e d o s e( s) of ot h er b a c k gr o u n d a g e nt s 
f or gl y c e mi c c o ntr ol
•
A n d, if li mit e d s u c c e s s, a d d a n e w a g e nt
I s F a sti n g Pl a s m a Gl u c o s e ≥ 2 0 0 m g/ d L  [1 1 . 1 m m ol/ L] or H b A 1 C > 8 % ( 6 4 m m ol/ m ol) 
at a n y vi sit b et w e e n W e e k 1 6/ Vi sit 1 1 a n d W e e k 4 8/ Vi sit 1 9 , i n cl u si v e, a s a s s e s s e d vi a 
S p o n s or -i d e ntifi e d c e ntr al l a b or at or y ?
N o
Y e s

I n cr e a s e d o s e( s) of ot h er b a c k gr o u n d a g e nt s f or 
gl y c e mi c c o ntr ol
•
A n d, if li mit e d s u c c e s s, a d d a n e w a g e nt

C o nti n u e t o n e xt 
S c h e d ul e d Vi sit
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 5
1 0. 1 1. A p pe n di x 1 1: G ui d a nce t o I n vesti g at ors – M a n a ge me nt of I n di vi d u al 
P artici p a nts Wit h Ele v ati o n i n F a sti n g Ser u m Tri gl yceri des
S er u m T ri gl y c eri d e r e s ult at Vi sit s st arti n g o n D a y 1/ Vi sit 5 t o W e e k 4 8/ Vi sit 1 9, i n cl u si v e, 
a s a s s e s s e d vi a S p o n s or -i d e ntifi e d c e ntr al l a b or at or y i s …
W a s S c h e d ul e d Vi sit c oll e cti o n p o st ≥ 8- h o ur o v er ni g ht f a st ?
Y e s
N o

Arr a n g e f or a n u n pl a n n e d vi sit wit hi n 5 ± 2 d a y s 
of r e c ei pt of r e s ult s fr o m s c h e d ul e d vi sit

C oll e ct li pi d p a n el p o st ≥ 8- h o ur o v er ni g ht f a st
≥ 6 0 0 a n d < 8 0 0 m g/ d L
[≥ 6. 8 a n d < 9. 0 m m ol/ L ]
≥ 8 0 0 m g/ d L
[≥ 9. 0 m m ol/ L ]

P arti ci p a nt t o r et ur n f or n e xt 
S c h e d ul e d Vi sit p o st ≥ 8- h o ur 
o v er ni g ht f a st
W a s S c h e d ul e d Vi sit c oll e cti o n p o st ≥ 8- h o ur o v er ni g ht f a st ?
N o
If u n pl a n n e d vi sit r e s ult i s …
•
≥ 6 0 0 a n d < 8 0 0 m g/ d L [≥ 6. 8 a n d < 9. 0 m m ol/ L ]
•
O pti mi z e p arti ci p a nt’ s b a c k gr o u n d li pi d -m o dif yi n g a g e nt s
• 1st b y i n cr e a si n g d o s e of alr e a d y a d mi ni st er e d a g e nt( s) 
•
a n d if li mit e d s u c c e s s , b y a d di n g a n e w a g e nt
• Parti ci p a nt t o r et ur n f or n e xt s c h e d ul e d vi sit p o st ≥ 8- h o ur o v er ni g ht f a st
•
At I n v e sti g at or di s cr eti o n , a d diti o n al u n pl a n n e d vi sit( s) b ef or e n e xt
S c h e d ul e d Vi sit p er mitt e d
•
≥ 8 0 0 m g/ d L [ ≥ 9. 0 m m ol/ L ]
•
P arti ci p a nt m u st di s c o nti n u e st u d y i nt er v e nti o n t h o u g h m a y
o pt t o r e m ai n 
i n st u d y a n d r et ur n f or n e xt S c h e d ul e d Vi sit
Y e s

Di s c o nti n u e st u d y i nt er v e nti o n
Y e s
N o

Wit h dr a w
p arti ci p a nt 
fr o m st u d y

P arti ci p a nt t o r et ur n f or 
n e xt S c h e d ul e d Vi sit
I s p arti ci p a nt willi n g t o st a y i n st u d y b ut 
of f st u d y i nt er v e nti o n ?
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 6
1 0. 1 2. A p pe n di x 1 2 : G ui d a nce t o I n vesti g at ors – M a n a ge me nt of I n di vi d u al 
P artici p a nts Wit h Decre ase i n Pl atelet C o u nt
Pl at el et C o u nt r e s ult at Vi sit s st arti n g o n D a y 1/ Vi sit 5 t o W e e k 4 8/ Vi sit 1 9, i n cl u si v e, 
a s a s s e s s e d vi a S p o n s or -i d e ntifi e d c e ntr al l a b or at or y i s …
W a s S c h e d ul e d Vi sit r e s ult r e pr e s e nti n g 
a c o nti n u e d d e cli n e r el ati v e t o r e s ult( s) 
fr o m pri or vi sit( s) ?
Y e s
N o

Arr a n g e f or a n u n pl a n n e d vi sit wit hi n 5 ± 2 d a y s 
of r e c ei pt of r e s ult s fr o m s c h e d ul e d vi sit

C oll e ct h e m at ol o g y p a n el
≥ 7 5, 0 0 0 p er m m 3
A n d < 1 0 0, 0 0 0 p er m m
3
< 7 5, 0 0 0 p er m m
3

P arti ci p a nt t o r et ur n f or 
n e xt S c h e d ul e d Vi sit
W a s S c h e d ul e d Vi sit r e s ult r e pr e s e nti n g 
a c o nti n u e d d e cli n e r el ati v e t o r e s ult( s) 
fr o m pri or vi sit( s) ?
Y e s
N o

If u n pl a n n e d vi sit r e s ult i s …
•
≥ 7 5, 0 0 0 a n d < 1 0 0, 0 0 0, p er m m
3
•
P arti ci p a nt t o r et ur n f or n e xt S c h e d ul e d Vi sit 
•
At I n v e sti g at or di s cr eti o n , a d diti o n al u n pl a n n e d vi sit( s) b ef or e n e xt S c h e d ul e d Vi sit p er mitt e d
•
< 7 5, 0 0 0 p er m m
3
•
P arti ci p a nt m u st di s c o nti n u e st u d y i nt er v e nti o n t h o u g h m a y
o pt t o r e m ai n i n st u d y a n d r et ur n f or n e xt S c h e d ul e d Vi sit

Di s c o nti n u e st u d y i nt er v e nti o n
Y e s
N o

Wit h dr a w
p arti ci p a nt 
fro m st u d y

P arti ci p a nt t o r et ur n f or 
n e xt S c h e d ul e d Vi sit
I s p arti ci p a nt willi n g t o st a y i n st u d y b ut 
off st u d y i nt er v e nti o n ?
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 7
1 0. 1 3. A p pe n di x 1 3 : A b bre vi ati o ns
T he f oll o wi n g a b bre viati o ns ma y  be use d i n t he pr ot oc ol –
A b bre vi ati o n
Ter m
% C D T
p erce nt car b o h y drate deficie nt tra nsferri n relati ve t o t otal tra nsferri n
A 1 A T
Al p ha -1 -a ntitr y psi n
A bs
a bs ol ute
A C C
acet yl-C o A car b o x ylase
A C Ci
acet yl-C o A car b o x ylase i n hi bit or ( P F-0 5 2 2 1 3 0 4)
A E
a d verse e ve nt
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase 
A N C O V A
A nal ysis of C o varia nce 
A p o
a p oli p o pr otei n
a P T T
acti vate d partial t hr o m b o plasti n ti me
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 0 -2 4
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs
A U C 2 4
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs
A U C i nf
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o i nfi nit y
A U C ta u
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o e n d of d osi n g peri o d
A U DI T
Alc o h ol use dis or ders i de ntificati o n test
A V
atri o ve ntric ular
B C R P
breast ca ncer resista nt pr otei n
BI D
bis i n die (t wice -a -d a y )
B MI
b o d y mass i n de x
B P
bl o o d press ure
b p m
beats per mi n ute
B U N
bl o o d urea nitr o ge n
C A P T M
C o ntr olle d atte n uati o n para meter
C a v g
A vera ge plas ma c o nce ntrati o n
C D T
Car b o h y drate deficie nt tra nsferri n
C F R
c o de of fe deral re g ulati o ns
CI
C o nfi de nce I nter val
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces
C K
Creati ne Ki nase
C K 1 8 -M 3 0
c yt o kerati n-1 8 -M 3 0
fra g me nt
C K 1 8 -M 6 5
c yt o kerati n-1 8 -M 6 5
fra g me nt
C K D -E PI
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n e q uati o n
C ma x
pea k or ma xi m u m o bser ve d c o nce ntrati o n
C O 2
car b o n di o xi de ( bicar b o nate)
C o A
c oe nz y me A
c o n me ds
c o nc o mita nt me diati o ns
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C O VI D -1 9
C or o na vir us Disease of 2 0 1 9
C R F
Case Re p ort F or m
C R N
Cli nical Researc h Net w or k
C R O
c o ntract researc h or ga nizati o n
C S R
cli nical st u d y re p ort
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 8
A b bre vi ati o n
Ter m
C T
cli nical trial
C tr o u g h
plas ma c o nce ntrati o n bef ore ne xt d ose
C V
car di o vasc ular
C Y P
C yt oc hr o me P -4 5 0 ( 3 A, 2 B 6, 2 C 9, 2 C 1 9)
D/ C
disc o nti n ue
D A G
diac yl gl ycer ol
d B/ m
deci bels per meter
D C C T
Dia betes C o ntr ol a n d C o m plicati o ns Tria l
D G A T 1
diac yl gl ycer ol ac yltra nsferase 1
D G A T 2
diac yl gl ycer ol ac yltra nsferase 2
D G A T 2i
diac yl gl ycer ol ac yltra nsferase 2 i n hi bit or ( P F -0 6 8 6 5 5 7 1)
DI LI
dr u g -i n d uce d li ver i nj ur y
D N L
de n o v o li p o ge nesis
D P PI V
Di pe pti d yl pe pti dase -I V 
D U
Dis pe nsi n g U nit
E 0
place b o res p o n der rate
E C
et hics c o m mittee
E C 5 0
c o nce ntrati o n of t he dr u g at half ma xi m u m res p o nse
E C G
electr ocar di o gra m
e C R F
Electr o nic case re p ort f or m
E D 5 0
D ose t hat pr o d uces half ma xi m u m dr u g effect 
E -D M C
e xter nal data m o nit ori n g c o m mittee
E D P
e x p os ure d uri n g pre g na nc y
E F D
e m br y o -fetal de vel o p me ntal
e G F R
Esti mate d gl o mer ular filtrati o n rate
E L F
E n ha nce d Li ver Fi br osis
E M A
E ur o pea n Me dical A ge nc y
E ma x
ma xi m u m effect of dr u g
e P R O
Electr o nic Patie nt Re p orte d O utc o me 
E U
E ur o pea n U ni o n
E U A
E mer ge nc y Use A ut h orizati o n
E u dra C T
E ur o pea n Cli nical Trials Data base
F /U
F oll o w -u p
F 2
Si g nifica nt sta ge of fi br osis w he n scarri n g has occ urre d a n d e xte n ds o utsi de t he li ver area
F 3
Se vere sta ge of fi br osis wit h s prea di n g a n d f or mi n g bri d ges wit h ot her fi br otic li ver areas 
F A S T T M
Deri ve d sc ore ( usi n g C A P T M , V C T ET M , a n d A S T) t o i de ntif y t hose wit h pr o gressi ve N A S H
F D A
F o o d a n d Dr u g A d mi nistrati o n
F F A
Free fatt y aci d
F P G
Fasti n g plas ma gl uc ose
F PI
Fasti n g plas ma i ns uli n
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 L P
G o o d La b orat or y Practice
G L P 1r
gl uca g o n -li ke pe pti de 1 rece pt or
H b A 1 C
Gl ycate d he m o gl o bi n
H Bs A g
he patitis B s urface a nti ge n
H C C
He pat ocell ular carci n o ma
H C V R N A
He patitis C vir us ge netic material (ie, Ri b o n ucleic aci d)
H C V A b
he patitis C vir us a nti b o d y
H D L
Hi g h de nsit y li p o pr otei n
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 9
A b bre vi ati o n
Ter m
H D L -C
hi g h de nsit y li p o pr otei n c h olester ol
HI P P A
T h e Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
HI V
h u ma n i m m u n o deficie nc y vir us
H O M A -I R
H o me ostatic m o del assess me nt of i ns uli n resista nce
H R
Heart rate
H R Q o L
healt h -relate d q ualit y of life
H R T
h or m o ne re place me nt t hera p y
hs -C R P
Hi g h -se nsiti ve C-reacti ve pr otei n
I B
I n vesti gat or’s br oc h ure
I C5 0
C o nce ntrati o n t hat res ults i n 5 0 % of i n hi bit or y effect
I C D
i nf or me d c o nse nt d oc u me nt
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 L
I nterle u ki n 
I N D
i n vesti gati o nal ne w dr u g a p plicati o n
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 P A L
I nte grate d Pat h t o Arc hitect ural Lice ns ure
I R B
i nstit uti o nal re vie w b oar d
I R T
i nteracti ve res p o nse tec h n ol o g y
I W R
i nteracti ve we b res p o nse
J A K
Ja n us Ki nase 
K 2E D T A
di p otassi u m et h yle ne dia mi netetraacetic aci d
k Pa
kil o pascals
L D L -C
l o w de nsit y li p o pr otei n-c h olester ol
L F T
li ver f u ncti o n test
L L N
l o wer li mit of n or mal
L S
least s q uare
L S M
Least S q uare Mea ns
M A C E
maj or a d verse car di o vasc ular e ve nt
M A T E
m ulti dr u g a n d t o xi n e xtr usi o n pr otei 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
Me d D R A
me dical Dicti o nar y f or Re g ulat or y Acti vities
M E L D -Na
m o del of e n d -sta ge li ver disease i ncl u di n g ser u m s o di u m (i n a d diti o n t o ser u m creati ni ne, 
bilir u bi n, a n d I N R)
MI R N A
Meta b olic I nter ve nti o ns t o Res ol ve N A S H wit h Fi br osis
M M R M
Mi xe d m o del re peate d meas ure
M R
ma g netic res o na nce
M RI
m a g netic res o na nce i ma gi n g
M RI -P D F F
Ma g netic res o na nce i ma gi n g usi n g pr ot o n de nsit y fat fracti o n ac q uisiti o n
msec
millisec o n d
M T D
m a xi m u m t olerate d d ose
N/ A
n ot a p plica ble
N A F L D
n o nalc o h olic fatt y li ver disease
N A S
N A F L D Acti vit y Sc ore
N A S H
N o nalc o h olic steat o he patitis
N G S P
Nati o nal Gl yc o he m o gl o bi n Sta n dar dizati o n Pr o gra m
N O A E L
n o o bser ve d a d verse effect le vel
n o n -H D L
n o n -hi g h de nsit y li p o pr otei n c h olester ol
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 0
A b bre vi ati o n
Ter m
N R S
n u meric rati n g scale
N S AI D s
N o n -ster oi dal a nti-i nfla m mat or y dr u gs 
N Y H A
Ne w  Y or k Heart Ass ociati o n
P A C L
Pr ot oc ol A d mi nistrati ve Clarificati o n Letter 
P C S K 9
pr o pr otei n c o n vertase s u btilisi n/ ke xi n t y pe 9
P D
P har m a c o d yna mic 
P E
p h ysical e xa m
P GI -C
Patie nt Gl o bal I m pressi o n of C ha n ge
P GI -S
Patie nt Gl o bal I m pressi o n of Se verit y
P -g p
P -gl yc o pr otei n
PI
pri nci pal i n vesti gat or
P K
p har mac o ki netics
P K /P D
p har mac o ki netic -p har mac o d y na mic
P N P L A 3
Patati n li ke p h os p h oli pase d o mai n c o ntai ni n g pr o tei n 3
P P A R 
Per o xis o me pr oliferat or -acti vate d rece pt or ga m ma
Pre Q
Pre q ualificati o n visit
P R O
Patie nt Re p orte d O utc o me
Pr o C 3
N -ter mi nal pr o pe pti de of t y pe III pr oc olla ge n
Pr o C 6
C -ter mi nal fra g me nt of α 3 c hai n of pr oc olla ge n t y pe VI
P R O MI S
Patie nt -Re p orte d Meas ure me nt O utc o me I nf or mati o n S yste m
P T
pr ot hr o m bi n ti me
P V C
pre mat ure ve ntric ular c o ntracti o n
Q 1 2 H
E ver y 1 2 h o urs (e g, d osi n g)
Q 8 H
e ver y 8 h o urs
Q D
q ua q ue die ( o nce -a-da y)
Q R S
C o m bi nati o n of Q -, R- a n d S- wa ve o n a n electr ocar di o gra m re prese nti n g ve ntric ular 
de p olarizati o n
Q S P
Q ua ntitati ve s yste ms p har mac ol o g y
Q T c
Q T i nter val c orrecte d f or heart rate 
Q T c F
Fri dericia’s f or m ula, a c orrecti o n f or m ula f or t he Q C i nter val
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 A R S -C O V -2
Se vere ac ute res pirat or y s y n dr o me c or o na vir us 2
S C R 1
Scree n 1 / Visit 1
S C R 2
Scree n 2 / Visit 2
S D
Sta n dar d de viati o n 
S G L T 2
S o di u m -gl uc ose c otra ns p orter 2
S G O T
ser u m gl uta mic o xal o-acetic tra nsa mi nase
S G P T
ser u m gl uta mic p yr u vic tra nsa mi nase
S o A
Sc he d ule of Acti vities
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
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 1
A b bre vi ati o n
Ter m
S SI D
Si n gle s u bject i de ntifier
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
S V R
S ustai ne d vir ol o g y res p o nse
T
Tele p h o ne c o ntact
t1/ 2
ter mi nal half-life
T 2 D M
t y pe 2 dia betes mellit us
T Bili
t otal bilir u bi n
T D D
T otal dail y d ose 
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
T G
tri gl yceri de
TI
t hera pe utic i n de x
T N F
T u m or Necr osis Fact or
T y r 2 8 5 X
T y r osi ne 2 8 5 m utati o n
U L N
u p per li mit of n or mal
U S
U nite d States
V C T E T M
Vi brati o n -C o ntr olle d Tra nsie nt Elast o gra p h y
V L D L
ver y l o w -de nsit y li p o pr otei n
V R S
Ver bal rati n g scale
W B C
w hite bl o o d cell
W O C B P
W o me n of c hil d beari n g p ote ntial
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 2
1 1. R E F E R E N C E S
1
Ye n C L , St o ne SJ, K oli wa d S, Harris C, Farese R V, Jr. T he matic re vie w series: 
gl yc er oli pi ds. D G A T e nz ymes a n d triac y l gl ycer ol bi os ynt hesis. J o ur n al of Li pi d 
Rese arc h . N o v 2 0 0 8; 4 9( 1 1): 2 2 8 3- 2 3 0 1.
2
B u h ma n K K, S mit h SJ, St o ne SJ, et al. D G A T 1 is n ot esse ntial f or i ntesti nal 
triac yl gl ycer ol a bs or pti o n or c h yl o micr o n s ynt hesis. T he J o ur n al of Bi ol o gic al 
C he mistry. J ul 1 2 2 0 0 2; 2 7 7( 2 8): 2 5 4 7 4- 2 5 4 7 9.
3
Cases S, St o ne SJ, Z h o u P, et al. Cl o ni n g of D G A T 2, a sec o n d ma m malia n 
diac y l gl ycer ol ac yltra nsferase, a n d relate d fa mil y me m bers. T he J o ur n al of Bi ol o gic al 
C he mistry . Oct 1 9 2 0 0 1; 2 7 6( 4 2): 3 8 8 7 0- 3 8 8 7 6.
4
Sa g gers o n D. Mal o n yl -C o A, a ke y  si g nali n g m olec ule i n ma m malia n cells. A n n u Rev 
N utr 2 0 0 8, 2 8, 2 5 3 - 7 2.
5
Ki m C W, A d d y  C, K us u n o ki J, et al. Acet yl C o A car b o x ylase i n hi biti o n re d uces he patic 
steat osis b ut ele vate d plas ma tri glyc eri des i n mice a n d h u ma ns: a be dsi de t o be nc h 
i n vesti gati o n. Cell Met a b 2 0 1 7; 2 6( 3): 3 9 4 - 4 0 6.
6
L a Brec q ue D, A b bas Z, A na nia F, et al. N o nalc o h olic fatt y  li ver disease a n d 
n o nalc o h olic steat o he patit is. In: W G O Gl o bal G ui deli nes N A F L D/ N A S H (l o n g 
versi o n). Mil wa u kee, WI: W o rl d G astr oe nter ol o gy Or g a nis ati o n; 2 0 1 2: 2 9 pa ges.
7
Sa n y al AJ, Frie d ma n S L, Mc C ull o u g h AJ, et al. C halle n ges a n d o p p ort u nities i n dr u g 
a n d bi o mar ker de vel o p me nt f or n o nalc o h olic steat o he patitis: fi n di n gs a n d 
rec o m me n dati o ns fr o m a n A merica n Ass ociati o n f or t he St u d y of Li ver Diseases-U. S. 
F o o d a n d Dr u g A d mi nistrati o n J oi nt W or ks h o p. He p at ol o gy 2 0 1 5; 6 1( 4): 1 3 9 2 - 4 0 5.
8
K ha n F, Per u m pail R, W o n g R, et al. A d va nces i n he pat ocell ular c arci n o ma: 
N o nalc o h olic steat o he patitis -relate d he pat ocell ular carci n o ma. W orl d J He p at ol 
2 0 1 5; 7( 1 8): 2 1 5 5 - 6 1.
9
Y o u n ossi Z, K oe ni g A, A b delatif D, et al. Gl o bal e pi de mi ol o g y  of n o nalc o h olic fatt y 
li ver disease – meta -a nal ytic assess me nt of pre vale nce, i ncide nce, a n d o utc o mes.
He p at ol o gy 2 0 1 6; 6 4( 1): 7 3 - 8 4.
1 0
La m bert J E, Ra m os -R o ma n M A, Br o w ni n g J D, et al. I ncrease d de n o v o li p o ge nesis is a 
disti nct c haracteristic of i n di vi d uals wit h n o nalc o h olic fatt y  li ver disease. 
G astr oe nter ol o gy 2 0 1 4; 1 4 6( 3): 7 2 6 - 3 5.
                                                
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 3
1 1
R oc ke y  D C, Cal d well S H, G o o d ma n Z D, et al. Li ver Bi o psy – A A S L D P ositi o n Pa per. 
He p at ol o gy 2 0 0 9; 4 9 ( 3): 1 0 1 7 - 1 0 4 4.
1 2
Ne ws o me P N, Sass o M, Dee ks JJ, et al. Fi br o Sca n base d F A S T ( Fi br o Sca n -A S T) sc ore 
f or t he n o n-i n vasi ve i de ntificati o n of patie nts wit h n o n-alco h olic steat o he patitis ( N A S H) 
a n d si g nifica nt acti vit y a n d fi br osis: a pr os pecti ve deri vati o n a n d gl o bal vali dati o n 
st u d y. L a ncet G astr oe nter ol o gy &  He p at ol o gy 2 0 2 0; 5: 3 6 2 - 7 3.
1 3
Re ge v A, Pal mer M, A vi ga n M I, et al. Re vie w article: c o nse ns us g ui deli nes: best
practices f or detecti o n, assess me nt a n d ma na ge me nt of s us pecte d ac ute dr u g -i n d uce d 
li ver i nj ur y d uri n g cli nical trials i n patie nts wit h n o nalc o h olic steat o he patitis. Ali me nt 
P h ar m ac ol T her 2 0 1 9; 1 - 1 2.
1 4
Klei ner D E, Br u nt E M, Wils o n L A, et al. Ass ociati o n of hist ol o gic disease acti vit y  wit h 
pr o gressi o n of n o nalc o h olic fatt y  li ver disease. J A M A Net w ork O pe n
2 0 1 9; 2( 1 0): e 1 9 1 2 5 6 5.
1 5
Die hl A M, Da y  C. Ca use, pat h o ge nesis, a n d treat me nt of n o nalc o h olic steat o he patitis. N 
E n gl J Me d 2 0 1 7; 3 7 7: 2 0 6 3 - 7 2.
1 6
C halasa ni N, Y o u n ossi Z, L a vi ne J E, et al. T he Dia g n osis a n d Ma na ge me nt of 
N o nalc o h olic Fatt y  Li ver Disease: Practice G ui da nce Fr o m t he A merica n Ass ociati o n 
f or t he St u d y of Li ver Disease. He p at ol o gy 2 0 1 8; 6 7( 1): 3 2 8 - 5 7.
1 7
Berzi g otti A, Ts oc hatzis E, B o ursie r J, et al. E A S L Cli nical Practice G ui deli nes o n n o n-
i n vasi ve tests f or e val uati o n of li ver disease se verit y a n d pr o g n osis – 2 0 2 1 u p date. J 
He p at ol . 2 0 2 1; 7 5( 3): 6 5 9 - 8 9.
1 8
Ba b or T F, Hi g gi ns -Bi d dle J C, Sa n u ders J B, M o nteir o M G. A U DI T – t he alc o h ol use 
dis or de rs i de ntificati o n test – g ui deli nes f or use i n pri mar y  care – 2 n d e diti o n. W orl d 
Healt h Or ga nizati o n; De part me nt of Me ntal Healt h a n d S u bsta nce De pe n de nce – 2 0 0 1.
1 9
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Fatt y Li ver Disease, N o nalc o h olic Steat o he patitis, a n d Ass ociate d Fi br osis. He p at ol o gy
2 0 1 8; 6 8( 1): 3 4 9 - 6 0.
2 0
I n ker L A, Sc h mi d C H, Ti g hi o uart H, et al. Esti mati n g Gl o mer ular Filtrati o n Rate fr o m 
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W o n g V W S,
A da ms L A, de Le di n g he n V, et al. N o ni n vasi ve bi o mar kers i n N A F L D a n d 
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He pat ol o g y  2 0 1 8; 1 5: 4 6 1- 7 8.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3
Fi nal Pr ot oc ol A me n d me nt 1 , 3 0 A u g ust 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 4
2 2
Y o u n ossi et al 2 0 1 9. Assess me nt of patie nt -re p orte d o utc o mes ( P R Os) i n patie nts wit h 
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2 3
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2 4
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Cli n Tr a nsl Me d 2 0 1 6; 5( 1) : 2 3- 3 7.
2 5
Ra y  Ki m W, Bi g gi ns S W, Kre mers W K, et al. H y p o natre mia a n d m ortalit y a m o n g 
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2 6
Gr u n d y S M, St o ne NJ, Baile y A L, et al. 2 0 1 8 A H A/ A C C/ A A C V P R/ A A P A/ A B C/
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c h olester ol: a re p ort of t he A merica n C olle ge of Car di ol o g y / A merica n Heart Ass ociati o n 
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D OI: 1 0. 1 1 6 1/ CI R. 0 0 0 0 0 0 0 0 0 0 0 0 0 6 2 5.
2 7
T h o mas N, R o y  D. A nal ysis of cli nical d ose-res p o nse i n s mall-m olec ule dr u g 
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2 8
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2 9
T h o mas N, S wee ne y  K, S o ma yaji V. Meta -a nal ysis of cli nical d ose res p o nse i n a lar ge 
dr u g de vel o p me nt p ortf oli o. St atistics i n Bi o p h ar m ace utic al Rese arc h 2 0 1 4; 6( 4): 3 0 2 - 1 7.
0 9 0 1 7 7 e 1 9 7f 0ff 7 6\ A p pr o v e d\ A p pr o v e d O n: 3 1- A u g- 2 0 2 1 0 4: 4 7 ( G M T)

SAP_001.pdf: 
P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1
T M F D oc I D: 9 8. 0 3
Pr ot oc ol C 2 5 4 1 0 1 3
A P H A S E 2, R A N D O MI Z E D, D O U B L E- B LI N D, D O U B L E -D U M M Y, P L A C E B O 
C O N T R O L L E D, D O S E R A N GI N G, D O S E -FI N DI N G, P A R A L L E L G R O U P S T U D Y 
T O A S S E S S E F FI C A C Y A N D S A F E T Y O F P F 0 6 8 6 5 5 7 1 ( D G A T 2I) A L O N E A N D 
W H E N C O A D MI NI S T E R E D WI T H P F 0 5 2 2 1 3 0 4 ( A C CI) I N A D U L T 
P A R TI CI P A N T S WI T H BI O P S Y C O N FI R M E D N O N A L C O H O LI C 
S T E A T O H E P A TI TI S A N D FI B R O SI S S T A G E 2 O R 3
St atistic al A n al ysis Pl a n 
( S A P)
Versi o n : 
3
D ate:
0 3 Ma y
2 0 2 4   
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2
T M F D oc I D: 9 8. 0 3
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 .....................................................................................................................6
LI S T O F FI G U R E S ...................................................................................................................6
A P P E N DI C E S ...........................................................................................................................7
1. V E R SI O N HI S T O R Y ............................................................................................................8
2. I N T R O D U C TI O N ...............................................................................................................1 4
2. 1. St u d y  O bjecti ves, E n d p oi nts, a n d Esti ma n ds..........................................................1 4
2. 1. 1. Pri mar y  Esti ma n d(s)...................................................................................1 4
2. 1. 2. Sec o n dar y  Esti ma n d(s)...............................................................................1 5
2. 1. 3. A d diti o nal Esti ma n d(s) ...............................................................................1 6
2. 2. St u d y  Desi g n...........................................................................................................1 8
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S:  D E FI N I TI O N S A N D 
C O N V E N TI O N S ................................................................................................................2 0
3. 1. Pri mar y  E n d p oi nt(s)................................................................................................2 0
3. 2. Sec o n dar y  E n d p oi nt(s)............................................................................................2 2
3. 3. Ot her E n d p oi nt(s) ....................................................................................................2 2
3. 4. Baseli ne Varia bles ...................................................................................................2 5
3. 5. Safet y E n d p oi nts .....................................................................................................2 5
3. 5. 1. A d verse E ve nts ...........................................................................................2 5
3. 5. 2. L a b orat or y Data..........................................................................................2 6
3. 5. 3. Ot her Sta n dar d Safet y ot her t ha n A Es................................ ........................2 9
4. A N A L Y SI S S E T S ( P O P U L A T I O N S F O R A N A L Y SI S)................................................... 3 1
4. 1. Treat me nt Misall ocati o ns................................ ........................................................3 3
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S ....................................................3 3
5. 1. H y p ot heses a n d Decisi o n R ules ..............................................................................3 3
5. 2. Ge neral Met h o ds .....................................................................................................3 4
5. 2. 1. A nal y ses f or Bi nar y E n d p oi nts...................................................................3 4
5. 2. 2. A nal y ses f or C o nti n u o us E n d p oi nts ...........................................................3 6
5. 2. 3. A nal yses f or Cate g orical E n d p oi nts ...........................................................3 7
5. 2. 4. A nal y ses f or Ti me-t o-E ve nt E n d p oi nts ......................................................3 7
5. 3. Met h o ds t o Ma na ge Missi n g Data ..........................................................................3 7
6. A N A L Y S E S A N D S U M M A RI E S ......................................................................................3 9
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3
T M F D oc I D: 9 8. 0 3
6. 1. Pri mar y  E n d p oi nt(s)................................................................................................3 9
6. 1. 1. Pr o p orti o n of partici pa nts ac hie vi n g ce ntrall y a dj u dicate d res ol uti o n 
of N A S H wit h o ut w orse ni n g of fi br osis or i m pr o ve me nt i n fi br osis b y  
≥1 sta ge wit h o ut w orse ni n g of N A S H, or b ot h, at Wee k 4 8 ...........................3 9
6. 1. 1. 1. Mai n A nal ys is ...........................................................................3 9
6. 1. 1. 2. Se nsiti vit y / S u p ple me ntar y A nal yses .........................................4 0
6. 2. Sec o n dar y  E n d p oi nt(s)............................................................................................4 1
6. 2. 1. Pr o p orti o n of partici pa nts ac hie vi n g ce ntrall y a dj u dicate d res ol uti o n 
of N A S H wit h o ut w orse ni n g of fi br osis, at Wee k 4 8...................................... 4 1
6. 2. 1. 1. Mai n A nal ys is ...........................................................................4 1
6. 2. 1. 2. Se nsiti vit y / S u p ple me ntar y A nal ysis .........................................4 2
6. 2. 2. Pr o p orti o n of partici pa nts ac hie vi n g ce ntrall y a dj u dicate d 
i m pr o ve me nt i n fi br osis b y ≥1 sta ge wit h o ut w orse ni n g of N A S H, at 
Wee k 4 8
...........................................................................................................4 2
6. 2. 2. 1. Mai n A nal ys is ...........................................................................4 2
6. 2. 2. 2. Se nsiti vit y / S u p ple me ntar y A nal ysis .........................................4 3
6. 2. 3. Pr o p orti o n of partici pa nts ac hie vi n g ce ntrall y a dj u dicate d 
i m pr o ve me nt i n fi br osis b y ≥2 sta ges wit h o ut w orse ni n g of N A S H, at 
Wee k 4 8
...........................................................................................................4 3
6. 2. 3. 1. Mai n A nal ys is ...........................................................................4 3
6. 2. 3. 2. Se nsiti vit y / S u p ple me ntar y A nal ysis .........................................4 3
6. 2. 4. Pr o p orti o n of partici pa nts ac hie vi n g ce ntrall y a dj u dicate d 
i m pr o ve me nt of ≥2 p oi nts i n T otal N A F L D Acti vit y  Sc ore ( N A S) 
wit h o ut w orse ni n g of fi br osis, at Wee k 4 8................................ ......................4 4
6. 2. 4. 1. Mai n A nal ys is ...........................................................................4 4
6. 2. 4. 2. Se nsiti vit y / S u p ple me ntar y A nal ysis .........................................4 4
6. 2. 5. Perce nta ge c ha n ge fr o m baseli ne i n li ver fat (assesse d via M RI -
P D F F) at Wee k 4 8 ........................................................................................... 4 4
6. 2. 5. 1. Mai n A nal ys is ...........................................................................4 4
6. 2. 5. 2. Se nsiti vit y / S u p ple me ntar y A nal ysis .........................................4 5
6. 3. Ot her E n d p oi nt(s) ....................................................................................................4 6
6. 3. 1. Pr o p orti o n of partici pa nts ac hie vi n g i m pr o ve me nt i n fi br osis b y  ≥1 
sta ge i n de pe n de nt of c ha n ges i n N A S, base d o n assess me nt b y s p o ns or-
i de ntifie d ce ntral pat h ol o gist(s), at Wee k 4 8 c o m pare d t o baseli ne ................4 6
6. 3. 1. 1. Mai n A nal ys is ...........................................................................4 6
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4
T M F D oc I D: 9 8. 0 3
6. 3. 2. Pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of N A S H wit h o ut 
w orse ni n g of fi br osis a n d i m pr o ve me nt i n fi br osis b y  ≥1 sta ge wit h o ut 
w orse ni n g of N A S H, base d o n assess me nt b y s p o ns or -i de ntifie d ce ntral 
pat h ol o gist(s), at Wee k 4 8 c o m pare d t o baseli ne ............................................4 6
6. 3. 2. 1. Mai n A nal ys is ...........................................................................4 6
6. 3. 3. Pr o p orti o n of partici pa nts wit h pr o gressi o n of fi br osis b y  ≥1 sta ge 
( defi ne d as a n i ncrease of at least 1 sta ge i n t he Br u nt-Klei ner scale 
c o m pare d t o baseli ne) i n de pe n de nt of c ha n ges i n N A S, at Wee k 4 8.............. 4 7
6. 3. 3. 1. Mai n A nal ys is ...........................................................................4 7
6. 3. 4. Pr o p orti o n of partici pa nts wit h pr o gressi o n of fi br osis b y  ≥1 sta ge 
a n d w orse ni n g of ≥2 p oi nts i n T otal N A S at Wee k 4 8 ....................................4 8
6. 3. 4. 1. Mai n A nal ys is ...........................................................................4 8
6. 3. 5. Pr o p orti o n of partici pa nts wit h W orse ni n g of ≥2 p oi nts i n T otal N A S 
( defi ne d as a n i ncrease of at least 2 p oi nts i n T otal N A S c o m pare d t o 
baseli ne) i n de pe n de nt of c ha n ges i n fi br osis at Wee k 4 8................................ 4 9
6. 3. 5. 1. Mai n A nal ys is ...........................................................................4 9
6. 3. 6. Ot her C o nti n u o us Tertiar y / E x pl orat or y E n d p oi nts ....................................5 0
6. 3. 6. 1. Mai n A nal ys is ...........................................................................5 1
6. 3. 7. E ve nt -base d Tertiar y / E x pl orat or y E n d p oi nts.............................................5 2
6. 3. 7. 1. Mai n A nal ys is ...........................................................................5 2
6. 3. 8. P har mac o ki netic ( P K) E n d p oi nts ............................................................... 5 3
6. 3. 8. 1. Mai n A nal ys is ...........................................................................5 3
6. 4. S u bset A nal y ses.......................................................................................................5 4
6. 5. Baseli ne a n d Ot her S u m maries a n d A nal ys es .........................................................5 4
6. 5. 1. Baseli ne S u m maries ....................................................................................5 4
6. 5. 2. St u d y  C o n d uct a n d Partici pa nt Dis p ositi o n................................................5 4
6. 5. 3. St u d y  Treat me nt E x p os ure .........................................................................5 4
6. 5. 4. Me dical Hist or y ..........................................................................................5 4
6. 5. 5. C o nc o mita nt Me dicati o ns a n d N o n dr u g Treat me nts.................................. 5 5
6. 6. Safet y S u m maries a n d A nal yses .............................................................................5 5
6. 6. 1. A d verse E ve nts ...........................................................................................5 5
6. 6. 2. L a b orat or y Data..........................................................................................5 6
6. 6. 3. Vital Si g ns ..................................................................................................5 6
6. 6. 4. Electr ocar di o gra ms..................................................................................... 5 6
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5
T M F D oc I D: 9 8. 0 3
7. I N T E RI M A N A L Y S E S .......................................................................................................5 6
7. 1. I ntr o d ucti o n .............................................................................................................5 6
7. 2. I nteri m A nal ys es a n d S u m maries ............................................................................5 7
8. R E F E R E N C E S ....................................................................................................................5 8
9. A P P E N DI C E S .....................................................................................................................5 9
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6
T M F D oc I D: 9 8. 0 3
LI S T O F T A B L E S
Ta ble 1.
S u m mar y  of C ha n ges.................................................................................. 8
Ta ble 2.
Bi o ps y  res ults t o be re p orte d f or eac h partici pa nt .................................... 2 1
Ta ble 3.
Cli nical L a b orat or y Para meters 
............................................... 2 6
Ta ble 4.
La b orat or y  Assess me nts ( n o n-fasted) ....................................................... 2 8
Ta ble 5.
La b orat or y  Assess me nts (faste d)..............................................................2 8
Ta ble 6.
Vital Si g ns t o be M o nit ore d ...................................................................... 2 9
Ta ble 7.
E C G Cate g ories ........................................................................................ 2 9
Ta bl e 8.
A nal y sis Set Defi niti o ns ........................................................................... 3 1
Ta ble 9.
S u m mar y  of A nalys is Met h o ds ................................................................ 3 3
Ta ble 1 0.
Ha n dli n g n o n -e val ua ble hist ol o gical c ha n ge -fr o m-baseli ne data ............. 3 8
LI S T O F FI G U R E S
Fi g ure 1.
St u d y  Desi g n.............................................................................................1 8
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7
T M F D oc I D: 9 8. 0 3
A P P E N DI C E S
A p pe n di x 1. S u m mar y  of Efficac y A nalys es ........................................................................... 5 9
A p pe n di x 2. Data Deri vati o n Details ....................................................................................... 6 7
A p pe n di x 2. 1. Defi niti o n a n d Use of Visit Wi n d o ws i n Re p orti n g ......................................... 6 7
A p pe n di x 2. 2. E n d p oi nt Deri vati o ns ....................................................................................... 7 0
A p pe n di x 2. 2. 1. % L i ver Fat usi n g M RI-P D F F a n d 
................................................. 7 0
A p pe n di x 2. 2. 2. M RI -deri ve d L i ver V ol u me .......................................................................... 7 1
A p pe n di x 2. 2. 3. M RI -deri ve d 
........................................................................ 7 1
A p pe n di x 2. 2. 4. Fasti n g Plas ma Gl uc ose a n d Fasti n g Plas ma I ns uli n ( T 2 D M 
Partici pa nts O nl y ) ..................................................................................... 7 1
A p pe n di x 2. 2. 5. H o me ostatic M o del Assess me nt f or I ns uli n Resista nce ( T 2 D M 
Partici pa nts O nl y ) ..................................................................................... 7 1
A p pe n di x 2. 3. Data Deri vati o n f or Patie nt Re p orte d O utc o mes ............................................. 7 2
A p pe n di x 2. 3. 1. N A S H -C H E C K ............................................................................................. 7 2
A p pe n di x 2. 3. 2. P R O MI S Fati g ue C ust o m 9 -Ite m Versi o n .................................................... 7 6
A p pe n di x 2. 3. 3. N A S H S y m pt o m Diar y ................................................................................. 7 6
A p pe n di x 2. 4. Data Deri vati o n f or N o n Sta n dar d Safet y E n d p oi nts ....................................... 7 7
A p pe n di x 2. 4. 1. E L F Test ........................................................................................................ 7 7
A p pe n di x 2. 4. 2. M E L D sc ore .................................................................................................. 7 8
A p pe n di x 2. 4. 3. Esti mate d Gl o mer ular Filtrati o n Rate ........................................................... 7 9
A p pe n di x 2. 4. 4. A U DI T T otal Sc ore ....................................................................................... 7 9
A p pe n di x 2. 5. Defi niti o n of Pr ot oc ol De viati o ns T hat Relate t o Stati stical 
A nal y ses/ P o p ulati o ns................................................................................ 8 1
A p pe n di x 2. 5. 1. C o m plia nce ................................................................................................... 8 1
A p pe n di x 3. Data Set Descri pti o ns ..........................................................................................8 1
A p pe n di x 4. Statistical Met h o d ol o g y  Details..........................................................................8 1
A p pe n di x 5. L ist of A b bre viati o ns...........................................................................................8 2
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 8
T M F D oc I D: 9 8. 0 3
1. V E R SI O N HI S T O R Y
T a ble 1 .
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
Versi o n 3/
0 3 Ma y  2 0 2 4
N/ A
Clarificati o n of 
a nal ys es or 
a d diti o nal 
details a d de d 
f oll o wi n g Draft 
T a ble R e vie ws
( D T Rs/ B D Rs)
a n d pri or t o 
Data base 
Release
C ha n ge d ‘ partici pa nts’ t o ‘ patie nts’ i n 
defi niti o n of esti ma n ds w he n descri bi n g 
t he wi der patie nt p o p ulati o n a n d 
clarifie d disease c o nfir mati o n will be 
base d o n o n eli gi bilit y  assess me nt of 
S C R 2 bi o ps y  ( Secti o ns 2. 1. 1, 2. 1. 2, 
2. 1 3).
A d de d clarificati o n h o w t o ha n dle 
e n d p oi nt deri vati o n f or partici pa nts w h o 
wit h dra w treat me nt f or ot her reas o ns b ut 
ha ve e val ua ble bi o ps y data at 
wit h dr a wal or Wee k 4 8 a n d partici pa nts 
wit h n o Wee k 4 8 bi o ps y  data ( Secti o ns 
2. 1. 2, 2. 1. 3)
A d de d e x pl orat or y  Esti ma n ds 3. 2 a n d 
3. 3, a n d t heir c orres p o n di n g e n d p oi nt 
defi niti o n a n d a nal ys is ( Secti o ns 2. 1. 3, 
3. 3, 6. 3, A p pe n di x 1)
A d de d t he dr u g na mes of t he 
i n vesti gati o nal pr o d ucts a n d t he 
c orres p o n di n g t otal daily d ose of BI D 
d ose ar ms ( Secti o n 2. 2)
A d de d clarificati o n f or pri mar y  e n d p oi nt 
deri vati o n ( Secti o n 3. 1)
A d de d clarificati o n f or sec o n dar y  
e n d p oi nts deri vati o n ( Secti o n 3. 2)
A d de d clarificati o n f or e x pl orat or y 
e n d p oi nts ( Secti o n 3. 3)
A d de d all o wa ble a nal ys is wi n d o ws f or 
Fi br o Sca n ® a n d la b res ults ( Secti o n 3. 4, 
A p pe n di x 4. 1)
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 9
T M F D oc I D: 9 8. 0 3
T a ble 1.
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
A d de d Fla g Le vel cate g ories f or e G F R 
i n Ta ble 3 Cli ncial La b orat or y 
Para meters  
 ( Secti o n 3. 5. 2)
Re m o ve d deri ve d n o n- H D L C i n 
he mat ol o g y  a nalyt es as direct V L D L is 
bei n g c ollecte d i nstea d a n d a d de d ot her 
Bi o mar kers ( or c o m p o ne nts) t hat s h o ul d 
be base d o n sa m ples c ollecte d i n a
faste d state( Secti o n 3. 5. 2)
A d de d cate g ories f or heart rate i n E C G 
criteria of cli nical c o n cer n ( Secti o n 
3. 5. 3)
U p date d missi n g data ha n dli n g f or 
h y p ot hetical esti ma n ds ( Secti o ns 4, 5. 3, 
A p pe n di x 1)
C ha n ge d ‘ CI’ t o ‘cre di ble i nter val’ f or 
res ults o btai ne d fr o m Ba yesia n E ma x 
m o del ( Secti o ns 5. 2. 1, 5. 2. 2, 6. 1. 1, 
6. 2. 1, 6. 2. 2, 6. 2. 3, 6. 2. 4, 6. 3. 3 , 6. 3. 5) 
C ha n ge d ' 9 5 %’ t o 9 0 % CIs/cre di ble 
i nter vals e xce pt f or t he 3-tier a p pr oac h 
f or t he a nal ysis of a d verse e ve nts 
( Secti o ns 5. 2. 1, 5. 2. 2, 6. 1. 1, 6. 2. 1 t o 
6. 2. 5, 6. 3. 1 t o 6. 3. 6)
A d de d clarificati o n t hat T otal Dail y  
D ose will be use d i n Ba yesia n E ma x
m o deli n g ( Secti o n 5. 2. 1)
A d de d esti mati o n of ris k differe nce i n 
treat me nt c o m paris o ns ( Secti o ns 5. 2. 1, 
6. 1. 1, 6. 2. 1 t o 6. 2. 4, 6. 3. 1 t o 6. 3. 5)
A d de d s pecificati o n o n Ba y esia n E ma x 
m o deli n g f or li ver fat ( Secti o ns 5. 2. 2, 
6. 2. 5)
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 0
T M F D oc I D: 9 8. 0 3
T a ble 1 .
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
A d de d i nstr ucti o ns o n h o w t o ha n dle 
n o n -e val ua ble hist ol o gical c ha n ge fr o m 
baseli ne data ( Secti o n 5. 3)
A d de d s pecificati o ns f or s u p ple me ntar y  
a nal ys es of t he pri mar y e n d p oi nt 
( Secti o n 6. 1. 1. 2)
A d de d pri or esti mates f or t he Ba y esia n 
E ma x m o deli n g of li ver fat ( Secti o n 
6. 2. 5)
A d de d s pecificati o ns f or t he a nal ys es of 
ot her c o nti n u o us tertiar y  e n d p oi nts 
( Secti o n 6. 3. 6)
A d de d a criteri o n f or e xcl usi o n of 
sa m ples i n P K s u m maries ( Secti o n 
6. 3. 8)
Re m o ve d te xt descri bi n g t he s u m mar y  
of partici pa nt dis p ositi o n b y  pre-defi ne d 
me dical hist or y  ter ms ( Secti o n 6. 5. 2)
I ncrease d t he n u m ber of cate g ories f or 
w hic h t he n u m ber of partici pa nts 
differi n g n u m bers wit h pres pecifi e d 
me dical hist ories will be s u m marize d
( Secti o n 6. 5. 4)
A d de d s pecificati o n f or i n di vi d ual pl ots 
t o be pr o d uce d f or selecte d la b orat or y 
para meters ( Secti o n 6. 6. 2)
A d de d refere nces t o esti ma n ds a n d 
a d diti o nal e x pl orat or y e n d p oi nts t o t he 
S u m mar y  of Effiac y A nal yses 
( A p pe n di x 1)
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 1
T M F D oc I D: 9 8. 0 3
T a ble 1 .
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
A d de d clarificati o ns i n a nal y sis visit 
wi n d o ws ( A p pe n di x 2. 1)
A d de d clarificati o n f or % li ver fat 
deri vati o n ( A p pe n di x 2. 2. 1)
A d de d s pecificati o n f or t he deri vati o n of 
N A S H S y m pt o m Diar y  Sc ore ( Secti o n 
2. 3. 3)
A d de d s pecificati o n f or t he deri vati o n of 
M E L D sc ore ( A p pe n di x 2. 4. 2)
A d de d s pecificati o n f or t he deri vati o n of 
A U DI T T otal Sc ore ( A p pe n di x 2. 4. 4)
Versi o n 2/
0 6 A pr 2 0 2 2
A me n d me nt 1
3 0 A u g ust 2 0 2 1
Clarificati o n of 
a nal ys es or 
a d diti o nal 
details a d de d t o 
pri or versi o n 
a n d u p dates t o 
reflect Pr ot oc ol 
A me n d me nt 1
U p date d t he defi niti o n of esti ma n ds b y  
re m o vi n g t he p hrase ”t he st u d y 
p o p ul ati o n of r a n d o mize d a n d 
tre ate d” i n t he descri pti o n of t he tar get 
i nfere ntial p o p ulati o n ( Secti o ns 2. 1. 1, 
2. 1. 2, 2. 1. 3, 3. 1)
T hr o u g h o ut t he d oc u me nt, e ns ure d t hat 
t he ter m p artici p a nts h as bee n use d 
w he n referri n g t o s u bjects c o nse nte d 
i nt o t his st u d y
A d de d e x pl orat or y  esti ma n d t o assess 
e n d p oi nts relate d t o w orse ni n g i n li ver 
bi o ps y  c o m p o ne nts as well as ca pt ure 
q ualitati ve assess me nt o n eac h of 4 
d o mai ns of hist ol o gical assess me nts          
( Secti o ns 2. 1. 3, 6. 3. 1, 6. 3. 2, A p pe n di x 
1)
A p plie d c ha n ges ma de i n Pr ot oc ol 
A me n d me nt 1 relate d t o t he 
disc o nti n ue d e val uati o n of 2 ar ms wit h 
a d mi nistrati o n of D G A T 2i al o ne ( 1 5 0 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 2
T M F D oc I D: 9 8. 0 3
T a ble 1.
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
m g Q D a n d 3 0 0 m g Q D) ( Secti o ns 2. 2, 
4, 4. 1, 5. 1, 5. 2, 5. 2. 1)
U p date d t he h y p ot hetical esti ma n d 
defi niti o n t o i ncl u de i nf or mati o n o n 
ce ns ore d dat a ( Secti o ns 2. 1. 2, 2. 1. 3, 4, 
A p pe n di x 1)
A d de d a d diti o nal details a b o ut t he 
defi niti o n a n d deri vati o n of t he pri mar y  
e n d p oi nt, a n d bi o ps y assess me nts
( Secti o n 3. 1)
A d de d 
 a n d 
 as 
e x pl orat or y e n d p oi nts ( Secti o n 3. 3, 
6. 3. 3, A p pe n di x 2. 2. 1, A p pe n di x 2. 2. 3)
A d de d deri vati o n of baseli ne vital si g ns 
( Secti o n 3. 4)
A d de d clarificati o n o n t he defi niti o n of 
treat me nt e mer ge nt a d verse e ve nts 
( Secti o n 3. 5. 1)
A d de d clarificati o n o n la b orat or y  
para meters ( Secti o n 3. 5. 2 a n d A p pe n di x 
2. 4)
U p date d t he f or m ula f or Q Tc F, 
defi niti o n of c ha n ges i n bac k gr o u n d 
me dicati o ns of s pecial i nterest , data t o 
be s u m marize d f or A U DI T, a n d a nal y sis 
of DI LI ( Secti o n 3. 5. 3)
A d de d e xcl usi o n of partici pa nts fr o m 
E val ua ble a n d Safet y A nal ysis Sets f or 
iss ues relate d t o q ualit y of pr ot oc ol 
e xec uti o n lea di n g t o a S p o ns or decisi o n 
t o pre mat urely wit h dra w ra n d o mize d 
partici pa nts a n d cl ose site(s) ( Secti o n 4)
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 3
T M F D oc I D: 9 8. 0 3
T a ble 1 .
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
U p date d t he defi niti o n of E nr olle d, 
E val ua ble a n d Safet y Set t o e x plai n h o w 
partici pa nts ori gi nall y  ra n d o mize d t o t he
2 D G A T 2i Q D gr o u ps will be ha n dle d
( Secti o n 4)
A d de d defi ne d a nal ys is data set f or 
bi o ps y -base d c o m p osite esti ma n ds 
relate d t o w orse ni n g i n li ver bi o ps y 
c o m p o ne nts a n d u p date d t he defi niti o n 
of defi ne d a nal ys is data set f or 
h y p ot hetical esti ma n ds ( Secti o n 4)
C orrecte d t he deri vati o n of perce nt 
c ha n ge fr o m baseli ne i n t he a nalys is of 
l o g-tra nsf or me d c o nti n u o us e n d p oi nts t o
first deter mi ne t he relati ve c ha n ge fr o m 
baseli ne ( Secti o n 5. 2. 2, 6. 2. 5. 1, 6. 3. 3. 1)
U p date d t he descri pti o n of M M R M 
a nal ys is ( Secti o ns 5. 2. 2, 6. 3. 3. 1)
A d de d deri vati o n of date of birt h 
( Secti o n 5. 3)
A d de d s u p ple me ntar y  a nal yses t o assess 
q ualit y  of bi o ps y assess me nts ( 6. 1. 1. 2)
U p date d t he list of e ve nt -base d 
e x pl orat or y e n d p oi nts t hat will be 
s u m marize d base d o n t he pre-s pecifie d 
e ve nts u n der g oi n g a dj u dicati o n ( Secti o n 
6. 3. 4. 1)
Re m o ve d s u bset a nal ys is o n L F T 
e n d p oi nts i n partici pa nts wit h 
A L T > U L N at baseli ne ( Secti o n 6. 4)
A d de d de m o gra p hic a n d baseli ne 
c haracteristics varia bles t o be 
s u m marize d ( Secti o n 6. 5. 1)
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 4
T M F D oc I D: 9 8. 0 3
T a ble 1 .
S u m m ar y of C h a n ges
Versi o n /
D ate
Ass oci ate d
Pr ot oc ol 
A m e n d me nt
R ati o n ale
S pecific C h a n ges
U p date d descr i pti o n of baseli ne a n d 
ot her s u m maries ( Secti o n 6. 5)
C ha n ge d t he perce nta ges of ra n d o mize d 
partici pa nts t o be use d t o tri g ger t he 
i nteri m a nal yses ( Secti o n 7. 1)
Clarifie d data i ncl usi o n a n d ha n dli n g of  
i nterc urre nt e ve nts a n d missi n g data i n 
efficac y a nalys es ( A p pe n di x 1)
U p date d defi niti o n a n d use of visit 
wi n d o ws ( A p pe n di x 2. 1)
I nc or p orate d a d diti o nal clarificati o n t o 
e n d p oi nt deri vati o ns ( A p pe n di x 2. 2)
Versi o n 1 /
3 1 Mar
2 0 2 0
Ori gi nal 
2 2 Ja n 2 0 2 0
N/ A
N/ A
2. I N T R O D U C TI O N
T his Statistical A nal y sis Pla n (S A P ) pr o vi des t he detaile d met h o d ol o g y f or s u m mar y a n d 
statistical a nal yses of t he data c ollecte d i n St u d y C 2 5 4 1 0 1 3 ( MIR N A) .  T his d oc u me nt ma y 
m o dif y  t he pla ns o utli ne d i n t he pr ot oc ol; h o we ver, a ny maj or m o dificati o ns of t he pri mar y 
e n d p oi nt defi niti o n or its a nal ys is will als o be reflecte d i n a pr ot oc ol a me n d me nt.
2. 1. St u d y O bjecti ves , E n d p oi nts, a n d Esti m a n ds
2. 1. 1. Pri m ar y Esti m a n d (s)

Esti m a n d 1. 1 : Usi n g a c o m p osite esti m a n d str ate gy i n patie nts wit h bi o psy -c o nfir me d 
N A S H a n d fi br osis o n eli gi bilit y assess me nt of S C R 2 bi o ps y , esti m ate t he tre at me nt 
effect of D iac yl gl ycer ol ac yltra nsferase 2 i n hi bit or (D G A T 2i ) d oses a d mi nistere d al o ne 
a n d c o a d mi nistr a ti o n of D G A T 2i + A cet yl -C o A car b o x y lase i n hi bit or (A C Ci ) rel ative t o 
pl ace b o, a n d c o a d mi nistr ati o n of D G A T 2i + A C Ci, rel ative t o D G A T 2i al o ne, i n ter ms of 
t he pr o p orti o n of ‘cli nic al res p o n ders’, defi ne d as p artici p a nts ac hievi n g ce ntr ally 
a dj u dic ate d: res ol uti o n of N o nalc o h olic steat o he patitis (N A S H ) wit h o ut w orse ni n g of 
fi br osis or i m pr ove me nt i n fi br osis by ≥1 st a ge wit h o ut w orse ni n g of N A S H, or b ot h, at 
Week 4 8 a n d tre ati n g all c ases of wit h dr a w al fr o m tre at me nt f or l ack of effic acy or 
t oler ati o n as n o n- res p o n ders.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 5
T M F D oc I D: 9 8. 0 3
T he mai n i nterc urre nt e ve nt of wit h dra wal fr o m treat me nt f or lac k of efficac y or t olerati o n is 
a d dresse d as part of t he res p o n der v aria ble defi niti o n, t heref ore t his is n ot ha n dle d se paratel y.
Partici pa nt s w h o wit h dra w fr o m treat me nt f or ot her reas o ns b ut ha ve e val ua ble bi o ps y  data at 
wit h dra wal or at Wee k 4 8 will ha ve t heir bi o ps y  data assesse d t o deter mi ne w het her t he y are 
res p o n ders or n ot. Partici pa nt s wit h n o Wee k 4 8 bi o ps y data will be c o nsi dere d t o be n o n -
res p o n ders. All treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba y esia n d ose -
res p o nse ( D R) a n d/ or e x p os ure- res p o nse ( E R) m o dels wit h a l o git tra nsf or mati o n, or l o gistic 
re gressi o n m o dels.
2. 1. 2. Sec o n d ar y Esti m a n d (s)
Sec o n dar y  esti ma n ds to assess sec o n dar y  o bjecti ves will be:

Esti m a n d 2. 1 : Usi n g a c o m p osite esti m a n d str ate gy, i n patie nts wit h bi o psy- c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as assesse d by t he s p o ns or -
i de ntifie d ce ntr al p at h ol o gist(s), esti m ate t he tre at me nt effect of D G A T 2i d oses 
a d mi nistere d al o ne a n d c o a d mi nistr ati o n of D G A T 2i + A C Ci rel ative t o pl ace b o, a n d 
c o a d mi nistr ati o n of D G A T 2i + A C Ci, rel ative t o D G A T 2i al o ne, i n t er ms of t he 
pr o p orti o n of ‘cli nic al res p o n ders’, defi ne d as p artici p a nts ac hievi n g ce ntr ally 
a dj u dic ate d res ol uti o n of N A S H wit h o ut w orse ni n g of fi br osis, at W eek 4 8 a n d tre ati n g 
all c ases of wit h dr a w al fr o m tre at me nt f or l ack of effic acy or t oler ati o n as n o n -
res p o n ders. Partici pa nts w h o wit h dra w fr o m treat me nt f or ot her reas o ns b ut ha ve 
e val ua ble bi o ps y data at wit h dra wal or at Wee k 4 8 will ha ve t heir bi o ps y  data assesse d t o 
deter mi ne w het her t he y are res p o n ders or n ot. Partici pa nts wit h n o Wee k 4 8 bi o ps y  data 
will be c o nsi dere d t o be n o n -res p o n ders. All tre at me nt effect c o ntr asts will be o bt ai ne d 
t hr o u g h fitti n g t he B ayesi a n d ose-res p o nse a n d/ or ex p os ure-res p o nse m o dels wit h a l o git 
tr a nsf or m ati o n, or l o gistic re gressi o n m o dels.

Esti m a n d 2. 2 : Usi n g a c o m p o site esti m a n d str ate gy, i n patie nts wit h bi o psy- c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as assesse d by t he s p o ns or -
i de ntifie d ce ntr al p at h ol o gist(s), esti m ate t he tre at me nt effect of D G A T 2i d oses 
a d mi nistere d al o ne a n d c o a d mi n istr ati o n of D G A T 2i + A C Ci rel ative t o pl ace b o, a n d 
c o a d mi nistr ati o n of D G A T 2i + A C Ci, rel ative t o D G A T 2i al o ne, i n ter ms of t he 
pr o p orti o n of ‘cli nic al res p o n ders’, defi ne d as p artici p a nts ac hievi n g ce ntr ally 
a dj u dic ate d i m pr ove me nt i n fi br osis by ≥1 st a g e wit h o ut w orse ni n g of N A S H, at Week 4 8 
a n d tre ati n g all c ases of wit h dr a w al fr o m tre at me nt f or l ack of effic acy or t oler ati o n as 
n o n -res p o n ders. Partici pa nts w h o wit h dra w fr o m treat me nt f or ot her reas o ns b ut ha ve 
e val ua ble bi o ps y data at wit h dra wal or at Wee k 4 8 will ha ve t heir bi o ps y  data assesse d t o 
deter mi ne w het her t he y are res p o n ders or n ot. Partici pa nts wit h n o Wee k 4 8 bi o ps y  data 
will be c o nsi dere d t o be n o n -res p o n ders. All tre at me nt effect c o ntr asts will be o bt ai ne d 
t hr o u g h fitti n g t he B ayesi a n d ose-res p o nse a n d/ or ex p os ure- res p o nse m o dels wit h a l o git 
tr a nsf or m ati o n, or l o gistic re gressi o n m o dels.

Esti m a n d 2. 3 : Usi n g a c o m p osite esti m a n d str ate gy, i n patie nts wit h bi o psy- c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as asses se d by t he s p o ns or-
i de ntifie d ce ntr al p at h ol o gist(s), esti m ate t he tre at me nt effect of D G A T 2i d oses 
a d mi nistere d al o ne a n d c o a d mi nistr ati o n of D G A T 2i + A C Ci rel ative t o pl ace b o, a n d 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 6
T M F D oc I D: 9 8. 0 3
c o a d mi nistr ati o n of D G A T 2i + A C Ci, rel ative t o D G A T 2i al o ne, i n ter ms of t he 
pr o p orti o n of ‘cli nic al res p o n ders’, defi ne d as p artici p a nts ac hievi n g ce ntr ally 
a dj u dic ate d i m pr ove me nt i n fi br osis by ≥2 st a ges wit h o ut w orse ni n g of N A S H, at Week 
4 8 a n d tre ati n g all c ases of wit h dr a w al fr o m tre at me nt f or l ack of effic acy or t oler ati o n 
as n o n -res p o n ders. Partici pa nts w h o wit h dra w fr o m treat me nt f or ot her reas o ns b ut ha ve 
e val ua ble bi o ps y data at wit h dra wal or at Wee k 4 8 will ha ve t heir bi o ps y  data assesse d t o 
deter mi ne w het her t he y  are res p o n ders or n ot. Partici pa nts wit h n o Wee k 4 8 bio ps y  data 
will be c o nsi dere d t o be n o n -res p o n ders. All tre at me nt effect c o ntr asts will be o bt ai ne d 
t hr o u g h fitti n g t he B ayesi a n d ose-res p o nse a n d/ or ex p os ure-res p o nse m o dels wit h a l o git 
tr a nsf or m ati o n, or l o gistic re gressi o n m o dels.

Esti m a n d 2. 4 : Usi n g a c o m p osite esti m a n d str ate gy, i n patie nts wit h bi o psy- c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as assesse d by t he s p o ns or -
i de ntifie d ce ntr al p at h ol o gist(s), esti m ate t he tre at me nt effect of D G A T 2i d oses 
a d mi nistere d al o ne a n d c o a d mi nistr ati o n of D G A T 2i + A C Ci rel ative t o pl ace b o, a n d 
c o a d mi nistr ati o n of D G A T 2i + A C Ci, rel ative t o D G A T 2i al o ne, i n ter ms of t he 
pr o p orti o n of ‘cli nic al res p o n ders’, defi ne d as p artici p a nts ac hievi n g ce ntr ally 
a dj u dic ate d i m pr ove me nt of ≥2 p oi nts i n Tot al N o nalc o h olic fatt y  li ver disease (N A F L D )
Activity Sc ore ( N A S) wit h o ut w orse ni n g of fi br osis at W eek 4 8 a n d tre ati n g all c ases of 
wit h dr a w al fr o m tre at me nt f or l ack of effic acy or t oler ati o n as n o n -res p o n ders. 
Partici pa nts w h o wit h dra w fr o m treat me nt f or ot her reas o ns b ut ha ve e val ua ble bi o ps y 
data at wit h dra wal or at Wee k 4 8 will ha ve t heir bi o ps y  data assesse d t o deter mi ne 
w het her t he y  are res p o n ders or n ot. Partici pa nts wit h n o Wee k 4 8 bi o ps y data will be 
c o nsi dere d t o be n o n -res p o n ders. All tre at me nt effect c o ntr asts will be o bt ai ne d t hr o u g h 
fitti n g t he B ayesi a n d ose-res p o nse a n d/ or ex p os ure-res p o nse m o dels wit h a l o git 
tr a nsf or m ati o n, or l o gistic re gressi o n m o dels.

Esti m a n d 2. 5 : Usi n g a hy p ot hetic al esti m a n d str ate gy, i n patie nts wit h bi o psy- c o nfirme d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as assesse d by t he s p o ns or -
i de ntifie d ce ntr al p at h ol o gist(s), esti m ate t he tre at me nt effect of D G A T 2i d oses 
a d mi nistere d al o ne a n d c o a d mi nistr ati o n of D G A T 2i + A C Ci rel ative t o pl ace b o, a n d 
c oa d mi nistr ati o n of D G A T 2i + A C Ci, rel ative t o D G A T 2i al o ne, i n ter ms of p o p ul ati o n 
level aver a ge perce nt a ge c h a n ge fr o m b aseli ne i n liver f at ( assesse d vi a M a g netic 
res o na nce i ma gi n g usi n g pr ot o n de nsit y fat fracti o n ac q uisiti o n (M RI -P D F F )) at Week 4 8 , 
ass u mi n g all p artici p a nts h a d re m ai ne d i n t he tri al a n d receive d tre at me nt as pl a n ne d 
wit h o ut wit h dr a w al u p t o 4 8 weeks. E n d p oi nt d at a c ollecte d after tre at me nt wit h dr a w al 
will be ce ns ore d. All tre at me nt effect c o ntr asts will be o bt ai ne d t hr o u g h fitti n g t he 
B ayesi a n d ose -res p o nse a n d/ or ex p os ure-res p o nse m o dels, or A nal ys is of c o varia nce
(A N C O V A ) m o dels.
2. 1. 3. A d diti o n al Esti m a n d (s)
A sec o n dar y  esti ma n d t o assess t he pri mar y o bjecti ve will be:

Esti m a n d 1. 2 : Usi n g a h y p ot hetical esti ma n d strate g y , i n patie nts wit h b i o psy-c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as assesse d by t he s p o ns or -
i de ntifie d ce ntr al p at h ol o gist(s), esti m ate t he tre at me nt effect of D G A T 2i d oses 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 7
T M F D oc I D: 9 8. 0 3
a d mi nistere d al o ne a n d c o a d mi nistr ati o n of D G A T 2i + A C Ci rel ative t o pl a ce b o, a n d 
c o a d mi nistr ati o n of D G A T 2i + A C Ci, rel ative t o D G A T 2i al o ne, i n ter ms of esti m ati n g 
t he pr o p orti o n of 'cli nic al res p o n ders', defi ne d as p artici p a nts ac hievi n g ce ntr ally 
a dj u dic ate d: res ol uti o n of N A S H wit h o ut w orse ni n g of fi br osis or i m pr ove me nt i n fi br osis 
by ≥1 st a ge wit h o ut w orse ni n g of N A S H, or b ot h, at W eek 4 8, ass u mi n g all p atie nts h a d 
re m ai ne d i n t he tri al a n d receive d tre at me nt as pl a n ne d wit h o ut wit h dr a w al u p t o 4 8 
weeks . E n d p oi nt d at a c ollecte d after tre at me nt wit h dr a w al will be ce ns ore d. All 
treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba yesia n d ose -res p o nse 
a n d/ or e x p os ure-res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n 
m o dels .
T his esti ma n d assesses t he treat me nt effect i n a n alter nati ve, h y p ot hetical setti n g of
a d here nce t o t heir treat me nt as pla n ne d .
A n e x pl orat or y  esti ma n d t o assess e n d p oi nts relate d t o w orse ni n g i n li ver bi o ps y  e n d p oi nt 
c o m p o ne nts at Wee k 4 8 is als o defi ne d as foll o ws :

Esti m a n d 3. 1 : Usi n g a c o m p osite esti ma n d strate g y , i n patie nts wit h bi o ps y -c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as assesse d b y t he s p o ns or -
i de ntifie d ce ntral pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i doses 
a d mi nistere d al o ne a n d c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he 
pr o p orti o n of ‘cli nical res p o n ders’ (f or t he p ur p oses of a nalys is), defi ne d as partici pa nts 
wit h w orse ni n g i n li ver bi o ps y  e n d p oi nt c o m p o ne nts at Wee k 4 8 a n d treati n g all cases of 
wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n als o as ‘res p o n ders’. 
Partici pa nts w h o wit h dra w fr o m treat me nt f or ot her reas o ns b ut ha ve e val ua ble bi o ps y  
data at wit h dra wal or at Wee k 4 8 will ha ve t heir bi o ps y  data assesse d t o deter mi ne 
w het her t he y  are ‘res p o n ders’ or n ot. Partici pa nts wit h n o Wee k 4 8 bi o ps y data will be 
c o nsi dere d t o be ‘res p o n ders’ . Partici pa nts w h o i m pr o ve or re mai n t he sa me c o m pare d t o 
baseli ne i n t heir li ver bi o ps y  e n d p oi nt c o m p o ne nts are treate d as ‘ n o n-res p o n ders’, as 
res p o nse f or t hese e n d p oi nts is defi ne d as a w orse ni n g i n li ver bi o psy e n d p oi nt 
c o m p o ne nts. All treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba y esia n 
d ose -res p o nse a n d/ or e x p os ure-res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic 
re gressi o n m o dels.
Fi nall y , e x pl orat or y esti ma n ds t o assess e n d p oi nts relate d t o a d diti o nal defi niti o ns of ‘cli ni cal 
res p o nse’ are defi ne d as f oll o ws :

Esti m a n d 3. 2 : Usi n g a c o m p osite esti ma n d strate g y, i n patie nts wit h bi o ps y -c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y  assess me nt of S C R 2 bi o ps y as assesse d b y t he s p o ns or -
i de ntifie d ce ntral pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i d oses 
a d mi nistere d al o ne a n d c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he 
pr o p orti o n of ‘cli nical res p o n ders’, defi ne d as partici pa nts ac hievi n g i m pr o ve me nt i n 
fi br osis b y ≥1 sta ge i n de pe n de nt of c ha n ges i n N A S, at Wee k 4 8 a n d treati n g all cases of 
wit h dra wal fr o m treat me nt f or lac k of efficac y  or t olerati o n as n o n-res p o n ders. 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 8
T M F D oc I D: 9 8. 0 3
Partici pa nts w h o wit h dra w fr o m treat me nt f or ot her reas o ns b ut ha ve e val ua ble bi o ps y  
data at wit h dra wal or at Wee k 4 8 will ha ve t heir bi o ps y  data assesse d t o deter mi ne 
w het her t he y  are res p o n ders or n ot. Partici pa nts wit h n o Wee k 4 8 bi o ps y data will be 
c o nsi dere d t o be n o n -res p o n ders. All treat me nt effect c o ntrasts wi ll be o btai ne d t hr o u g h 
fitti n g t he Ba yesia n d ose -res p o nse a n d/ or e x p os ure-res p o nse m o dels wit h a l o git 
tra nsf or mati o n, or l o gistic re gressi o n m o dels.

Esti m a n d 3. 3 : Usi n g a c o m p osite esti ma n d strate g y, i n patie nts wit h bi o ps y -c o nfir me d 
N A S H a n d fi br osis, o n eli gi bilit y assess me nt of S C R 2 bi o ps y as assesse d b y t he s p o ns or -
i de ntifie d ce ntral pat h ol o gist(s), esti mate t he treat me nt effect of D G A T 2i d oses 
a d mi nistere d al o ne a n d c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne, i n ter ms of t he 
pr o p orti o n of ‘cli nical res p o n ders’, defi ne d as partici pa nts ac hie vi n g res ol uti o n of N A S H 
wit h o ut w orse ni n g of fi br osis a n d i m pr o ve me nt i n fi br osis b y  ≥1 sta ge wit h o ut w orse ni n g 
of N A S H , at Wee k 4 8 a n d treati n g all cases of wit h dra wal fr o m treat me nt f or lac k of 
efficac y or t olerati o n as n o n-res p o n ders. Partici pa nts w h o wit h dra w fr o m treat me nt f or 
ot her reas o ns b ut ha ve e val ua ble bi o ps y  data at wit h dra wal or at Wee k 4 8 will ha ve t heir 
bi o ps y  data assesse d t o deter mi ne w het her t he y are res p o n ders or n ot. Partici pa nts wit h 
n o Wee k 4 8 bi o ps y  data will be c o nsi dere d t o be n o n-res p o n ders. All treat me nt effect 
c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba yesia n d ose- res p o nse a n d/ or e x p os ure-
res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n m o dels.
2. 2. St u d y Desi g n
T he det aile d set -u p of t he st u dy is s u m m arize d bel o w –
Fi g ure 1 .
St u d y Desi g n
Pr e - Q u alifi c ati o n
(1 st n o n-i n v a si v e a s s e s s m e nt s)
S cr e e n 2
( Ultr a s o u n d- g ui d e d li v er B x)
R u n-I n a
(      or o n sit e)
B a s eli n e 
[ Si n gl e- Bli n d Pl a c e b o ( BI D)]
R a n d o mi z ati o n / D a y 1
W e e k 4 8
( Ultr a s o u n d- g ui d e d li v er B x)
F/ U # 1
F/ U # 2
W e e k 2
S cr e e n 1
(2 n d n o n-i n v a si v e a s s e s s m e nt s)
W e e k 4
W e e k 6
W e e k 8
W e e k 1 2
W e e k 1 6
W e e k 2 4
W e e k 3 2
W e e k 4 0
S cr e e ni n g P h a s e 
Tr e at m e nt P h a s e 
F oll o w -u p
a.
R u n -I n/ Vi sit 3 r e q uir e d t o b e o n sit e if c h a n g e s t o b a c k gr o u n d m e di c ati o n s ( pr ot o c ol m a n d at e d or c h a n g e s t o i m pr o v e di s e a s e m a n a g e m e nt) ar e b ei n g m a d e; 
ot h er wi s e, t hi s vi sit p er mitt e d a s a t el e p h o n e c o nt a ct o n t h e s a m e d a y, or u p t o 4 d a y s, p o st c o n d u ct of S C R 2 li v er bi o p s y
b.
St a bili z ati o n p eri o d d efi n e d a s i nt er v al of ti m e fr o m R u n -I n/ Vi sit 3 ( o n-sit e or t el e p h o n e c o nt a ct) t o D a y 1/ Vi sit 5
1 0 - t o 1 6- w e e k s
At l e a st 6 w e e k s b
1 4 ± 4 d a y s
4 8 w e e k s ± 4 d a y s
~ 5 2 w e e k s
M RI -P D F F i n ~ 5 0 % 
of r a n d o mi z e d 
[I m a gi n g S u b- st u d y]
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 1 9
T M F D oc I D: 9 8. 0 3
T his is a m ultice nter, m ulti n ati o n al, r a n d o mize d, d o u ble -bli n d, d o u ble -d u m my, pl ace b o -
c o ntr olle d, p ar allel- gr o u p, ev al u ati o n of D G A T 2i al o ne, a n d D G A T 2i + A C Ci. A p pr oxi m ately 
3 5 0 p artici p a nts ( 5 0 per ar m) wit h bi o psy c o nfir me d N A S H wit h F 2- F 3 fi br osis, as as sesse d 
by s p o ns or -i de ntifie d ce ntr al p at h ol o gist(s), will be r a n d o mly assi g ne d t o t he st u dy 
i nterve nti o n t o e ns ure a p pr oxi m ately 2 8 0 ev al u a ble p artici p a nts ( 4 0 per ar m) offer ev al u a ble 
d at a f or t he pri m ary o bjective. 
P artici p a nts will be r a n d o mize d i n a b al a nce d r ati o, usi n g a c o m p uter -ge ner ate d 
r a n d o miz ati o n c o de, t o receive eit her d o u ble-bli n d, d o u ble -d u m my pl ace b o, 1 of 4
d oses/ d osi n g re gi me ns of D G A T 2i al o ne, or 1 of 2 d ose- levels of D G A T 2i + A C Ci f or a 
tre at me nt d ur ati o n of u p t o 4 8-weeks . 
F or p artici p a nts r a n d o mize d bef ore P r ot oc ol A me n d me nt 1 is e n acte d , t h ose r a n d o mize d t o 
eit her of t he 2 Q D ( D G A T 2i 1 5 0 m g Q D a n d D G A T 2i 3 0 0 m g Q D) d osi n g re gi me ns of 
D G A T 2i al o ne will re m ai n i n t he st u dy b ut will be s witc he d t o t he c orres p o n di n g BI D d osi n g
re gi me n of D G A T 2i al o ne, m ai nt ai ni n g t he assi g ne d t ot al d aily d ose a n d t he d o u ble-bli n d, 
d o u ble - d u m my desi g n. N e w ra n d o mizati o n t o t he Q D treat me nt ar ms will cease, after Healt h 
A ut h orit y  ( w here a p plica ble) a n d I R B/ E C a p pr o vals of P r ot oc ol A me n d me nt 1 . T h eref ore, 
f oll o wi n g Pr ot oc ol A me n d me nt 1, partici pa nts will be ra n d o mize d t o o ne of t he f oll o wi n g 
treat me nt ar ms:

Place b o
D G A T 2i ( Er v o gastat) BI D d ose ar ms (f or c haracterizati o n of d ose -res p o nse):

D G A T 2i 2 5 m g BI D , t otal dail y d ose of 5 0 m g 

D G A T 2i 7 5 m g BI D , t otal dail y d ose of 1 5 0 m g 

D G A T 2i 1 5 0 m g BI D , t otal dail y d ose of 3 0 0 m g 

D G A T 2i 3 0 0 m g BI D , t otal dail y d ose of 6 0 0 m g 
D G A T 2i ( Er v o gastat) + A C Ci ( Clesac ostat) c oa d mi nistrati o n d ose ar ms:

D G A T 2i 1 5 0 m g BI D + A C Ci 5 m g BI D

D G A T 2i 3 0 0 m g BI D + A C Ci 1 0 m g BI D
T he treat me nt gr o u p la bels i n pr o gra m me d o ut p uts will be as f oll o ws:
Place b o
P F -5 5 7 1
2 5 m g 
BI D
P F -5 5 7 1
7 5 m g 
BI D
P F -5 5 7 1
1 5 0 m g 
BI D
P F -5 5 7 1
1 5 0 m g 
BI D + 
P F 1 3 0 4 5 
m g BI D
P F -5 5 7 1
3 0 0 m g 
BI D
P F -5 5 7 1
3 0 0 m g 
BI D + 
P F 1 3 0 4 1 0 
m g BI D
T otal
F oll o wi n g f o ot n ote t o be i ncl u de d o n all ta bles: P F 5 5 7 1 = Er v o gastat a n d P F 1 3 0 4 = Cl esac ostat
N ote: A ‘ T otal’ c ol u m n is re q uire d w he n s u m marizi n g baseli ne of p o p ulati o n ra n d o mize d
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 0
T M F D oc I D: 9 8. 0 3
T he ‘ P F 5 5 7 1 7 5 m g BI D’ gr o u p will als o i ncl u de t h ose ra n d o mize d t o D G A T 2i 1 5 0 m g Q D
a n d ‘P F 5 5 7 1 1 5 0 m g  BI D’ gr o u p will als o i ncl u de t h ose ra n d o mize d t o D G A T 2i 3 0 0 m g 
Q D , t heref ore, t here will be n o refere nce t o t he Q D treat me nt ar ms i n a n y of t he pr o gra m me d 
o ut p uts (i ncl u di n g d ose at o nset f or A Es a n d treat me nt d urati o n – t hese will o nl y refer t o t he 
BI D gr o u ps as descri be d a b o ve).
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI NI TI O N S A N D 
C O N V E N TI O N S
3. 1. Pri m ar y E n d p oi nt(s)
T he Pri mar y  E n d p oi nt is t he pr o p orti o n of p artici p a nts ac hievi n g res ol uti o n of N A S H wit h o ut 
w orse ni n g of fi br osis or i m pr ove me nt i n fi br osis by ≥1 st a ge wit h o ut w orse ni n g of N A S H or 
b ot h, b ase d o n assess me nt by s p o ns or- i de ntifie d ce ntr al p at h ol o gist(s), at Week 4 8, 
c o m pare d t o baseli ne.
I n or der t o deri ve t his e n d p oi nt, t he c o m p o ne nts are defi ne d as f oll o ws:

Res ol uti o n of N A S H: disa p peara nce of ball o o ni n g ( N A S ball o o ni n g sc ore = 0) a n d 
resi d ual or n o l o b ular i nfla m mati o n (N A S l o b ular i nfla m mati o n sc ore of 0 or 1) a n d N A S 
steat osis sc ore of 0 , 1, 2 or 3 .

N o w orse ni n g of fi br osis: n o c ha n ge or a decrease of at least 1 sta ge i n t he Br u nt -Klei ner 
scale c o m pare d t o baseli ne
a n d

Im pr o ve me nt i n fi br osis b y  ≥1 sta ge: a decrease of at least 1 sta ge i n t he Br u nt- Klei ner 
scale c o m pare d t o baseli ne

N o w orse ni n g of N A S H: n o c ha n ge or n o i n crease i n N A S f or ball o o ni n g, i nfla m mati o n, 
or steat osis c o m pare d t o baseli ne
F or a ll bi o ps y e n d p oi nts e val uati n g c ha n ge fr o m baseli ne, assess me nt will be base d o n t he 
paire d d o u ble pat h ol o gist re vie w of di gitize d s li des. As a res ult of t he fi nal paire d d o u ble 
pat h ol o gist re vie w, if a partici pa nt is f o u n d n ot t o be eli gi ble f or t he st u d y (e. g. if t he y  are re-
cate g orize d as F 1 or F 4) , t he y will still be i ncl u de d i n t he a nalys is. If t here has bee n a 
differe nt assi g n me nt of bi o ps y  gra di n g (e. g. if t he fi nal assi g n me nt of t he baseli ne bi o ps y  is 
F 3 b ut at t he ti me of eli gi bilit y deter mi nati o n t his sa me bi o ps y was assesse d as F 2), t he n 
partici pa nts will be i ncl u de d i n a n y a nal ys es base d o n t he fi nal paire d assess me nt, rat h er t ha n 
t he o ne at t he ti me of eli gi bilit y  deter mi nati o n, h o we ver, t he fi br osis gra de at eli gi bilit y 
deter mi nati o n ( S C R 2 Eli gi bilit y) will be use d as a c o variate, as t his is w hat will be use d f or 
stratificati o n. Pla n ne d bi o ps y  assess me nts are s u m marize d i n Ta ble 2 . 

T here will be t w o t y pes of bi o ps y assess me nts c o n d ucte d b y t he pat h ol o gists:

Q ua ntitati ve: N A S gra di n g a n d fi br osis sta gi n g

Q ualitati ve: I n t he bli n de d si de -b y -si de re vie w, a n assess me nt of w hic h bi o ps y  ( S C R 2 
or Wee k 4 8/ D C) is c o nsi dere d t o be better, w orse or are b ot h t he sa me 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 1
T M F D oc I D: 9 8. 0 3
T a ble 2 .
Bi o ps y res ults t o be re p orte d f or e ac h p artici p a nt
Bli n de d si de-b y -si de ( C ha n ge fr o m Baseli ne)
re vie w of S C R 2 a n d O n-treat me nt bi o psies
Li mite d t o o nl y t h ose wit h o n -tre at me nt bi o ps y
S C R 2 (f or 
Eli gi bilit y : 
q u a ntit ati ve 
assess me nt o nl y )
S C R 2 (f or A nal y sis: 
q u a ntit ati ve a n d 
q u alit ati ve
assess me nts )
O n treat me nt - W k 4 8 or 
D/ C (f or A nal ys is: 
q u a ntit ati ve a n d 
q u alit ati ve 
assess me nts )
Pat h ol o gist 1
parallel re vie w
All partici pa nts
All partici pa nts wit h 
o n -treat me nt bi o psy
All partici pa nts wit h o n -
treat me nt bi o ps y
Pat h ol o gist 2
parallel re vie w
All partici pa nts
All partici pa nts wit h 
o n -treat me nt bi o psy
All partici pa nts wit h o n -
treat me nt bi o ps y
C o nse ns us re vie w
If nee de d1
If nee de d, f or b ot h 
q ua ntitati ve a n d 
q ualitati ve 
c o m paris o ns 2
If nee de d, f or b ot h 
q ua ntitati ve a n d 
q ualitati ve c o m paris o ns 2
1.
C o nse ns us re vie w t o reac h a gree me nt is n ot re q uire d if b ot h ce ntral pat h ol o gists a gree t hat (a) eit her t he 
N A S or Fi br osis gra de re n ders partici pa nt i neli gi ble; ( b) t otal N A S sc ore ≥4 , wit h ≥1 f or steat osis, 
i nfla m mati o n, a n d ball o o ni n g, is met, e ve n if  ali g n me nt of sc ore f or eac h c o m p o ne nt of N A S [steat osis, 
i nfla m mati o n, ball o o ni n g] is a bse nt; a n d/ or (c) fi br osis sta ge is ali g ne d f or hi g her gr o u p [ F 3 or F 4] b ut 
ma y n ot be ali g ne d f or s u b -gr o u p [ F 3a, F 3 b, F 4a, F 4 b]
2.
C o nse ns us re vie w t o reac h a gree me nt re q uire d f or all cases of mi sali g n me nt o n parallel re vie w – ie, 
misali g n me nt o n sc ori n g of e ac h c o mp o ne nt of N A S sc ore, s u b -gr o u p of fi br osis sta ge [ F 3a, F 3 b, F 4a or 
F 4 b] , q ualitati ve assess me nt of better, sa me, w orse 
N ote t hat T ric hr o me S tai n s h o ul d o nl y be use d f or t he Fi br osis res ults a n d t he He m ot o x yli n 
a n d E osi n S tai n s h o ul d be use d f or t he N A S res ults, o nl y. A d diti o nall y , i n c ha n ge-fro m-
baseli ne assess me nt, if t here is a C o nse ns us res ult (i.e. ‘ P A T H O L O GI S T 1 A N D 
P A T H O L O GI S T 2 ’) t he n t his is t he o ne t hat s h o ul d be use d, a n d if a C o nse ns us res ult is n ot 
re p orte d, t he P A T H O L O GIS T 1 a n d P A T H O L O GI S T 2 res ults s h o ul d be i de ntical f or all 4 
d o mai ns ( 3 relate d t o N A S + 1 relate d t o fi br osis) , s o eit her P A T H O L O GI S T 1 or
P A T H O L O GI S T 2 res ult s ca n be use d.

Ma p pi n g of Fi br osis Gra des f or a nal y sis:
Acce pt a ble V al ues
L a bc or p Res ult
Fi br osis Gr a de t o 
use f or a n al ysis
0
0 - N o fi br osis
0
1
1a
1a - Z o ne 3 mil d perisi n fi b
1
1 b
1 b - Z o ne 3 m o d perisi n fi b
1
1c
1c - Peri p ortal/ p ortal fi b
1
2
2 - Z o ne 3 + peri p ort/ p ort fi b
2
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 2
T M F D oc I D: 9 8. 0 3
Acce pt a ble V al ues
L a bc or p Res ult
Fi br osis Gr a de t o 
use f or a n al ysis
3a
3a - Bri d gi n g fi br osis (fe w)
3
3 b
3 b - Bri d gi n g fi br osis ( n u m)
3
4a
4a - Cirr h osis (i nc o m plete)
4
4 b
4 b - Cirr h osis (esta blis he d)
4
N O N E V A L U A B L E
N ot e val ua ble
N ot e val ua ble
3. 2. Sec o n d ar y E n d p oi nt(s)
Sec o n d ary E n d p oi nts are:

Pr o p orti o n of p artici p a nts ac hievi n g i m pr ove me nt i n differe nt res p o n der defi niti o ns 
b ase d o n assess me nt by s p o ns or-i de ntifie d ce ntr al p at h ol o gist(s) at Week 4 8 c o m pare d t o 
baseli ne (eac h defi ne d as a b o ve f or t he pri mar y e n d p oi nt):
o
Res ol uti o n of N A S H, wit h o ut w orse ni n g of fi br osis
o
I m pr ove me nt i n fi br osis by ≥1 st a ge, wit h o ut w orse ni n g of N A S H
o
I m pr ove me nt i n fi br osis by ≥2 st a ges ( defi ne d as a decrease of at least 2 sta ges i n 
t he Br u nt-Klei ner scale c o m pare d t o baseli ne) , wit h o ut w orse ni n g of N A S H
o
I m pr ove me nt of ≥2 p oi nts i n T ot al N A S ( defi ne d as a de crease of at least 2 p oi nts 
i n T otal N A S c o m pare d t o baseli ne), wit h o ut pr o gressi o n of fi br osis
T otal N A S ca n ra n ge fr o m 0 t o 8 a n d is calc ulate d as t he s u m of sc ores of 
steat osis ( 0 t o 3), l o b ular i nfla m mati o n ( 0 t o 3) a n d ball o o ni n g ( 0 t o 2). If a n y of 
t he s u b-scale sc ores are n o n-e val ua ble/ missi n g, t he n t he t otal sc ore s h o ul d be 
deri ve d as missi n g .

Perce nt c h a n ge i n liver f at ( assesse d vi a M RI - P D F F i n s u bst u dy p o p ul ati o n), at Week 4 8

Assess me nt of Treat me nt E mer ge nt A d verse E ve nts (T E A Es ), s afety-rel ate d cli nic al 
l a b or at ory tests, vit al si g ns, a n d 1 2-le a d E lectr ocar di o gra ms ( E C Gs), over ti me u p t o 
Week 4 8
3. 3. Ot her E n d p oi nt (s)

Pr o p orti o n of partici pa nts ac hie vi n g i m pr o ve me nt i n fi br osis b y ≥1 sta ge i n de pe n de nt of 
c ha n ges i n N A S, base d o n assess me nt b y  s p o ns or-i de ntifie d ce ntral pat h ol o gist(s), at 
Wee k 4 8 c o m pare d t o baseli ne 

Pr o p orti o n of partici pa nts ac hie vi n g res ol uti o n of N A S H wit h o ut w orse ni n g of fi br osis 
a n d i m pr o ve me nt i n fi br osis b y  ≥1 sta ge wit h o ut w orse ni n g of N A S H, base d o n 
assess me nt b y s p o ns or-i de ntifie d ce ntral pat h ol o gist(s), at Wee k 4 8 c o m pare d t o baseli ne
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 3
T M F D oc I D: 9 8. 0 3

Pr o p orti o n of p artici p a nts wit h w orse ni n g i n liver bi o psy e n d p oi nt c o m p o ne nts b ase d o n 
assess me nt by s p o ns or -i de ntifie d ce ntr al p ath ol o gist(s) at Week 4 8:
o
Pr o gressi o n of fi br osis by ≥1 st a ge ( defi ne d as an i ncrease of at least 1 sta ge i n 
t he Br u nt -Klei ner scale c o m pare d t o baseli ne ) i n de pe n de nt of c ha n ges i n N A S
o
Pr o gressi o n of fi br osis b y  ≥1 sta ge a n d w orse ni n g of ≥2 p oi nts i n T otal N A S
o
W orse ni n g of ≥2 p oi nts i n T ot al N A S ( defi ne d as an i ncrease of at least 2 p oi nts i n 
T otal N A S c o m pare d t o baseli ne) i n de pe n de nt of c ha n ges i n fi br osis
Ot her tertiar y /e x pl orat or y e n d p oi nts are as s h o w n bel o w. T he a nal y ses of t hese e n d p oi nts are 
assesse d f or efficac y u p t o Wee k 4 8, b ut t he a nalyses of bl o o d base d bi o mar kers will als o 
i ncl u de data u p t o a n d i ncl u di n g Wee k 5 0 t o all o w a n assess me nt of off-treat me nt effects::

Perce nt c ha n ge i n li ver fat (assesse d via M RI -P D F F i n I ma gi n g s u bst u d y  p o p ulati o n), 
o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge i n li ver v ol u me (assesse d via M a g netic res o na nce i ma gi n g (M RI ) i n 
I ma gi n g s u bst u dy p o p ulati o n), o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge i n 
 (assesse d via M RI i n I ma gi n g s u bst u d y p o pulati o n), 
o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge i n 
 (assesse d via M RI i n I ma gi n g s u bst u d y p o p ulati o n), o ver ti me 
u p t o Wee k 4 8

Perce nt c ha n ge fr o m baseli ne i n li ver fat as assesse d via C o ntr olle d atte n uati o n para meter
(C A P ™)
meas ure b y Fi br o Sca n ® , (e ntire st u dy p o p ulati o n), o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge fr o m baseli ne i n li ver stiff ness (assesse d via Vi brati o n -C o ntr olle d 
Tra nsie nt Elast o gra p h y (V C T E ™) usi n g Fi br o Sca n ® (e ntire st u d y p o p ulati o n)), o ver ti me 
u p t o Wee k 4 8

Perce nt c ha n ge fr o m ba seli ne i n Li ver F u ncti o n Tests – A la ni ne a mi n otra nsferase (A L T ), 
As partate a mi n otra nsferase ( A S T ), Al kali ne p h os p hatase (A L P ), Ga m ma -gl uta m y l 
tra nsferase (G G T ), T otal Bilir u bi n, Direct Bilir u bi n, a n d T otal Bile Aci ds o ver ti me u p t o 
Wee k 5 0

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 i n Mec ha nis m -Relate d a n d 
Meta b olic Para meters – Pr o pr otei n c o n vertase s u btilisi n/ ke xi n t y pe 9 (P C S K 9 ), 
A di p o necti n, Platelet c o u nt, e G F R-C K D -E PI -C y stati n- C, a n d B o dy Wei g ht 

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 i n C yt o kerati n -1 8- M 3 0
fra g me nt
(C K 1 8 -M 3 0 ) a n d C yt o kerati n -1 8 -M 6 5
fra g me nt (C K 1 8 -M 6 5 )
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 4
T M F D oc I D: 9 8. 0 3

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 i n N- ter mi nal pr o pe pti de of t ype 
III pr oc olla ge n (Pr o C 3 ) a n d C- ter mi nal fra g me nt of α 3 c hai n of pr oc olla ge n t ype VI   
(Pr o C 6 )

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 i n E n ha nce d Li ver Fi br osis (E L F )
sc ore (i ncl u di n g t he i n di vi d ual para meters assa ye d - Ser u m h y al ur o nic aci d ( H A), Ser u m 
a mi n o-ter mi nal pr o pe pti de of t ype III pr oc olla ge n ( PIII N P) a n d Ser u m tiss ue i n hi bit or of 
metall o pr otei nases 1 ( TI M P - 1))

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 i n Hi g h -se nsiti ve C-reacti ve 
pr otei n ( hs-C R P )

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 A p oli p o pr otei n A 1, B (t otal), 
B 1 0 0, B 4 8, C 3, E ( P ote ntiall y  mec ha nis m-relate d para meters)

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 i n Fasti n g li pi d pa nel (t otal 
c h olester ol, direct L o w de nsit y  li p o pr otei n-c h olester ol (L D L- C), Hi g h de nsit y  li p o pr otei n
c h olester ol (H D L - C), tri gl yceri des, direct Ver y  l o w-de nsit y  li p o pr otei n (V L D L )),

C ha n ge fr o m baseli ne, o verti me u p t o Wee k 5 0 i n H b A 1 C, Fasti n g plas ma gl uc ose 
( F P G), Fasti n g plas ma i ns uli n ( F PI), H o me ostatic M o del Assess me nt f or I ns uli n 
Resista nce ( H O M A -I R)   

C ha n ge fr o m baseli ne, (a d ults wit h T 2 D M o nl y), o ver ti me u p t o Wee k 5 0 , i n H b A 1 C, 
Fasti n g plas ma gl uc ose (F P G ), Fasti n g plas ma i ns uli n (F PI ), H o me ostatic M o del 
Assess me nt f or I ns uli n Resista nce (H O M A -I R)

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n a b d o mi nal pai n a n d bl oati n g q uesti o ns 
fr o m t he N A S H S ym pt o m Diar y  

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n fati g ue, sle e p dist ur ba nce, a n d da yti me 
slee pi ness q uesti o ns fr o m t he N A S H S ym pt o m Diar y  

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n fati g ue as meas ure d b y Patie nt -Re p orte d 
Meas ure me nt O utc o me I nf or mati o n S y ste m (P R O MI S) Fati g ue q uesti o n naire

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n H ealt h-relate d q ualit y of life (H R Q o L )
s u b-scale sc ores as meas ure d by N A S H -C hec k

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n P GI - S

A bs ol ute sc ore o ver ti me i n Patie nt Gl o bal I m pressi o n of Se verit y (P GI - S)

A bs ol ute sc ore o ver ti me i n Patie nt Gl o bal I m pressi o n of C ha n ge (P GI - C)
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 5
T M F D oc I D: 9 8. 0 3
3. 4. B aseli ne V ari a bles
T he f oll o wi n g baseli ne varia ble will be i ncl u de d as a fact or:

Baseli ne fi br osis sta ge ( F 2/F 3) 
F or all bi o ps y base d efficac y e n d p oi nts, baseli ne will be defi ne d as t he bi o ps y  res ults
o btai ne d at S C R 2 or a hist orical bi o ps y  wit hi n 1 2-wee ks pri or t o S C R 2 ( t h o u g h wit hi n 2 4-
wee ks of Da y  1 ( Visit 5).
F or Li ver Fat as meas ure d b y  M RI-P D F F, baseli ne is defi ne d as t he val ue of t otal mea n li ver 
fat o btai ne d bet wee n Visit 4 a nd Visit 5 (ie, la bele d as baseli ne) .
F or Li ver V ol u me as meas ure d b y M RI -P D F F, baseli ne is defi ne d as t he val ue of t otal mea n 
li ver v ol u me o btai ne d bet wee n Visit 4 a n d Visit 5 (ie, la bele d as baseli ne).
Baseli ne f or Fi br o Sca n ® base d e n d p oi nts will als o be defi ne d as t he e val ua ble val ues 
o btai ne d bet wee n Visit 4 a n d Visit 5 or S C R 1 if t here is n’t a n e val ua ble val ue bet wee n Visit 
4 a n d Visit 5 (ie, la bele d as baseli ne).
F or all Patie nt Re p orte d O utc o mes, a n y ot her c o nti n u o us efficac y e n d p oi nts a n d all safet y-
relate d c o nti n u o us e n d p oi nts, baseli ne will be defi ne d as t he cl osest res ults o btai ne d pri or t o 
d osi n g o n Da y  1 ( Visit 5 )
F or la b orat or y res ults, t he baseli ne val ue t o be use d will be eit her Da y 1 or Da y - 1 4 (pl us a n y 
all o wa ble a nal ysis wi n d o ws – see A p pe n di x 2. 1 ), b ut n ot a n y f urt her bac k t ha n t his. If 
la borat or y c ollecti o ns ha ve bee n ta ke n i n t he c orrect faste d state (as i n dicate d i n t he C R F), 
D a y  1 s h o ul d be use d, b ut if n ot, t he n Da y -1 4 s h o ul d be use d (a gai n, if i n t he c orrect faste d 
state f or t he s pecific la borat or y para meter) . 
F or vital si g ns , t he baseli ne val ue t o be use d will be eit her Da y 1 or Da y -1 4, b ut n ot a n y  
f urt her bac k t ha n t his. If p ossi ble, Da y  1 s h o ul d be use d, b ut if t his is missi n g , t he n Da y - 1 4 
s h o ul d be use d. If b ot h Da y -1 4 a n d Da y  1 is missi n g f or a partic ular para meter, t he n t he 
baseli ne s h o ul d be c o nsi dere d as “ Missi n g”.
3. 5. S afet y E n d p oi nts
3. 5. 1. A d verse E ve nts
A n a d verse e ve nt will be c o nsi dere d tre at me nt e mer ge nt relati ve t o a gi ve n treat me nt if: 

T he e ve nt starts o n or after t he first d osi n g da y of d o u ble -bli n de d st u d y  me dicati o n o n 
D a y  1 [ Visit 5], b ut bef ore t he last d ose pl us t he la g ti me.  T he al g orit h m will n ot 
c o nsi der a n y e ve nts t hat starte d pri or t o t he fi rst d ose date.  If a n A E starts o n t he 
sa me da y as t he first d ose date, it will be c o nsi dere d treat me nt e mer ge nt.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 6
T M F D oc I D: 9 8. 0 3

A n y  A Es t hat occ ur after si g ni n g I nf or me d C o nse nt a n d bef ore ra n d o mizati o n a n d t he 
first d ose of d o u ble-bli n d st u d y  me dicati o n s h o ul d be rec orde d i n Me dical Hist or y ; 
wit h o nly treat me nt e mer ge nt A Es re p orte d o n t he A E C R F pa ge.
T he effecti ve d urati o n of treat me nt is deter mi ne d b y t he la g ti me defi ne d as t he Pfizer 
Sta n dar d of 9 9 9 da ys p ost last d ose of d o u ble -bli n de d st u d y  me dicati o n (i.e. a n i nfi nite la g). 
A n y  tre at me nt-e mer ge nt e ve nt occ urri n g wit hi n t he la g ti me, w het her it occ urs d uri n g a 
brea k i n treat me nt or at t he e n d of treat me nt, will be attri b ute d t o t he assi g ne d ra n d o mize d 
re gi me n. 
A 3 -tier a p pr oac h will be use d t o s u m marize A Es. U n der t his a p pr oac h, A Es are classifie d 
i nt o 1 of 3 tiers. Differe nt a nal yses will be perf or me d f or differe nt tiers (see Secti o n 6. 6. 1 ).
Tier 1 e ve nts: T hese are pres pecifie d e ve nts of cli nical i m p orta nce a n d are mai ntai ne d i n a 
list i n t he pr o d uct’s Safet y Re vie w Pla n.
Tier 2 e ve nts: T hese are e ve nts t hat are n ot tier 1 b ut are “c o m m o n.”   A Me dical Dicti o na r y 
f or Re g ulat or y Acti vities (Me d D R A ) preferre d ter m ( P T) is defi ne d as a Tier 2 e ve nt if t here 
are at least 4 partici pa nt s wit h at least o ne occ urre nce i n a ny treat me nt gr o u p.
Tier 3 e ve nts: T hese are e ve nts t hat are neit her Tier 1 n or Tier 2 e ve nts.
3. 5. 2. L a b or at or y D at a
F or t he s pecific la b orat or y para meters liste d i n Ta ble 3 bel o w, t he f oll o wi n g e n d p oi nts will 
be e val uate d usi n g C DI S C a n d Pfizer sta n dar ds (Ca P S ): 

A bs ol ute val ue a n d c ha n ge fr o m baseli ne at eac h visit ( W ee k 2, 4, 6, 8, 1 2, 1 6, 2 4, 3 2, 
4 0, 4 8 a n d F oll o w -u p ). 

N u m ber of occ urre nces of t hese a b n or malities defi ne d as “ Fla g Le vel” or “ Alert 
Le vel” 

N u m ber of partici pa nts wit h t hese a b n or malities defi ne d a s “ Fla g Le vel” or “ Alert 
Le vel”
T a ble 3.  
Cli nic al L a b or at or y P ar a meters 
P a r a m eter
Fl a g Le vel *
Alert Le vel ^
C o n ve nti o n al U nits
Fasti n g Ser u m Tri gl yceri des
≥4 0 0 
≥6 0 0
m g/ d L
--
≥8 0 0
m g/ d L
Platelet C o u nt 
< 1 0 0
< 7 5
1 0 ^ 9 / L
Fasti n g Plas ma Gl uc ose 
< 7 0
≤4 9
m g/ d L
≥1 4 0
> 2 7 0
m g/ d L
Ala ni ne a mi n otra nsferase
≥2 x U L N
Pfizer st d 
fla g f or P C C
I U/ L
> 3 x U L N
Pfizer st d 
fl a g f or P C C
I U/ L
> 5 x U L N
> 8 x U L N
IU/ L
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 7
T M F D oc I D: 9 8. 0 3
T a ble 3.  
Cli nic al L a b or at or y P ar a meters 
P a r a m eter
Fl a g Le vel *
Alert Le vel ^
C o n ve nti o n al U nits
As partate a mi n otra nsferase
≥2 x U L N
Pfizer st d 
fl a g f or P C C
I U/ L
> 3 x U L N
Pfizer st d 
fl a g f or P C C
I U/ L
> 5 x U L N
> 8 x U L N
IU/ L
Al kali ne P h os p hatase
≥2 x U L N
Pfizer st d 
fl a g f or P C C
I U/ L
> 3 x U L N
Pfizer st d 
fl a g f or P C C
I U/ L
> 5 x U L N
Pfizer st d 
fl a g f or P C C
I U/ L
Ga m ma Gl uta m yl Tra nsferase 
> U L N
Pfizer st d 
fl a g f or P C C
I U/ L
T otal Bilir u bi n
> 1. 5 x U L N
> 3 x U L N
m g/ d L
Direct ( C o nj u gate d) Bilir u bi n
> U L N
Pfizer st d 
fl a g f or P C C
m g/ d L
Esti mate d gl o mer ular filtrati o n rate (e G F R) * *
< 6 0
Pfizer st d 
fl a g f or P C C
m L/ mi n/ 1. 7 3 m 2
< 4 5
Pfizer st d 
fl a g f or P C C
m L/ mi n/ 1. 7 3 m 2
< 3 0
Pfizer st d 
fl a g f or P C C
m L/ mi n/ 1. 7 3 m 2
* All fla g le vel c ha n ges are c u m ulati ve fr o m baseli ne ( defi ne d as res ult cl osest pri or t o d osi n g at Visit 5 ( Da y 
1); reflect eit her t hres h ol d f or e ntr y criteria i nt o st u d y or cli nicall y si g nifica nt t hres h ol ds
^ All alert c ha n ges are c u m ulati ve fr o m baseli ne ( defi ne d as res ult cl osest pri or t o d osi n g at Visit 5 ( Da y 1); 
val ues w he n n ote d d uri n g t he st u d y, b y ce ntral la b orat or y necessitates ra pi d n otificati o n ( via fa x/e -mail) t o 
site a n d St ud y  Cli nicia n 
P C C – P ote ntial Cli nical C o ncer n
U L N – u p per li mit of n or mal as deter mi ne d b y t he ce ntral la b orat or y
* * e G F R s h o ul d be base d o n c ystati n -C – see A p pe n di x 2. 4 f or deri vati o ns. 
T he safet y e ve nts 
 as defi ne d i n Ta ble 3 will be s u m marize d a n d 
t he fre q ue nc y of la b orat or y a b n or malities ( b ot h n u m ber of occ urre nces a n d n u m ber of 
partici pa nt s).
Acr oss all t he la b orat or y -relate d a nalyt es (f or safet y a n d p har mac o d y n a mics/ bi o mar ker s),
i ncl usi o n of res ults w he n assesse d at sc he d ule d n o mi nal visits m ust be ( 1) c ollecte d pri or t o 
A M d ose of d o u ble -bli n de d st u d y  me dicati o n, a n d s h o ul d be s u m marize d as n ote d eit her f or 
criteria ( 2) or criteria ( 3):
( 2) C ollecti o n per mitte d t o be n o nfaste d f or t he f oll o wi n g a nal y tes a n d will be per mitte d t o 
be gr o u pe d wit h faste d res ults gi ve n t hat n o nfaste d state is n ot k n o w n t o i m pact res ults
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 8
T M F D oc I D: 9 8. 0 3
T a ble 4.
L a b or at or y Assess me nts ( n o n-f aste d)
C he mistr y p a nel
H e m at ol o g y
Ot her
Uri n al ysis
T otal bilir u bi n
Direct bilir u bi n
I n direct bilir u bi n
Al k P h os
A L T
A S T
G G T
Urea Nitr o ge n
Creati ni ne
Uric aci d
Calci u m
T otal pr otei n
Al b u mi n
Creati ne ki nase
S o di u m
P otassi u m
Bicar b o nate
C hl ori de
H e m o gl o bi n
H e m at ocrit
R B C
M C V
M C H
M C H C
W B C
Ne utr o p hils (a bs)
L y m p h oc ytes (a bs)
M o n oc ytes (a bs)
E osi n o p hils (a bs)
Bas o p hils (a bs)
Platelets
Retic ul oc yte c o u nt %
Retic ul oc yte c o u nt
C ystati n - C ( a n d e G F R 
usi n g C K D -E PI -
C ystati n -C)
a P T T
P T
I N R
Uri ne -dr u g -testi n g
Ser ol o g y testi n g
[H Bs A g, H C V A b ( a n d 
if p ositi v e, r efl e x H C V 
R N A) , HI V]
Al p ha- 1- a ntitr y psi n
Cer ul o plas mi n
H b A 1 C
hs -C R P
β- h C G
F S H
p H
Pr otei n
Gl uc ose
Ket o nes
Bilir u bi n
Ur o bili n o ge n
Bl o o d
Nitrite
Le u k oc yte esterase
Micr osc o pic U A
Or
( 3) T he f oll o wi n g a nal yt es will o nl y  be i ncl u de d i n s u m mar y o ut p uts if c ollecti o ns are
co nfir me d t o be f oll o wi n g a n o ver ni g ht fast of at least 8 h o urs (as rec or de d o n t he la borat or y
C R F pa ge) as it is well k n o w n t hat fasti n g stat us i m pacts n u merical res ults ( or t here is 
i ns ufficie nt data re gar di n g effect of meals o n res ults).
T a ble 5.
L a b or a t or y Assess me nts (f aste d)
Bi o m ar kers
Li pi d -rel ate d
Ot her Bl o o d -
rel ate d
% C D T
Plas ma Gl uc ose
Plas ma I ns uli n
T otal Bile Aci ds
C K 1 8 -M 3 0
C K 1 8 -M 6 5
Pr o C 3
Pr o C 6
Pl as m a P C S K 9
I n di vi d ual c o m p o ne nts of E L F Sc ore (ie, H A, PIII N P, TI M P -
1)
A di p o necti n
I n di vi dual c o m p o ne nts of H O M A -I R (i.e. Fasti n g Plas ma 
Gl uc ose a n d Fasti n g Plas ma I ns uli n)
T otal c h olester ol
H D L - C
Direct L D L - C
Tri gl yceri des
Direct V L D L
A p oli p o pr otei n A 1
A p oli p o pr otei n B t otal
A p oli p o pr otei n B 1 0 0
A p oli p o pr otei n B 4 8
A p oli p o pr otei n C 3
A p oli p o pr otei n E
 
 
 
 
, usi n g t hese sa m ples will be s u m marize d i n a sta n d al o ne re p ort ( o utsi de of 
st u d y-le vel C S R).
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 2 9
T M F D oc I D: 9 8. 0 3
3. 5. 3. Ot her St a n d ar d S afet y ot her t h a n A Es
I n di vi d ual partici pa nt s’ vital si g ns meeti n g t he criteria o utli ne d i n Ta ble 6 of s pecial cli nical 
c o ncer n, w hic h ali g n wit h t he Pfizer sta n dar d criteria, will be s u m marize d b y  ra n d o mize d 
ar m, as part of sta n dar d safet y- relate d o ut p uts. 
T a ble 6 .
Vit al Si g ns t o be M o nit ore d
P ar a meter 
Fl a g Le vel * 
C o n ve nti o n al U nits 
S yst olic Bl o o d Press ure (seate d) 
< 9 0 
m m H g 
≥ 3 0 c ha n ge fr o m baseli ne
m m H g 
Diast olic Bl o o d Press ure (seate d) 
< 5 0 
m m H g 
≥ 2 0 c ha n ge fr o m baseli ne
m m H g 
P ulse rate (seate d) 
< 4 0 
Beats per mi n ute ( b p m )
> 1 2 0
b p m 
* All fla g le vel c ha n ges are c u m ulati ve fr o m baseli ne ( defi ne d as res ult cl osest pri or t o d osi n g at Visit 5 ( Da y 
1) 
I n a d diti o n, Pfizer sta n dar d criteria f or re p orti n g of car diac c o n d ucti o n i nter vals will be 
s u m marize d b y ra n d o mize d ar m. 
I n di vi d ual partici pa nt s’ E C Gs meeti n g t he criteria o utli ne d i n Ta ble 7 , w hic h ali g n wit h t he 
Pfizer sta n dar d criteria, will be s u m marize d b y ra n d o mize d ar m, as part of sta n dar d s afet y-relate d 
o ut p uts. 
T a ble 7 .
E C G C ate g ories
P ar a meter 
Fl a g Le vel * 
Ma xi m u m P ost - d ose C orrecte d Q T ( Fri dericia 
met h o d) ( Q Tc F) ( msec) 
≤4 5 0
4 5 0 - ≤4 8 0
4 8 0 - ≤5 0 0
> 5 0 0
Ma xi m u m I ncrease fr o m Baseli ne i n Q Tc F ( msec)
≤3 0
3 0 - ≤6 0
> 6 0
Ma xi m u m P ost -d ose P R ( msec)
≥3 0 0 
Ma xi m u m I ncrease fr o m Baseli ne i n P R ( msec)
Baseli ne > 2 0 0 a n d ma x ≥2 5 % i ncrease
Baseli ne ≤2 0 0 a n d ma x ≥5 0 % i ncrease
Ma xi m u m P ost -d ose Q R S ( msec)
≥1 4 0
Ma xi m u m I ncrease fr o m Baseli ne i n Q R S ( msec)
≥5 0 % i ncrease
Heart Rate ( b p m)
< 4 0
> 1 2 0
* All fla g le vel c ha n ges are c u m ulati ve fr o m baseli ne ( defi ne d as res ult cl osest pri or t o d osi n g at Visit 5 ( Da y 
1) 

Q Tc F – deri ve d b y pr o gra m mi n g as f oll o ws –
Q Tc F (i n msec ) = [ Q T (i n msec )/[c u be r o ot of R R i nterv al (i n sec)] wit h R R (i n sec) = R R (i n 
msec) x 1 0 0 0
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 0
T M F D oc I D: 9 8. 0 3
I n a d diti o n, c ha n ges i n bac k gr o u n d me dicati o ns (i.e. fi nal T otal Daily D ose ( T D D) i n t he 
st u d y, i.e. E n d of Treat me nt, c o m pare d t o Baseli ne ( pre -Da y  1) T D D) f or a ge nts use d f or 
gl yc e mic c o ntr ol, li pi d c o ntr ol, or bl o o d press ure , a n d selecte d ot her s pecific bac k gr o u n d 
me dicati o ns will be s u m marize d as f oll o ws:

D ose i ncrease a n d decrease i n c o nc o mita nt me dicati o n f or gl yc e mic c o ntr ol , i.e. 
me dicati o ns f or
o
T y pe 1 a n d 2 Dia betes
o
M etf or mi n d ose cate g ories will als o be s u m mari ze d b y visit a n d treat me nt gr o u p
o
T he rele va nt data ca n be o btai ne d fr o m t he C M 0 0 1 _ 1 pa ge ( A nti-dia betic a ge nts 
cate g or y) fr o m t he e C R F.

D ose i ncrease a n d se paratel y decrease i n c o nc o mita nt li pi d -m o dif y i n g me dicati o ns, i.e. 
me dicati o ns f or
o
H D L -C decrease d
o
L D L -C i ncrease d
o
Tri gl yc eri des i ncrease d
o
T he rele va nt data ca n be o btai ne d fr o m t he C M 0 0 1 _ 2, 3 a n d 5 pa ges 
( Hy perc h olester ole mia cate g or y) fr o m t he e C R F.

D ose i ncrease a n d se paratel y decrease i n c o nc o mita nt bl o o d press ure ma na ge me nt 
me dicati o ns , i.e. me dicati o ns f or 
o
H y perte nsi o n
o
T he rele va nt data ca n be o btai ne d fr o m t he C M 0 0 1 _ 4 pa ges ( A nti-h y perte nsi o n 
a ge nts cate g or y) fr o m t he e C R F.

D ose i ncrease a n d se paratel y decrease i n c o nc o mita nt t hera pies relati n g t o:
o
H y p ot h y r oi dis m
o
T he rele va nt data ca n be o btai ne d fr o m t he C M 0 0 1 _ 6 pa ges ( Hy p ot h yr oi dis m 
me dicati o ns cate g or y ) fr o m t he e C R F.
T o assess f or c ha n ges i n alc o h ol c o ns u m pti o n d uri n g t he st u d y, c ha n ges fr o m baseli ne i n t he 
Alc o h ol use dis or ders i de ntificat i o n test (A U DI T ) q uesti o n naire t otal sc ore a n d t he A bs ol ute
Val ue i n P erce nt car b o h y drate deficie nt tra nsferri n relati ve t o t otal tra nsferri n (% C D T ), will 
als o be s u m marize d descri pti vel y o ver ti me .
Dr u g -I n d uce d Li ver I nj ur y ( DI LI) a n d H y’s L a w Criteri a  
A s u m mar y  ta ble will cate g orize t he n u m ber a n d perce nta ge of partici pa nts i n eac h treat me nt 
gr o u p w h o meet t he  
 criteria, defi ne d differe ntl y  f or partici pa nts wit h N or mal baseli ne 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 1
T M F D oc I D: 9 8. 0 3
a n d A b n or mal baseli ne (see A p pe n di x 6 of pr ot oc ol f or defi niti o n of p ote ntial H y ’s La w a n d 
P ote ntial DI LI )
Partici pa nt s meeti n g t he A S T/ A LT a n d T Bili criteria will be cate g orize d as p ote ntial H y ’s 
La w cases, a n d partici pa nt s w h o meet t he A S T/ A L T criteria b ut n ot t he T Bili criteria will be 
cate g orize d as p ote ntial DI LI cases.
e Dis h pl ots will be pr o d uce d ( Pea k A L T vs Pea k T Bili a n d Pea k A S T vs Pea k T Bili), wit h 
sect ors deli neate d by t he f oll o wi n g li nes t o i n dicate ele vati o ns i n A L T, A S T a n d T Bili:

t w o vertical li ne s at t he p oi nt at w hic h Pea k A L T ( or A S T) = 3 x U L N a n d at 8 x
U L N

a h oriz o ntal li ne at t he p oi nt at w hic h Pea k T otal Bilir u bi n = 1 x U L N a n d at 2 x U L N
Se parate pl ots will be pr o d uce d f or eac h treat me nt gr o u p, wit h males a n d fe males i de ntifie d 
usi n g differe nt s y m b ols.
4. A N A L Y SI S S E T S ( P O P U L A TI O N S F O R A N A L Y SI S )
F or p ur p oses of a n alysis, t he f oll o wi n g a n alysis sets are defi ne d:
N ote t hat partici pa nt s ra n d o mize d at sites ter mi nate d b y  t he S p o ns or f or G o o d Cli nical 
Practice ( G C) n o n -c o m plia nce will n ot ha ve t heir data i ncl u de d i n a n y s u m mar y o ut p uts or 
a nal ys es (i.e. th e y  will be e xcl u de d fr o m t he E val ua ble a n d Safet y A nalys is Sets), b ut t heir 
data will be retai ne d i n listi n gs as part of t he All Ra n d o mize d Par tici pa nts set bel o w.
T a ble 8.
A n al ysis Set Defi niti o ns
P artici p a nts A n alysis Set
Descri pti o n
E nr olle d 
All p artici p a nts w h o si g n t he 
I C D a n d are e nr olle d i nt o t he Mai n 
st u d y
R a n d o mly assi g ne d t o 
i nvesti g ati o n al pr o d uct
All r a n d o mize d p artici p a nts
Ev al u a ble (i.e. F ull A n alysis 
Set)
Defi ne d acc or di n g t o t he F ull A n alysis Set:
All r a n d o mize d p artici p a nts w h o t ake at le ast 1 d ose of i nvesti g ati o n al 
pr o d uct w h o h ave pr ovi de d b aseli ne d at a f or t he pri m ary e n d p oi nt (i.e. 
e val ua ble b aseli ne bi o psy d at a). P artici p a nts will be a n alyze d 
acc or di n g t o t he tre at me nt gr o u p t hey are r a n d o miz e d t o.

T he o nly exce pti o n t o t his is f or p artici p a nts r a n d o mize d bef ore
P r ot oc ol A me n d me nt 1 is e n acte d w h o are r a n d o mize d t o eit her of
t he 2 Q D d osi n g re gi me ns of D G A T 2i al o ne, will be a n alyze d
u n der t he c orres p o n di n g D G A T 2i BI D tre at me nt gr o u p.
S afety
All p artici p a nts w h o t ake at le ast 1 d ose of i nvesti g ati o n al pr o d uct. 
P artici p a nts will be a n alyze d acc or di n g t o t he tre at me nt t hey act u ally 
receive d.

T he o nly exce pti o n t o t his is f or p artici p a nts r a n d o mize d bef ore
P r ot oc ol A me n d me nt 1 is e n acte d w h o are r a n d o mize d t o eit her of
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 2
T M F D oc I D: 9 8. 0 3
T a ble 8 .
A n al ysis Set Defi niti o ns
t he 2 Q D d osi n g re gi me ns of D G A T 2i al o ne, will be a n alyze d 
u n der t he c orres p o n di n g D G A T 2i BI D tre at me nt gr o u p.
Defi ne d A n alysis D at a Set ( at 
t he d at a level) – e n d p oi nt 
s pecific
Descri pti o n
All bi o psy -derive d e n d p oi nts
Bi o psy -b ase d C o m p osite 
Esti m a n d
If a p artici p a nt disc o nti n ues tre at me nt or fr o m t he st u dy d ue t o l ack of 
effic acy or t oler ati o n pri or t o Week 4 8 or if t hey d o n ot h ave e val ua ble 
Week 4 8 Bi o psy d at a, t hey will be c o nsi dere d t o be a n o n -res p o n der. If 
t he y wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of 
efficac y or t olerati o n) a n d ha ve e val ua ble bi o ps y data at wit h dra w al or 
Wee k 4 8, t hese data w ill be utilize d t o deter mi ne w het her t he y are a 
res p o n der or n ot.
Bi o ps y -base d C o m p osi te 
Esti ma n d f or ‘ W orse ni n g fr o m 
Baseli ne’ e x pl orat or y li ver 
bi o ps y e n d p oi nts
If a partici pa nt disc o nti n ues treat me nt or fr o m t he st u d y d ue t o lac k of 
efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, t he y will be c o nsi dere d t o be a res p o n der . If a 
partici pa nt i m pr o ve s or r e mai ns t he sa me c o mpare d t o baseli ne, t he n 
t hat partici pa nt will be ter me d as a n o n-res p o n der. If t he y wit h dra w 
fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or 
t olerati o n) a n d ha ve e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, 
t hese data will be utilize d t o deter mi ne w het her t he y are a res p o n der or 
n ot.
Bi o psy -b ase d H y p ot hetical
Esti m a n d
A ny av ail a ble bi o psy d at a f or all p artici p a nts c ollecte d bef ore or at t he 
ti me of tre at me nt wit h dr a w al will be i ncl u de d i n t he a n alysis, eve n if 
t hey h ave wit h dr a w n fr o m tre at me nt f or l ack of effic acy or t oler ati o n. 
E n d p oi nt d at a c ollecte d after tre at me nt wit h dr a w al will be ce ns ore d.
T his a nal ysis will be carrie d o ut u n der t he ass u m pti o n t hat missi n g 
data at Wee k 4 8 are missi n g at ra n d o m c o n diti o nal o n d ose a n d t he 
strata f or me d b y t he c o variates 
All M RI -P D F F -derive d e n d p oi nts (i n I m a gi n g S u bst u dy)
M RI -b ase d H y p ot hetical 
Esti m a n d
A ny av ail a ble M RI d a t a f or all p artici p a nts c ollecte d bef ore or at t he 
ti me of tre at me nt wit h dr a w al will be i ncl u de d i n t he a n alysis, eve n if 
t hey h ave wit h dr a w n fr o m tre at me nt f or l ack of effic acy or t oler ati o n. 
E n d p oi nt d at a c ollecte d after tre at me nt wit h dr a w al will be ce ns ore d.
M issi n g data at Wee k 4 8 will n ot be i m p ute d. M M R M a dj uste d f or 
c o variates will be use d t o o btai n L S mea n esti mate at Wee k 4 8 f or 
eac h d ose, w hic h will t he n be use d i n fitti n g t he Ba yesia n E ma x m o del 
D ata f or all partici pa nts will be assesse d t o deter mi ne if partici pa nts meet t he criteria f or 
i ncl usi o n i n eac h a nalys is p o p ulati o n pri or t o u n bli n di n g a n d releasi n g t he data base a n d 
classificati o ns will be d oc u me nte d per sta n dar d o perati n g pr oce d ures.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 3
T M F D oc I D: 9 8. 0 3
4. 1. Tre at me nt Mis all oc ati o ns 
I n or der t o assess treat me nt misall ocati o ns , dr u g d osi n g i nf or mati o n will be c ollecte d. 
Treat me nt misall ocati o ns will be ha n dle d as f oll o ws. If a partici pa nt is: 

Ra n d o mize d b ut n ot treate d (i.e. if t he partici pa nt has a ra n d o mizati o n n u m ber b ut n o 
treat me nt or P K data) , t he n t he partici pa nt will be e xcl u de d fr o m all t he statistical 
a nal ys es. 

Ra n d o mize d b ut t o o k i nc orrect treat me nt, t he n t he partici pa nt will be re p orte d u n der 
his/ her ra n d o mize d gr o u p f or all efficac y a nal ys es. T he partici pa nt will be re p orte d f or 
safety a n d P har mac o ki netic (P K ) a nal ys is u n der his/ her act ual ra n d o mize d ar m. 

Partici pa nts ra n d o mize d t o t he i nc orrect strat u m at baseli ne will be all ocate d t o t he 
c orrect strat u m f or a nal yses usi n g S C R 2 bi o ps y  eli gi bilit y res ults c ollecte d i n t he st u d y.

Treate d b ut n ot ra n d o mize d, t he n b y  defi niti o n t he partici pa nt will be e xcl u de d fr o m t he 
efficac y a nalys es si nce ra n d o mize d ar m is missi n g, b ut will be re p orte d u n der t he d osi n g 
re gi me n t he y act uall y recei ve d f or all safety a n d P K a nal ys es. 
N ote: Pa rtici pa nts ra n d o mize d t o eit her of t he 2 Q D d osi n g re gi me ns of D G A T 2i will be 
a nal yz e d acc or di n g t o t he c orres p o n di n g BI D d osi n g re gi me n of D G A T 2i al o ne ( mai ntai ni n g 
t he sa me t otal dail y d ose). If a partici pa nt has bee n re -scree ne d t he n t he y will o nl y be 
c o u nte d o nce i n all s u m maries u n der t he ori gi nal u ni q ue S SI D # . I nf or mati o n c ollecte d o n t he 
De m o gra p h y pa ge of t he C R F ca n be use d t o deter mi ne a n y pre vi o us partici pa nt I D t hat a 
partici pa nt m a y  ha ve bee n scree ne d u n der i n t his st u dy.  
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S
T he st u d y  will be a nalyz e d a n d re p orte d o nce all ra n d o mize d partici pa nt s ha ve c o m plete d t he 
st u d y ( or disc o nti n ue d), a n d f oll o wi n g st u d y-le vel data set release .
5. 1. H y p ot heses a n d Decisi o n R ules
T he re are n o f or mal hy p ot hesis tests pla n ne d f or t his st u d y, a n d a s u m mar y of t he ge neral 
a nal ys is met h o d ol o gies t o be utilize d is s h o w n in Ta ble 9 bel o w . 
T a ble 9 . 
S u m m ar y of A n al ysis Met h o ds
Tre at me nt
D ose gr o u p 
C o m p ar at or
Pri m ar y A n al ysis Met h o d ol o g y f or e ac h 
c o m p aris o n
Place b o 
Place b o
-
-
D G A T 2i
2 5 m g BI D 
Place b o
Ba yesia n E ma x D R m o delli n g /E R m o delli n g
7 5 m g BI D 
Place b o
Ba yesia n E ma x D R m o delli n g /E R m o delli n g
1 5 0 m g BI D
Place b o
Ba yesia n E ma x D R m o delli n g /E R m o delli n g
3 0 0 m g BI D
Place b o
Ba yesia n E ma x D R m o delli n g /E R m o delli n g
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 4
T M F D oc I D: 9 8. 0 3
T a ble 9 . 
S u m m ar y of A n al ysis Met h o ds
Tre at me nt
D ose gr o u p 
C o m p ar at or
Pri m ar y A n al ysis Met h o d ol o g y f or e ac h 
c o m p aris o n
D G A T 2i + A C Ci
1 5 0 m g BI D + 5 
m g BI D
1 5 0 m g BI D
Pair wise c o m paris o n ( L o gistic Re gressi o n or 
A N C O V A) / Li near D R m o delli n g (if 
re q uire d)
3 0 0 m g BI D + 
1 0 m g BI D
3 0 0 m g BI D
Pair wise c o m paris o n ( L o gistic Re gressi o n or 
A N C O V A) / Li near D R m o delli n g (if 
re q uire d)
All 9 0 % cre di ble or c o nfi de nce i nter vals a n d 5 0 % c o nfi de nce i nter vals will be assesse d as 
o ne- si de d.
5. 2. Ge ner al Met h o ds
F or t he assess me nt of d ose -res p o nse, t he f oll o wi n g BI D treat me nt gr o u ps (at a mi ni m u m) 
will be i ncl u de d i n a Ba yesia n E ma x d ose -res p o nse m o del:

Place b o

D G A T 2i 2 5 m g BI D 

D G A T 2i 7 5 m g BI D – i ncl u di n g t h ose ra n d o mize d t o 1 5 0 m g Q D

D G A T 2i 1 5 0 m g BI D – i ncl u di n g t h ose ra n d o mize d t o 3 0 0 m g Q D

D G A T 2i 3 0 0 m g BI D
Ot her treat me nt gr o u ps will be a nal yz e d t o assess t he c o m paris o ns as s h o w n bel o w:

D G A T 2i 1 5 0 m g BI D + A C Ci 5 m g BI D vs Place b o a n d vs D G A T 2i 1 5 0 m g BI D

D G A T 2i 3 0 0 m g BI D + A C Ci 1 0 m g BI D vs Place b o a n d vs D G A T 2i 3 0 0 m g BI D
5. 2. 1. A n al yses f or Bi n ar y E n d p oi nts
D ose Res p o nse A nal ys es
F or bi nar y  (res p o n der) e n d p oi nts i n t he st u d y, t o be a nal yz e d u n der a c o m p osite esti ma n d 
strate g y all c ases of wit h dr a w al fr o m tre at me nt f or l ack of effic acy or t oler ati o n or if a Wee k 
4 8 bi o ps y  is n ot perf or me d will be c o nsi dere d t o be n o n -res p o n ders. S uc h e n d p oi nts will be 
a n alyze d by fitti n g a B ayesi a n E m ax d ose -res p o nse m o del. T his m o del will be utilize d t o 
c h ar acterize t he d ose res p o nse acr oss all BI D tre at me nt gr o u ps, t o esti m ate t he pr o p orti o n of 
res p o n ders ( a n d 9 0 % cre di ble i nterv al) f or e ac h BI D d ose st u die d, a n d t o esti m ate t he 
pl ace b o - a dj uste d pr o p orti o n of res p o n ders f or e ac h d ose ( a n d 9 0% cre di ble i nterv al). If t he 
E m ax d ose -res p o nse m o del c a n n ot be fitte d t o t he d at a, t he n ot her m o dels t h at all o w d ose 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 5
T M F D oc I D: 9 8. 0 3
res p o nse t o be esti m ate d will be fitte d, ie, li ne ar, l o g-li ne ar or ex p o ne nti al. N o a dj ust me nt f or 
m ulti ple c o m p aris o ns will be m a de.
T he 3 p ara meter E ma x m o del will be fit te d t o t he res p o nse at Wee k 4 8 o n place b o a n d all 
D G A T 2i m o n ot hera p y BI D d oses – t he act ual d ose t o be m o delle d s h o ul d be t he T otal Daily 
D ose (i.e. BI D d ose * 2) . If t he m o del c o n ver ges, m o del esti mate d para meters will be 
pres e nte d al o n g wit h t heir 9 0 % cre di ble i nter vals. T he m o del pr ojecte d place b o a dj uste d 
treat me nt effect f or eac h BI D d ose (i.e. T otal Dail y  D ose) will als o be prese nte d al o n g wit h 
t heir cre di ble i nter vals. 
T he Ba y esia n esti mati o n of t he E ma x m o del uses pri or distri b uti o ns o n t he place b o res p o nse
( E 0), d ose t hat pr o d uces half ma xi mal dr u g effect ( E D5 0) a n d E ma x para meters.  T he 
s pecificati o n of t he E ma x m o del a n d t he pri or distri b uti o ns f or s o me of its para meters are 
base d o n t hree meta -a nal yses of cli nical d ose res p o nse fr o m m ore t ha n 1 0 0 c o m p o u n ds 
(T h o mas, 2 0 1 4 ; T h o mas & R o y, 2 0 1 7 ; W u, 2 0 1 7 ).  
T he D G A T 2i E D 5 0 f or t he hist ol o gical -base d pri mar y  e n d p oi nt has bee n ass u me d t o be 
sli g htl y hi g her t ha n t he pr ojecte d E C5 0 f or re d ucti o n i n li ver fat w hic h was esti mate d fr o m a 
preli mi nar y  p o p ulati o n p har mac o ki netic m o del base d o n pre vi o us cli nical st u dies wit h 
D G A T 2i. T heref ore, t he D G A T 2i E D 5 0 was esti mate d t o be a p pr o xi matel y  3 0 m g BI D ( T D D 
= 6 0 m g) . T he s u bsta ntial u ncertai nt y i n E D 5 0 val ues was assesse d i n t he meta -a nal yses of 
cli nical d ose res p o nse st u dies ( T h o mas, 2 0 1 4 ). T heref ore, base d o n t he meta-a nal ys es, a 
scale d t-distri b uti o n ( w it h 5 de grees of free d o m) is pla n ne d t o be use d t hat is f oc use d o n t he 
i nitial pr ojecte d E D5 0= 3 0 m g BI D, wit h a scale para meter of 0. 6.  A n or mal pri or distri b uti o n 
f or t he l o git of t he place b o res p o nse ce ntere d at l o git( 0. 1 6) wit h a pri or sta n dar d de viatio n of 
2. 0 (l o gistic scale) is pla n ne d t o be use d, w hic h yi el ds a wea k diff use pri or distri b uti o n f or 
t he place b o res p o nse.  A n or mal pri or distri b uti o n f or t he E ma x para meter will als o be use d, 
ce ntre d o n t he a ntici pate d E ma x ( 0. 6) o n t he l o gistic scale. T his pri or distri b uti o n will als o be 
diff use o n t he l o gistic scale wit h a pri or sta n dar d de viati o n of 2. 0.
T he pr o p orti o n of pri mar y e n d p oi nt res p o n ders i n eac h treat me nt gr o u p will be a nal yz e d b y 
fitti n g a Ba yesia n E ma x m o del t o t he data t o c haracterize t he d ose res p o nse acr oss all 
treat me nt gr o u ps a n d t o esti mate t he pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or 
eac h d ose st u die d, a n d t o esti mate t he place b o -a dj uste d pr o p orti o n of res p o n ders f or eac h 
d ose (a n d 9 0 % cre di ble i nter val). If a n E ma x m o del ca n n ot be fitte d t o t he data, t he n ot her 
m o dels t hat all o w d ose res p o nse t o be esti mate d will be fitte d, i.e. li near, l o g -li near or 
e x p o ne ntial.
N ote t hat a si milar met h o d ol o g y will be use d f or t he e x pl orat or y  ‘ w orse ni n g fr o m baseli ne’ 
li ver bi o ps y e n d p oi nts, b ut f or t his E sti ma n d 3. 1 will be utilize d.
Pair wise Treat me nt C o m paris o ns
T he c o m p aris o n of t he pr o p orti o n of res p o n ders f or bi nar y  res p o n der e n d p oi nts f or D G A T 2i 
BI D d oses vs place b o, a n d D G A T 2i + A C Ci BI D d oses vs place b o a n d c orres p o n di n g 
D G A T 2i BI D m o n ot hera p y  d oses will be a n alyze d usi n g l o gistic re gressi o n m o dels, 
i ncl u di n g baseli ne ( S C R 2 Eli gi bilit y) fi br osis sta ge ( F 2/F 3) as a fact or, t o esti m ate t he 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 6
T M F D oc I D: 9 8. 0 3
pr o p orti o n of res p o n ders i n e ac h tre at me nt gr o u p a n d o d ds r ati o a n d ris k differe nce ( a n d 
c orres p o n di n g 9 0 % C Is) f or e ac h tre at me nt c o m p aris o n. Ris k differe nce a n d 2- si de d 9 0 % 
c o nfi de nce i nter val f or ris k differe nce will be calc ulate d b y  usi n g t he o bser ve d place b o rate 
a n d esti mate d o d ds rati o fr o m t he l o gistic re gressi o n m o del.  F or c o m p aris o ns of 
D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot her a py d oses c orres p o n di n g 
5 0 % CI will als o be pr ovi de d. N o a dj ust me nt f or m ulti ple c o m p aris o ns will be m a de.
5. 2. 2. A n al yses f or C o nti n u o us E n d p oi nts
D ose Res p o nse A nal ys es
C o nti n u o us e n d p oi nt s will be a nal yz e d usi n g a Ba yesia n E ma x d ose-res p o nse m o del, fitte d t o 
L S mea ns o btai ne d fr o m t he M M R M m o del fitte d t o t he c o nti n u o us e n d p oi nt t o be a nal yz e d. 
T his Ba yesia n E ma x m o del will be utilize d t o c haracterize t he d ose res p o nse acr oss all BI D 
treat ment gr o u ps, t o esti mate t he p ost eri or mea n relati ve c ha n ge fr o m baseli ne (a n d 9 0 % 
cre di ble i nter val) f or eac h BI D d ose st u die d, a n d t o esti mate t he place b o-a dj uste d p osteri or 
mea n relati ve c ha n ge fr o m baseli ne f or eac h d ose (a n d 9 0 % cre di ble i nter val ). If t he Ema x
d ose -res p o nse m o del ca n n ot be fitte d t o t he data, t he n ot her m o dels t hat all o w d ose res p o nse 
t o be esti mate d will be fitte d, ie, li near, l o g-li near or e x p o ne ntial. N o a dj ust me nt f or m ulti ple 
c o m paris o ns will be ma de.
A pri or of 
% f or t he place b o res p o nse has bee n esti mate d fr o m t he  
 st u d y a n d a 
pri or sta n dar d de viati o n of 
 ti mes t he resi d ual S D fr o m t he M M R M m o del will be use d, 
w hic h y iel ds a wea k diff use pri or distri b uti o n f or t he place b o res p o nse.  T he mea n of t he 
pri or distri b uti o n of t he differe nce i n res p o nse bet wee n t he tar get d ose a n d place b o is set t o 
zer o s o t hat t he pri or of t he mea n differe nce o ver place b o is ce ntre d at n o effect. T he S D of 
t he pri or distri b uti o n of t he differe nce i n res p o nse bet wee n t he tar get d ose a n d place b o will 
be
 ti mes t he resi d ual S D fr o m t he M M R M m o del.
Pair wise Treat me nt C o m paris o ns
T o esti mate pair wise treat me nt c o m paris o n s f or D G A T 2i BI D d oses vs place b o, a n d 
D G A T 2i + A C Ci BI D d oses vs place b o a n d c orres p o n di n g D G A T 2i BI D m o n ot hera p y d oses, 
c o nti n u o us e n d p oi nts will be a n alyze d usi n g a n A N C O V A perf or me d o n l o g -tr a nsf or me d 
relati ve c h a n ge fr o m b aseli ne wit h tre at me nt ( w here rel ative c h a n ge fr o m b aseli ne = p ost 
b aseli ne v al ue/ b aseli ne v al ue) a n d b aseli ne fi br osis st a ge ( F 2/ F 3) as f act ors, a n d l o g -
tr a nsf or me d b aseli ne val ue of t he e n d p oi nt as a c ov ari ate. Esti m ates of t he me a n rel ative 
c h a n ges f or e ac h tre at me nt c o m p aris o n a n d t he c orres p o n di n g 9 0 % CI will be o bt ai ne d fr o m 
t he m o del. T he L S me a n rel ative c h a n ges ( R C) a n d t heir C Is will be ex p o ne nti ate d, a n d 
perce nt c h a n ge will t he n be deter mi ne d as f oll o ws: Perce nt c h a n ge = 1 0 0 * ( R C – 1) .  F or 
c o m p aris o ns of D G A T 2i + A C Ci BI D vs t he c orres p o n di n g D G A T 2i BI D m o n ot her a py d oses 
t he c orres p o n di n g 5 0 % CI will als o be pr ovi de d. N o a dj us t me nt f or m ulti ple c o m p aris o ns 
will be m a de.
Descri ptive s u m m aries of t he o bserve d v al ues a n d perce nt c h a n ge fr o m b aseli ne f or e ac h 
tre at me nt gr o u p will als o be pr o d uce d.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 7
T M F D oc I D: 9 8. 0 3
Treat me nt effects o ver ti me
A M i xe d-effects m o del wit h re peate d meas ures (M M R M ) will be use d f or t he a n alysis of 
c o nti n u o us e n d p oi nts wit h m ore t h a n o ne p ost -b aseli ne c ollecti o n ti me p oi nt. All o bserve d 
d at a c ollecte d d uri n g t he p ost -b aseli ne tre at me nt peri o d will be utilize d , i ncl u di n g f oll o w- u p 
data i n or der t o assess t he i m pact of st o p pi n g treat me nt o n t he e n d p oi nt 
. T he 
M M R M a n alysis will be perf or me d wit h tre at me nt, st u dy week ( n o mi n al ti me p oi nt) a n d 
tre at me nt- by-st u dy week i nter acti o n as fixe d effects, a n d b aseli ne v al ue of t he a n alysis 
e n d p oi nt as a c o variate , baseli ne ( S C R 2 Eli gi bilit y) fi br osis sta ge ( F 2/ F 3) as a fact or. If t he 
e n d p oi nt bei n g a n alyze d is l o g -tr a nsf or me d, t he b aseli ne v al ue of t he a n alysis e n d p oi nt will 
als o be l o g -tr a nsf or me d. Re pe ate d me as ures m o del wit h u nstr uct ure d c o varia nce m atrix will 
be utili ze d. If t his d oes n ot c o nver ge t he n c o m p o u n d sy m metry str uct ure will be c o nsi dere d. 
A d diti o n ally, t he n u m ber of c ov ari ates m ay be re d uce d t o i m pr ove m o del fit. Esti m ates of 
tre at me nt effects will be assesse d usi n g Least S q uare Mea ns (L S Ms ) a n d CIs at e ac h ti me 
p oi nt. L S M differe nce f or e ac h c o m p aris o n al o n g wit h t he c orres p o n di n g 9 0 % CI will be 
pr ovi de d. F or l o g -tra nsf or me d e n d p oi nts, the mea n relati ve c ha n ges ( R C) a n d t heir C Is will 
be e x p o ne ntiate d a n d perce nt c ha n ge will t he n be deter mi ne d as f oll o ws : Perce nt c ha n ge = 
1 0 0 * ( R C – 1).  If t here are m aj or devi ati o ns fr o m t he st atistic al ass u m pti o ns u n derlyi n g t his 
m o del t he n alter n ative tr a nsf or m ati o ns (e g, l o g) or n o n -p ar a metric a n alyses m ay be 
prese nte d.
5. 2. 3. A n al yses f or C ate g oric al E n d p oi nts
N ot a p plica bl e
5. 2. 4. A n al yses f or Ti me -t o- E ve nt E n d p oi nt s
T he occ urre nce of a dj u dicate d ti me-t o-e ve nt e n d p oi nts over ti me u p t o Week 4 8 will be 
s u m m arize d descri ptively by tre at me nt gr o u p.
5. 3. Met h o ds t o M a n a ge Missi n g D at a
F or c o m p osite esti ma n ds, if a partici pa nt disc o nti n ue s treat me nt or fr o m t he st u d y d ue t o lac k 
of efficac y  or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve a n y e val ua ble Wee k 4 8 
Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n-res p o n der (i.e. res p o nse will be i m p ute d as 
‘ n o n-res p o nse’). If t he y wit h dra w fr o m t he st u d y f or ot her reas o ns ( n ot relate d t o lac k of 
efficac y or t olerati o n) a n d ha ve e val ua ble bi o psy data at wit h dra wal or Wee k 4 8, t hese data 
will be utilize d t o deter mi ne w het her t he y  are a res p o n der or n ot.
F or h y p ot hetical estima n ds , f or t he bi o ps y res p o n der e n d p oi nts, a nal ys is will be carrie d o ut 
u n der t he ass u m pti o n t hat missi n g data at Wee k 4 8 are missi n g at ra n d o m c o n diti o nal o n 
d ose a n d t he strata f or me d b y t he c o variates ., T he u nc o n diti o nal esti mate of treat me nt effect
wil l be o btai ne d t hr o u g h c o variate a dj ust me nt (ie, a vera ge d o ver strata f or me d b y baseli ne 
fi br osis stat us ( F 2/ F 3) a n d meta b olic stat us ( wit h or wit h o ut T 2 D M)). F or t he c o nti n u o us 
e n d p oi nt (i.e. perce nta ge c ha n ge fr o m baseli ne i n li ver fat), missi n g data at W ee k 4 8 will n ot 
be i m p ute d. M M R M a dj uste d f or c o variates will be use d t o o btai n L S  mea n esti mate at Wee k 
4 8 f or eac h d ose, w hic h will t he n be use d i n fitti n g t he Ba yesia n E ma x m o del .
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 8
T M F D oc I D: 9 8. 0 3
F or q ua ntitati ve bi o ps y a nal yses, i f t he S C R 2 C ha n ge fr o m Baseli ne bi o ps y assess me nt is 
dee me d t o be ‘ N o n -e val ua ble’ t he S C R 2 El igi bilit y  bi o ps y assess me nt will be use d i nstea d. If 
t he Wee k 4 8 C ha n ge fr o m Baseli ne bi o ps y assess me nt is dee me d t o be ‘ N o n -e val ua ble’, t he 
Wee k 4 8 I P V bi o ps y assess me nt will be use d i nstea d (if t his is a vaila ble, as n ot all 
partici pa nts ha d a Wee k 4 8 I P V assess me nt).
T a ble 1 0 . H a n dli n g n o n -e v al u a ble hist ol o gic al c h a n ge-fr o m-b aseli ne d at a 
Sce n ari o
H a n dli n g
C F B -S C R = n o ne val ua ble (f or 
N A S or fi br osis c o mp o ne nt(s) 
re q uire d f or e n d p oi nt)

Utilize S C R 2 eli gi bilit y res ults f or w hic he ver c o m p o ne nt(s) is/are 
n o ne val ua ble (ie, c o nse ns us res ults if a vaila ble); if o nl y parallel is 
a vaila ble, select res ults fr o m pat h ol o gists t hat ha d b ot h t he l o west
N A S sc ore a n d / or l o west fi br osis sta ge

Q ualitati ve assess me nt will o nl y i ncl u de data fr o m w hic he ver
c o m p o ne nt is e val ua ble, if a n y (eit her N A S c o m p o ne nts or fi br osis)
C F B -W k 4 8/ D C = n o ne val ua ble 
(f or N A S or fi br osis 
c o m p o ne nt(s) re q uire d f or 
e n d p oi nt)

If case di d n ot c o m plete I P V 
c o u nt as n o n -res p o n der 

If case c o m plete d I P V, utilize Wee k 4 8 -I P V res ults f or w hic he ver 
c o m p o ne nt(s) is/are n o ne val ua ble as Wee k 4 8 res ult i n C F B (ie, 
I P V c o nse ns us res ults if a vaila ble); if o nl y parallel is a vaila ble, 
select res ults fr o m pat h ol o gist t hat ha d hi g hest N A S sc ore a n d/ or 
fi br osis sta ge

Q ualitati ve assess me nt will o nl y i ncl u de data fr o m w hic he ver 
c o m p o ne nt is e v al ua ble, if a n y (eit her N A S c o m p o ne nts or fi br osis)
O bser ve d cases (i ncl u di n g a ny alter nati ve cases utilize d f or a nal ysis as descri be d a b o ve) will 
be use d w he n a nal yz i n g varia bles usi n g a n M M R M .
F or t he a nal ys is of safet y e n d p oi nts, t he s p o ns or data sta ndar d r ules f or i m p utati o n will be 
a p plie d.
P K C o nce ntr ati o ns bel o w t he li mit of q u a ntific ati o n

I n all data prese ntati o ns (e xce pt listi n gs), c o nce ntrati o ns bel o w t he li mit of q ua ntificati o n 
( B L Q) will be set t o zer o. In listi n gs B L Q val ues will be re p orte d as “ < L L Q”, w here L L Q 
will be re place d wit h t he val ue f or t he l o wer li mit of q ua ntificati o n.
De vi ati o ns, missi n g c o nce ntr ati o ns, a n d a n o m al o us v al ues f or P K
I n s u m mar y ta bles, statistics will be calc ulate d ha vi n g set c o nce ntrati o ns t o missi n g if o ne of 
t he f oll o wi n g cases is tr ue:
1. A c o nce ntrati o n has bee n c ollecte d as N D (ie n ot d o ne) or N S (ie n o sa m ple),
2. A de viati o n i n visit wi n d o w is of s ufficie nt c o ncer n or a c o nce ntrati o n has bee n fla g ge d 
a n o mal o us b y t he p har mac o ki neticist.
N ote t hat s u m mar y  statistics will n ot be prese nte d at a partic ular visit if m ore t ha n 5 0 % of t he 
P K data are missi n g.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 3 9
T M F D oc I D: 9 8. 0 3
Effic ac y a n d P h ar m ac o d y n a mic (P D ) e n d p oi nts

Missi n g data f or all efficac y a n d P D e n d p oi nts will be treate d as s uc h a n d n o i m p ute d 
val ues will be deri ve d w he n prese nti n g descri pti ve statistics at sc he d ule d assess me nts.

C o nce ntrati o ns bel o w L o wer Li mit of Q ua ntificati o n ( L L Q) will be set t o half -L L Q (ie 
L L Q/ 2) f or s u m mar y  o ut p uts; i n listi n gs B L Q val ues will be re p orte d as “ < L L Q”. 

Deri ve d data b y calc ulati o n (e g i n direct bilir u bi n) will n ot f oll o w t he r ule descri be d 
a b o ve a n d will be re p orte d as < L L Q (i n listi n gs) wit h a deri ve d val ue of ( < ne gati ve 
val ue > mi n us 0. 0 0 0 1 = p ositi ve val ue) w he n ge nerati n g s u m mar y  statistics, as re q uire d.

A n y  val ues a b o ve t he U p per Li mit of Q ua ntificati o n ( U L Q) will be assi g ne d t o t he U L Q 
f or dis pla y  p ur p oses i n fi gures a n d f or c o m p utati o n of s u m mar y  statistics; i n listi n gs 
U L Q val ues will be re p orte d as “ > U L Q”.

La b orat or y para meters t hat are n ot c orrectl y  c ollecte d (e g, c ollecte d i n n o n-faste d w he n 
re q uire d t o be c ollecte d i n faste d state) s h oul d n ot be use d a n d set t o missi n g.
D ate of Birt h

O nl y  t he ye ar of birt h is c ollecte d i n t he C R F, t heref ore t he da y a n d t he m o nt h will be 
i m p ute d as 0 1 -Ja n i n or der t o deri ve a c o m plete Date of Birt h. 
6. A N A L Y S E S A N D S U M M A RI E S
6. 1. Pri m ar y E n d p oi nt (s)
6. 1. 1. Pr o p orti o n of p artici p a nts ac hie vi n g ce ntr all y a dj u dic ate d res ol uti o n of N A S H 
wit h o ut w orse ni n g of fi br osis or i m pr o ve me nt i n fi br osis b y ≥1 st a ge wit h o ut w orse ni n g 
of N A S H, or b ot h, at Wee k 4 8
6. 1. 1. 1. M ai n
A n al ysis

Esti ma n d strate g y: C o m p osite (Secti o n 2. 1. 1 ).

A nal y sis set: E val ua ble ( S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he pri mar y  
e n d p oi nt (i.e. baseli ne bi o ps y  data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 will be a nal yz e d usi n g a Ba yesia n E ma x d ose -res p o nse m o del. F or assessi n g 
pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal yze d usi n g 
l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as factors
( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or to Wee k 4 8 or if t he y  d o n ot ha ve 
e val ua ble Wee k 4 8 Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n-res p o n der. If t he y 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 0
T M F D oc I D: 9 8. 0 3
wit h dra w f or ot her reas o ns ( n ot relate d t o lac k of efficac y or t olerati o n) a n d ha ve 
e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, t hese data will be utilize d t o deter mi ne 
w het her t he y  are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t he pri mar y  e n d p oi nt at Wee k 4 8 will be 
prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese n te d at Wee k 4 8.  F or 
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y 
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d .  
6. 1. 1. 2. Se nsiti vit y /S u p ple me nt ar y A n al yse s
Se nsiti vit y  A nalys es
I n or der t o assess t he se nsiti vit y of t he d ose B a y esia n E ma x d ose -res p o nse m o del t o t he 
l ocati o n a n d i nf or mati ve ness of t he pri or distri b uti o ns, se nsiti vit y a nal yses ma y be perf or me d 
t hat will utilize alter nati ve pri or distri b uti o ns.
S u p ple me ntar y A nal ys es
A n a nal ys is t hat assesses t he pri mar y e n d p oi nt usi n g a h y p ot hetical esti ma n d strate g y 
( Secti o n 2. 1. 3 ) will be perf or me d. Usi n g a hy p ot hetical esti ma n d strate g y i n t he st u d y  
p o p ulati o n of ra n d o mize d a n d treate d partici pa nts wit h bi o ps y-c o nfir me d N A S H a n d fi br osis, 
as assesse d b y t he s p o ns or -i de ntifie d ce ntral pat h ol o gist(s), t he treat me nt effect of D G A T 2i 
d oses a d mi nistere d al o ne a n d c oa d mi nistrati o n of D G A T 2i + A C Ci relati ve t o place b o, a n d 
c oa d mi nistrati o n of D G A T 2i + A C Ci, relati ve t o D G A T 2i al o ne will be esti mate d , i n ter ms 
of esti mati n g t he pr o p orti o n of 'cli nical res p o n ders', defi ne d as partici pa nts ac hie vi n g 
ce ntrall y a dj u dicate d: res ol uti o n of N A S H wit h o ut w orse ni n g of fi br osis or i m pr o ve me nt i n 
fi br osis b y ≥1 sta ge wit h o ut w orse ni n g of N A S H, or b ot h, at Wee k 48, ass u mi n g all patie nts 
ha d re mai ne d i n t he trial a n d recei ve d treat me nt as pla n ne d wit h o ut wit h dra wal u p t o 4 8 
wee ks. All treat me nt effect c o ntrasts will be o btai ne d t hr o u g h fitti n g t he Ba y esia n d ose-
res p o nse a n d/ or e x p os ure-res p o nse m o dels wit h a l o git tra nsf or mati o n, or l o gistic re gressi o n 
m o dels.
A d diti o nal a nal y ses ma y als o be perf or me d t o assess partici pa nts w h ose S C R 2 assess me nt 
w he n as part of t he fi nal paire d bi o psy assess me nt was differe nt t o t he ori gi nal S C R 2 
assess me nt f or eli gi bilit y . S u m marie s of pr o p orti o n of partici pa nts wit h N o C ha n ge, 
I m pr o ve me nt or W orse ni n g i n eac h c o m p o ne nt of N A S a n d Fi br osis fr o m t he q ualitati ve 
c o m paris o n of baseli ne t o t he e n d of treat me nt bi o ps y res ults will be pr o vi de d. S hift ta bles of 
B aseli ne/S C R 2 vs Wee k 4 8/ E O T i n di vi d ual N A S c o m po ne nt sc ores a n d fi br osis gra des will 
be pr o d uce d. If a partici pa nt d oes n’t ha ve a pair of C F B res ult s (f or S C R 2 a n d Wee k 
4 8/ E O T ) (e ven after assessi n g if ot her p ossi ble res ults are a ble t o be ut ilize d as descri be d i n 
Ta ble 1 0 ), t he n t heir S C R 2 E li gi bilit y res ult will be ta b ulate d vs a ‘ Missi n g’ W ee k 4 8 res ult.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 1
T M F D oc I D: 9 8. 0 3
T o assess c o nc or da nce of i ntra- pat h ol o gist re vie ws, a ra n d o m sa m ple of bi o psies will be 
selecte d ( 1 0 % f or eac h of t he scree ni n g bi o psies a m o n gst t h ose ulti matel y ra n d o mize d a n d a 
se parate 1 0 % f or t he e n d of treatme nt bi o psies o btai ne d ) t o be re vie we d a gai n b y  t he 2 
ce ntral pat h ol o gists (i.e. I P V re vie w) – wit h t he re vie w pr ocess i de ntical t o t hat use d f or 
S C R 2 eli gi bilit y . Ka p pa statistics (si m ple a n d wei g hte d) a n d 9 0 % CI will be esti mate d base d 
o n t he i nitial a n d sec o n d assess me nts of eac h ce ntral pat h ol o g ist. F or t he scree ni n g bi o ps y 
c o m paris o ns , t he S C R 2 E li gi bilit y bi o ps y  will be t he i nitial assess me nt t hat is c o m pare d t he 
sec o n d assess me nt. F or t he Wee k 4 8/ E O T
bi o ps y c o m paris o ns , t he Wee k 4 8/ e n d of treat ment 
bi o ps y fr o m t he Bli n de d si de -b y -si de (C ha n ge fr o m B aseli ne) assess me nt will be t he i nitial 
assess me nt t hat is c o m pare d t he sec o n d assess me nt. C o nc or da nce of i nter -pat h ol o gist 
re vie ws ( Pat h ol o gist 1 vs Pat h ol o gist 2) will als o be assesse d f or Baseli ne/ S C R 2 a n d Wee k 
4 8/ E O T se paratel y.  I n a d diti on, s u m maries of t he pr o p orti o n of bi o psies at eac h visit t hat 
ha d t o u n der g o c o nse ns us re vie w a n d a s u m mar y of s cree ni n g bi o ps ies t hat re mai ni n g 
eli gi ble w h e n re vie we d as part of t he C F B assess me nt will be pr o d uce d ( b y treat me nt gr o u p).
6. 2. Sec o n d ar y E n d p oi nt( s)
6. 2. 1. Pr o p orti o n of p artici p a nts ac hie vi n g ce ntr all y a dj u dic ate d res ol uti o n of N A S H 
wit h o ut w orse ni n g of fi br osis, at Wee k 4 8
6. 2. 1. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (S ecti o n 2. 1. 2 ).

A nal y sis set:  E val ua ble (S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vest i gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 will be a nal yz e d usi n g a Ba yesia n E ma x d ose -res p o nse m o del. F or assessi n g 
pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal yze d a n usi n g 
l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors 
( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n -res p o n der. If t he y 
wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or t olerati o n) 
a n d ha ve e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, t hese data will be utilize d t o 
deter mi ne w het her t he y  are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his sec o n dar y e n d p oi nt at Wee k 4 8 will be 
prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese nte d at Wee k 4 8 .  F or 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 2
T M F D oc I D: 9 8. 0 3
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y  
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d .
6. 2. 1. 2. Se nsiti vit y/ S u p ple me nt ar y A n al ysis
Se nsiti vit y  A nalys es
I n or der t o assess t he se nsiti vit y of t he d ose B a y esia n E ma x d ose -res p o nse m o del t o t he 
l ocati o n a n d i nf or mati ve ness of t he pri or distri b uti o ns, se nsiti vit y  a nal yses ma y be perf or me d 
t hat will utilize alter nati ve pri or distri b uti o ns.
6. 2. 2. Pr o p orti o n of p artici p a nts ac hie vi n g ce ntr all y a dj u dic ate d i m pr o ve me nt i n 
fi br osis b y ≥1 st a ge wit h o ut w orse ni n g of N A S H, at Wee k 4 8
6. 2. 2. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (S ecti o n 2. 1. 2 ).

A nal y sis set:  E val ua ble (S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 will be a nal yz e d usi n g a Ba yesia n E ma x d ose -res p o nse m o del. F or assessi n g 
pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal yze d a n usi n g 
l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors 
( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data: If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n-res p o n der. If t he y 
wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or t olerati o n) 
a n d ha ve e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, t hese data will be utilize d t o 
deter mi ne w het her t he y  are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his sec o n dar y e n d p oi nt at Wee k 4 8 will be 
prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres po n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese nte d at Wee k 4 8 .  F or 
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y 
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d .
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 3
T M F D oc I D: 9 8. 0 3
6. 2. 2. 2. Se nsiti vit y/ S u p ple me nt ar y A n al ysis
Se nsiti vit y  A nalys es
I n or der t o assess t he se nsiti vit y of t he d ose B a y esia n E ma x d ose -res p o nse m o del t o t he 
l ocati o n a n d i nf or mati ve ness of t he pri or distri b uti o ns, se nsiti vit y  a nal yses ma y be perf or me d 
t hat will utilize alter nati ve pri or distri b uti o ns.
6. 2. 3. Pr o p orti o n of p artici p a nts ac hie vi n g ce ntr all y a dj u dic ate d i m pr o ve me nt i n 
fi br osis b y ≥2 st a ges wit h o ut w orse ni n g of N A S H, at Wee k 4 8
6. 2. 3. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (S ecti o n 2. 1. 2 ).

A nal y sis set:  E val ua ble (S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vest i gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 will be a nal yz e d usi n g a Ba yesia n E ma x d ose -res p o nse m o del. F or assessi n g 
pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal yze d a n usi n g 
l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors 
( Secti o n 5. 2. 1 ).

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n-res p o n der. If t he y 
wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or t olerati o n) 
a n d ha ve e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, t hese data will be utilize d t o 
deter mi ne w het her t he y  are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his sec o n dar y e n d p oi nt at Wee k 4 8 will be 
prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese n te d at Wee k 4 8.  F or 
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y 
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d .
6. 2. 3. 2. Se nsiti vit y/ S u p ple me nt ar y A n al ysis
Se nsiti vit y  A nalys es
I n or der t o assess t he se nsiti vit y of t he d ose B a y esia n E ma x d ose -res p o nse m o del t o t he 
l ocati o n a n d i nf or mati ve ness of t he pri or distri b uti o ns, se nsiti vit y  a nal yses ma y be perf or me d 
t hat will utilize alter nati ve pri or distri b uti o ns.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 4
T M F D oc I D: 9 8. 0 3
6. 2. 4. Pr o p orti o n of p artici p a nts ac hie vi n g ce ntr all y a dj u dic ate d i m pr o ve me nt of ≥2 
p oi nts in T ot al N A F L D Acti vit y Sc ore ( N A S) wit h o ut w orse ni n g of fi br osis, at Wee k 4 8
6. 2. 4. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (S ecti o n 2. 1. 2 ).

A nal y sis set:  E val ua ble (S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vest i gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 will be a nal yz e d usi n g a Ba yesia n E ma x d ose -res p o nse m o del. F or assessi n g 
pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal yze d a n usi n g 
l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors 
( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n -res p o n der. If t he y 
wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or t olerati o n) 
a n d ha ve e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, t hese data will be utilize d t o 
deter mi ne w het her t he y  are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his sec o n dar y e n d p oi nt at Wee k 4 8 will be 
prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese nte d at Wee k 4 8 .  F or 
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y  
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d .
6. 2. 4. 2. Se nsiti vit y/ S u p ple me nt ar y A n al ysis
Se nsiti vit y  A nalys es
I n or der t o assess t he se nsiti vit y of t he d ose B a y esia n E ma x d ose -res p o nse m o del t o t he 
l ocati o n a n d i nf or mati ve ness of t he pri or distri b uti o ns, se nsiti vit y  a nal yses ma y be perf or me d 
t hat will utilize alter nati ve pri or distri b uti o ns.
6. 2. 5. Perce nt a ge c h a n ge fr o m b aseli ne i n li ver f at ( assesse d vi a M RI -P D F F) at Wee k 4 8
6. 2. 5. 1. M ai n A n al ysis

Esti ma n d strate g y: H y p ot hetical ( Secti o n 2. 1. 2 ).
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 5
T M F D oc I D: 9 8. 0 3

A nal y sis set:  E val ua ble (S ecti o n 4 ). All ra n d o mize d partici pa nts i n t he i ma gi n g s u b-
st u d y, w h o ta ke at least 1 d ose of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble 
baseli ne data f or t he e n d p oi nt, i.e. baseli ne M RI -P D F F data . 

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he perce nta ge c ha n ge fr o m 
baseli ne i n li ver fat at Wee k 4 8 will be a nal y ze d usi n g a Ba yesia n E ma x d ose -res p o nse 
m o del , fitte d t o LS mea ns o btai ne d fr o m t he M M R M m o del. F or assessi n g pair wise 
c o m paris o ns, t he perce nta ge c ha n ge fr o m baseli ne i n li ver fat at Wee k 4 8 will be 
a nal yz e d usi n g a n A N C O V A perf or me d o n l o g-tra nsf or me d relati ve c ha n ge fr o m 
baseli ne i n li ver fat wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors, a n d l o g-
tra nsf or me d baseli ne li ver fat as a c o variate.   All treat me nt effect c o ntrasts will be 
o btai ne d t hr o u g h fitti n g t he Ba y esia n d ose -res p o nse a n d/ or e x p os ure-res p o nse m o dels, or 
a n A N C O V A m o del ( Secti o n 5. 2. 2 ).

I nterc urre nt e ve nts a n d missi n g data: A n y a vaila ble M RI  data f or all partici pa nts 
c ollecte d bef ore or at t he ti me of treat me nt wit h dra wal will be i ncl u de d i n t he a nal ys is, 
b ut e n d p oi nt data c ollecte d after treat me nt wit h dra wal will be ce ns ore d. Missi n g data d ue 
t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or d ue t o ot her reas o ns ( n ot relate d t o 
lac k of efficac y or t olerati o n), will be ass u me d t o be missi n g at ra n d o m a n d will n ot be 
i m pute d. I nstea d, M M R M will be use d t o o btai n L S mea n esti mate at Wee k 4 8 f or eac h 
d ose, w hic h will t he n be use d i n fitti n g t he Ba y esia n E ma x m o del .

T he sa m ple size, mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m at t he 
baseli ne a n d p ost baseli ne visi ts f or o bser ve d li ver fat a n d relati ve a n d a bs ol ute c ha n ge 
fr o m baseli ne will be prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d mea n relati ve c ha n ges f or eac h treat me nt c o m paris o n a n d t he 
c orres p o n di n g 9 0 % cre di ble i nter val will be o btai ne d fr o m t he m o del . T he mea n relati ve 
c ha n ges ( R C) a n d t heir CIs will be e x p o ne ntiate d a n d perce nt c ha n ge will t he n be 
deter mi ne d as f oll o ws : Perce nt c ha n ge = 1 0 0 * ( R C - 1). F or c o m paris o ns of D G A T 2i + 
A C Ci BI D d oses vs c orres p o n di n g D G A T 2i B I D m o n ot hera p y d oses c orres p o n di n g 5 0 %
c o nfi de nce i nter vals will als o be pr o vi de d.
6. 2. 5. 2. Se nsiti vit y/ S u p ple me nt ar y A n al ysis
Se nsiti vit y  A nalys es
I n or der t o assess t he se nsiti vit y of t he d ose B a y esia n E ma x d ose -res p o nse m o del t o t he 
l ocati o n a n d i nf or mati ve ness of t he pri or distri b uti o ns, se nsiti vit y  a nal yses ma y be perf or me d 
t hat will utilize alter nati ve pri or distri b uti o ns.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 6
T M F D oc I D: 9 8. 0 3
6. 3. Ot her E n d p oi nt(s)
6. 3. 1. Pr o p orti o n of p artici p a nts ac hie vi n g i m pr o ve me nt i n fi br osis b y ≥1 st a ge
i n de pe n de nt of c h a n ges i n N A S, b ase d o n assess me nt b y s p o ns or -i de ntifie d ce ntr al 
p at h ol o gist(s) , at Wee k 4 8 c o m p are d t o b aseli ne
6. 3. 1. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (S ecti o n 2. 1. 2 ).

A nal y sis set:  Eval ua ble ( S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o ps y data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 will be a nal yz e d usi n g a Ba yesia n E ma x d ose -res p o nse m o del. F or assessi n g 
pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal y ze d a n usi n g 
l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors 
( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n-res p o n der. If t he y 
wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or t olerati o n) 
a n d ha ve e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, t hese data will be utilize d t o 
deter mi ne w het her t he y  are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his tertiar y en d p oi nt at Wee k 4 8 will be 
prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), an d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese nte d at Wee k 4 8.  F or 
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y 
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d.
6. 3. 2. Pr o p orti o n of p artici p a nts ac hie vi n g res ol uti o n of N A S H wit h o ut w orse ni n g of 
fi br osis a n d i m pr o ve me nt i n fi br osis b y ≥1 st a ge wit h o ut w orse ni n g of N A S H, b ase d o n 
assess me nt b y s p o ns or -i de ntifie d ce ntr al p at h ol o gist(s), at W ee k 4 8 c o m p are d t o 
b aseli ne
6. 3. 2. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (S ecti o n 2. 1. 2 ).

A nal y sis set:  E val ua ble (S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 7
T M F D oc I D: 9 8. 0 3

A nal y sis met h o d ol o g y: F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 will be a nal yz e d usi n g a Ba yesia n E ma x d ose-res p o nse m o del. F or assessi n g 
pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal yze d a n usi n g 
l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors 
( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 Bi o ps y  data, t he y will be c o nsi dere d t o be a n o n-res p o n der. If t he y 
wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or t olerati o n) 
a n d ha ve e val ua ble bi o ps y data at wit h dra wal or Wee k 4 8, t hese data will be utilize d t o 
deter mi ne w het her t he y  are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his tertiar y e n d p oi nt at Wee k 4 8 will be 
prese nte d f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese nte d at Wee k 4 8.  F or 
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y 
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d.
6. 3. 3. Pr o p orti o n of p artici p a nts wit h pr o gressi o n of fi br osis b y ≥1 st a ge ( defi ne d as a n 
i ncre ase of at le ast 1 st a ge i n t he Br u nt-Klei ner sc ale c o m p are d t o b aseli ne )
i n de pe n de nt of c h a n ges i n N A S, at Wee k 4 8
6. 3. 3. 1.
M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (Secti o n 2. 1. 3 ).

A nal y sis set:  E val ua ble ( Secti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 ( defi ne d as t he pr o p orti o n of partici pa nts wit h w orse ni n g of fi br osis b y  ≥1 sta ge 
o n li ver bi o ps y , as assesse d b y s p o ns or i de ntifie d ce ntral pat h ol o gist(s), at Wee k 4 8) will 
be a nal yz e d usi n g a Ba yesia n E ma x d ose-resp o nse m o del. F or assessi n g pair wise 
c o m paris o ns, t he pr o p orti o n of res p o n ders at Wee k 4 8 will be a nal yz e d usi n g l o gistic 
re gressi o n m o dels wit h treat me nt a n d baseli ne fi br osis sta ge ( F 2/ F 3) as fact ors 
( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 bi o ps y  data, t he y  will be c o nsi dere d t o be a res p o n der (as t his 
ass u mes t hat t hese partici pa nts will als o ha ve w orse ne d) . If a partici pa nt has i m pr o ve d or 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 8
T M F D oc I D: 9 8. 0 3
mai ntai ne d t he sa me le vel of fi br osis c o m pare d t o baseli ne, t he n t hat partici pa nt will be 
ter me d as a n o n-res p o n der.

If t he y wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or 
t olerati o n) a n d ha ve e val ua ble data at wit h dra wal or Wee k 4 8, t hese data will be utilize d 
t o deter mi ne w het her t he y are a res p o n der or n ot.

T he n u m ber a n d pr o p or ti o n of res p o n ders f or t his e n d p oi nt at Wee k 4 8 will be prese nte d 
f or eac h treat me nt ar m.T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble
i nter val) f or eac h treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or 
BI D eac h d ose (a n d 9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d 
c orres p o n di n g 9 0 % c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be 
prese nte d at Wee k 4 8.  F or c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g 
D G A T 2i BI D m o n ot hera p y  d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be 
pr o vi de d.  
6. 3. 4. Pr o p orti o n of p artic i p a nts wit h pr o gressi o n of fi br osis b y ≥1 st a ge a n d w orse ni n g
of ≥2 p oi nts i n T ot al N A S at Wee k 4 8
6. 3. 4. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite (Secti o n 2. 1. 3 ).

A nal y sis set:  E val ua ble ( Secti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).

A nal y sis met h o d ol o g y:  F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 ( defi ne d as t he pr o p orti o n of partici pa nts wit h w orse ni n g of fi br osis b y  ≥1 sta ge 
a n d w orse ni n g of ≥2 p oi nts i n T otal N A S o n li ver bi o ps y , as assesse d by s p o ns or 
i de ntifie d ce ntral pat h ol o gist(s), at Wee k 4 8) will be a nal yz e d usi n g a Ba yesia n E ma x 
d ose -res p o nse m o del. F or assessi n g pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders 
at Wee k 4 8 will be a nal yze d usi n g l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne 
fi br osis sta ge ( F 2/ F 3) as fact ors ( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y d o n ot ha ve 
e val ua ble Wee k 4 8 bi o ps y  data, t he y  will be c o nsi dere d t o be a res p o n der (as t his 
ass u mes t hat t hese partici pa nts will als o ha ve w orse ne d). If a partici pa nt has i m pr o ve d or 
mai ntai ne d t he sa me le vel of fi br osis c o m pare d t o baseli ne, t he n t hat partici pa nt will be 
ter me d as a n o n-res p o n der.

If t he y wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of efficac y or 
t olerati o n) a n d ha ve e val ua ble data at wit h dra wal or Wee k 4 8, t hese data will be utilize d 
t o deter mi ne w het her t he y are a res p o n der or n ot.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 4 9
T M F D oc I D: 9 8. 0 3

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his e n d p oi nt at Wee k 4 8 will be prese nte d 
f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he place b o-a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese nte d at Wee k 4 8.  F or 
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y 
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d.
6. 3. 5. Pr o p orti o n of p artici p a nts w it h W orse ni n g of ≥2 p oi nts i n T ot al N A S ( defi ne d as 
a n i ncre ase of at le ast 2 p oi nts i n T ot al N A S c o m p are d t o b aseli ne) i n de pe n de nt of 
c h a n ges i n fi br osis at Wee k 4 8
6. 3. 5. 1. M ai n A n al ysis

Esti ma n d strate g y : C o m p osite ( Secti o n 2. 1. 3 ).

A nal y sis set:  E val ua ble ( Secti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d e val ua ble baseli ne data f or t he e n d p oi nt 
(i.e. baseli ne bi o psy data).

A nal y sis met h o d ol o g y: F or assessi n g d ose res p o nse, t he pr o p orti o n of res p o n ders at 
Wee k 4 8 ( defi ne d as t he pr o p orti o n of partici pa nts wit h w orse ni n g of ≥2 p oi nts i n T otal 
N A S i n de pe n de nt of c ha n ges i n fi br osis, o n li ver bi o ps y , as assesse d by s p o ns or 
i de ntifie d ce ntral pat h ol ogist(s), at Wee k 4 8 ) will be a nal yz e d usi n g a Ba yesia n E ma x 
d ose -res p o nse m o del. F or assessi n g pair wise c o m paris o ns, t he pr o p orti o n of res p o n ders 
at Wee k 4 8 will be a nal yze d usi n g l o gistic re gressi o n m o dels wit h treat me nt a n d baseli ne 
fi br osis sta ge ( F 2/ F 3) as fact ors ( Secti o n 5. 2. 1 ).  

I nterc urre nt e ve nts a n d missi n g data:  If a partici pa nt disc o nti n ues treat me nt or fr o m t he 
st u d y d ue t o lac k of efficac y or t olerati o n pri or t o Wee k 4 8 or if t he y  d o n ot ha ve 
e val ua ble Wee k 4 8 bi o ps y data, t he y  will be c o nsi dere d t o be a res p o n der (as t his 
ass u mes t hat t hese partici pa nts will als o ha ve w orse ne d) . If a partici pa nt’s T otal N A S has 
i m pr o ve d or sta ye d t he sa me c o m pare d t o baseli ne, t he n t hat partici pa nt will be ter me d as 
a n o n-res p o n der. If t he y wit h dra w fr o m treat me nt f or ot her reas o ns ( n ot relate d t o lac k of 
efficac y or t olerati o n) a n d ha ve e val ua ble data at wit h dra wal or Wee k 4 8, t hese data will 
be utilize d t o deter mi ne w h et her t he y are a res p o n der or n ot.

T he n u m ber a n d pr o p orti o n of res p o n ders f or t his e n d p oi nt at Wee k 4 8 will be prese nte d 
f or eac h treat me nt ar m.

T he m o del -esti mate d pr o p orti o n of res p o n ders (a n d 9 0 % cre di ble i nter val) f or eac h 
treat me nt ar m, a n d t he placeb o- a dj uste d pr o p orti o n of res p o n ders f or BI D eac h d ose (a n d 
9 0 % cre di ble i nter val), a n d o d ds rati o a n d ris k differe nce (a n d c orres p o n di n g 9 0 % 
c o nfi de nce i nter val) f or ot her treat me nt c o m paris o ns will be prese nte d at Wee k 4 8.  F or 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 0
T M F D oc I D: 9 8. 0 3
c o m paris o ns of D G A T 2i + A C Ci BI D d oses vs c orres p o n di n g D G A T 2i BI D m o n ot hera p y 
d oses c orres p o n di n g 5 0 % c o nfi de nce i nter val will als o be pr o vi de d.
6. 3. 6. Ot her C o nti n u o us Terti ar y/ E x pl or at or y E n d p oi nts
T he f oll o wi n g c o nti n u o us tertiar y/e x pl orat or y e n d p oi nts will be s u m marize d a n d a nalyz e d as
descri be d bel o w . T he a nal yses of t hese e n d p oi nts are assesse d f or efficac y u p t o Wee k 4 8, 
b ut t he a nal ys es of bl o o d base d bi o mar kers will als o i ncl u de data u p t o a n d i ncl u di n g Wee k 
5 0 t o all o w a n assess me nt of off-treat me nt effects:

Perce nt c ha n ge i n li ve r fat (assesse d via M RI-P D F F i n I ma gi n g s u bst u d y  p o p ulati o n), 
o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge i n li ver v ol u me (assesse d via M RI i n I ma gi n g s u bst u d y  p o p ulati o n), o ver 
ti me u p t o Wee k 4 8

Perce nt c ha n ge i n 
 (assesse d via M RI i n I ma gi n g s u bst u d y p o p ulati o n), 
o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge i n 
 (assesse d via M RI i n I ma gi n g s u bst u d y p o p ulati o n), o ver ti me 
u p t o Wee k 4 8

Perce nt c ha n ge fr o m baseli ne i n li ver fat as assesse d via C A P ™
meas ure b y Fi br o Sca n ®, 
(e ntire st u dy p o p ulati o n), o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge fr o m baseli ne i n li ver stiff ness (assesse d via V C T E ™
usi n g Fi br o Sca n ® 
(e ntire st u dy p o p ulati o n), o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge fr o m baseli ne i n Li ver F u ncti o n Tests – A L T, A S T, A L P, G G T , Total 
B ilir u bi n, Direct Bilir u bi n, a n d T otal Bile Aci ds, o ver ti me u p t o Wee k 4 8

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 4 8 i n Mec ha nis m -Relate d a n d 
Meta b olic Para meters – P C S K 9 , A di p o necti n, Platelet c o u nt, e G F R -C K D -E PI -C y stati n-
C, a n d B o d y Wei g ht .

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 4 8 i n C K 1 8 -M 3 0 a n d C K 1 8 -M 6 5

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 4 8 i n Pr o C 3 a n d Pr o C 6 

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 4 8 i n E L F test (i ncl u di n g t he 
i n di vi d ual para meters assa ye d - Ser u m h yal ur o nic aci d ( H A), Ser u m a mi n o -ter mi nal 
pr o pe pti de of t y pe III pr oc olla ge n ( PIII N P) a n d Ser u m tiss ue i n hi bit or of 
metall o pr otei nases 1 ( TI M P -1))

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 4 8 i n hs- C R P
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 1
T M F D oc I D: 9 8. 0 3

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 4 8 A p oli p o pr otei n A 1, B (t otal), 
B 1 0 0, B 4 8, C 3, E (P ote ntiall y  mec ha nis m-relate d para meters)

Perce nt c ha n ge fr o m baseli ne, o verti me u p t o Wee k 4 8 i n Fasti n g li pi d pa nel (t otal 
c h olester ol, direct L D L-C, H D L -C, tri gl yc eri des, direct V L D L), , f or all partici pa nts .

C ha n ge fr o m baseli ne, o ver ti me u p t o Wee k 4 8, i n H b A 1 C , F P G , F PI , H O M A -I R (f or all 
partici pa nts (e xce pt H b A 1c) a n d als o partici pa nt s wit h T 2 D M o nl y (i ncl u di n g H b A 1c))

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n a b d o mi nal pai n a n d bl oati n g q uesti o ns 
fr o m t he N A S H S ym pt o m Diar y  

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n fati g ue, slee p dist ur ba nce, a n d da yti me 
slee pi ness q uesti o ns fr o m t he N A S H S ym pt o m Diar y  

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n fati g ue as meas ure d by P R O MI S Fati g ue 
q uesti o n naire

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n H R Q o L  s u b-scale sc ores as meas ure d by 
N A S H -C hec k

C ha n ge fr o m baseli ne, o ver ti me t o Wee k 4 8 i n P GI - S

A bs ol ute sc ore o ver ti me i n P GI - S

A bs ol ute sc ore o ver ti me i n P GI - C
6. 3. 6. 1. M ai n A n al ysis

Esti m a n d strate g y: N ot a p plica ble

A nal y sis set:  E val ua ble (S ecti o n 4 ). All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose 
of i n vesti gati o nal pr o d uct w h o ha ve pr o vi de d baseli ne data f or t he e n d p oi nt , a n d i n 
a d diti o n ha ve at least 1 e val ua ble data p oi n t p ost ra n d o mizati o n .

A nal y sis met h o d ol o g y: A M M R M will be use d f or t he a nal ys is of c o nti n u o us e n d p oi nts 
wit h m ore t ha n o ne p ost -baseli ne c ollecti o n ti me p oi nt. T he M M R M a nal ysis will be 
perf or me d wit h treat me nt, st u d y  wee k ( n o mi nal ti me p oi nt) a n d treat me nt -b y -st u dy wee k
i nteracti o n as fi xe d effects, a n d baseli ne fi br osis sta ge ( F 2/ F 3) as a fact or a n d baseli ne 
val ue of t he a nal ys is e n d p oi nt as a c o variate . If t he e n d p oi nt bei n g a nalyz e d is l o g-
tra nsf or me d (i.e. f or all p erce nta ge c ha n ge s fr o m baseli ne i n c o nti n u o us e n d p oi nts w hic h 
will be de ri ve d fr o m t he a nalys is of l o g-tra nsf or me d relati ve c ha n ges fr o m baseli ne), t he 
baseli ne val ue of t he a nal ysis e n d p oi nt will als o be l o g- tra nsf or me d. Re peate d meas ures 
m o del wit h u nstr uct ure d c o varia nce matri x will be u tilize d ( Secti o n 5. 2. 2 ).

I nterc urre nt e ve nts a n d missi n g data:  All o bserve d d at a c ollecte d d uri n g t he p ost -
b aseli ne tre at me nt peri o d will be utilize d. Missi n g data
will n ot be e x plicitl y  i m p ute d.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 2
T M F D oc I D: 9 8. 0 3

T he sa m ple size, mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m at t he 
baseli ne a n d p ost baseli ne visits f or o bser ve d val ues a n d relati ve a n d a bs ol ute c ha n ge 
fr o m baseli ne will be prese nte d f or eac h treat me nt ar m. 
o
B o x a n d w his ker pl ots b y ra n d o mize d ar m a n d b y wee k will als o be dis pla ye d t o 
c haracterize t he distri b uti o n of perce nt c ha n ges fr o m baseli ne o ver ti me.

F or perce nta ge c ha n ges fr o m baseli ne the m o del -esti mate d mea n relati ve c ha n ges f or 
eac h treat me nt c o m par is o n a n d t he c orres p o n di n g 9 0 % CI  will be o btai ne d fr o m t he 
m o del. T he mea n relati ve c ha n ges ( R C) a n d t heir CI s will be e x p o ne ntiate d a n d perce nt 
c ha n ge will t he n be deter mi ne d as f oll o ws : Perce nt c ha n ge = 1 0 0 * ( R C - 1).  F or 
c o m paris o ns of D G A T 2i + A C Ci B I D d oses vs c orres p o n di n g D G A T 2i BI D 
m o n ot hera p y d oses c orres p o n di n g 5 0 % c o nfi de nce i nter vals will als o be pr o vi de d.

 
per mit retr os pecti ve a nal ysis of 
) 
o
T hese res ults ma y  or ma y n ot be ge nerate d i n t he c o nte xt of t he prese nt st u d y.
6. 3. 7. E ve nt -b ase d Terti ar y/ E x pl or at or y E n d p oi nts
6. 3. 7. 1. M ai n A n al ysis
T he f oll o wi n g e n d p oi nts will be s u m marize d descri pti vel y  b y treat me nt gr o u p ( Secti o n 5. 2. 4 )
f or ra n d o mize d partici pa nt s, se parately f or pre -ra n d o mizati o n e ve nts a n d treat me nt-e mer ge nt 
e ve nts (as S A Es will be c ollecte d pri or t o ra n d o mizati o n s o c o ul d als o be se nt f or 
a dj udicati o n) :

Occ urre nce of a n y o ne of t he f oll o wi n g o ver ti me u p t o Wee k 4 8 base d o n fi nal 
a dj u dicati o n: 
Deat hs

All ca use m ortalit y ( deat hs re gar dless of ca use)

Deat h d ue t o M y ocar dial I nfarcti o n

Deat h d ue t o Cere br o vasc ular Acci de nt

Deat h d ue t o He patic fail ure
F or n o n -f at al e ve nts. 

Car di o vasc ular e ve nts 
o
M y ocar dial i nfarcti o n
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 3
T M F D oc I D: 9 8. 0 3
o
Cere br o vasc ular e ve nt (str o ke) or tra nsie nt isc hae mic attac k
o
H os pitali z ati o ns d ue t o u nsta ble a n gi na
o
H os pitalizati o n f or heart fail ure

Li ver e ve nts 
o
He patic e nce p hal o pat h y
o
U p per Gastr oi ntesti nal blee d d ue t o p ortal h y p erte nsi o n
o
Li ver tra ns pla nt e val uati o n
o
N e w dia g n osis of he pat ocell ular carci n o ma 
o
Ascites
o
Ac ute ki d ne y  i nj ur y d ue t o he pat ore nal s yn dr o me
o
Dr u g i n d uce d li ver i nj ur y
o
I ncrease of M o del of e n d -sta ge li ver disease ( M E L D) sc ore fr o m ≤1 2 t o ≥1 5 
i n dicati n g listi n g f or li ver tra ns pla nt ( See A p pe n di x 2. 4. 2 )
6. 3. 8. P h ar m ac o ki netic ( P K) E n d p oi nts
6. 3. 8. 1. M ai n A n al ysis
c o nce ntrati o n data will be liste d a n d s u m marize d b y  treat me nt gr o u p, visit a n d 
n o mi nal ti me p oi nt f or D G A T 2i a n d A C Ci se paratel y .
As a ge ner al r ule, sa m ples c ollecte d i n t h ose assi g ne d place b o will n ot u n der g o a nal ys is f or 
D G A T 2i a n d A C Ci .  H o we ver, w he n a nalys is is u n derta ke n, f or e xa m ple: f or cases of q uality 
iss ues at selecte d site(s), P K res ults will be liste d.  
A n y  sa m ples t hat ha ve bee n rec or de d wit h a stat us of ‘ La bel i nf or mati o n a n d pa per w or k 
disa gree ’ will be e xcl u de d fr o m a n y P K s u m maries , as t hese sa m ples are c o nsi dere d t o be 
u nrelia ble wit h t he sa m ple details at t he a nal y zi n g la b orat or y n ot matc hi n g sites’ s o urce 
d oc u me nts .
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 4
T M F D oc I D: 9 8. 0 3
6. 4. S u bset A n al yses
T o e val uate t he effect of treat me nt o n li ver fat a n d li ver v ol u me as assesse d b y M RI-P D F F , 
t hese i ma gi n g e n d p oi nts will o nl y be a nal yze d i n t he s u bset of partici pa nts i ncl u de d i n t he 
I ma gi n g s u bst u dy p o p ulati o n. T he a nal ys is of t hese e n d p oi nts is i ncl u de d i n Secti o ns 6. 2. 5
a n d 6. 3. 6 . 
T he f oll o wi n g s u bset a nal y sis will als o be perf or me d:

A nal ysis of g l yce mic e n d p oi nts i n t h e T y p e 2 dia betes mellit us (T 2 D M ) p o p ulati o n
6. 5. B aseli ne a n d Ot her S u m m aries a n d A n al yses
S u m maries t hat acc o u nt f or all partici pa nt s w h o offere d at least c o nse nt f or pre-q ualificati o n 
a n d w het her scree n faile d or ra n d o mize d will be prese nte d. 
6. 5. 1. B aseli ne S u m m aries
De m o gra p hic a n d ot her baseli ne c haracteristics s uc h as partici pa nt a ge, ge n der, wei g ht, b o d y 
mass i n de x ( B MI ), waist circ u mfere nce, re gi o n, stratificati o n fact ors, et h nicit y a n d race, will 
be s u m marize d b y  ra n d o mize d ar m. 
F or eac h efficac y  e n d poi nt (ie pri mar y , sec o n dar y or tertiar y e n d p oi nt), baseli ne val ues will 
be liste d a n d descri pti vel y  s u m marize d b y ra n d o mize d ar m. 
6. 5. 2. St u d y C o n d uct a n d P artici p a nt Dis p ositi o n
T he n u m ber of partici pa nt s ra n d o mize d, treate d, c o m pleti n g a n d disc o nti n ui n g st u dy 
me dicati o n a n d fr o m t he st u d y , will be s u m marize d b y ra n d o mize d ar m. F or partici pa nt s w h o 
di d n ot c o m plete st u d y me dicati o n or t he st u d y, t he reas o ns f or wit h dra wal will be prese nte d. 
6. 5. 3. St u d y Tre at me nt E x p os ure
T he n u m ber of da y s of st u d y treat me nt e x p os ure will be s u m marize d b y  ra n d o mize d 
treat me nt gr o u p a n d n u m ber of partici pa nts wit h ≤8 wee ks, > 8 t o 2 4 wee ks, > 2 4 t o 3 6 wee ks, 
> 3 6 t o 4 8 wee ks ( + 4 da ys – t o all o w f or t he ma xi m u m wi n d o w f or a d mi nistrati o n of st u d y 
treat me nt), a n d > 4 8 wee ks ( + 5 da ys) e x p os ure res pecti vely. T he f or m ula t o c o m p ute 
c o m plia nce is defi ne d i n A p pe n di x 2. 5 . O verall c o m plia nce ( Da y 1 t o Wee k 4 8 or pre mat ure 
ter mi nati o n d uri n g treat me nt p hase) will be s u m marize d usi n g descri pti ve s u m mar y statistics 
a n d b y  fre q ue nc y n ( %) i n t he f oll o wi n g t w o cate gories b y  ra n d o mize d ar m:
o
< 5 0 %
o
≥5 0 a n d < 8 0 % , i ncl usi ve
o
≥8 0 %
6. 5. 4. Me dic al Hist or y
T he n u m ber a n d pr o p orti o n of partici pa nts wit h eac h of t he u p t o 1 2 pres pecifie d me dical 
hist ories  
 will be s u m marize d b y  ra n d o mize d treat me nt gr o u p. I n a d diti o n, t he 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 5
T M F D oc I D: 9 8. 0 3
n u m ber of partici pa nts wit h 0, 1, 2, 3 , 4, 5, 6, 7, 8 or > 8 of t hese pre s pecifie d me dical 
hist ories will be s u m marize d.
6. 5. 5. C o nc o mit a nt Me dic ati o ns a n d N o n dr u g T re at me nts
T he n u m ber a n d pr o p orti o n of partici pa nts ta ki n g s pecific c o nc o mita nt me dicati o ns  
f or me dical hist ories  
 o n D a y  1 a n d as c o nc o mita nt me dicati o ns at t he e n d 
of treat me nt/ Wee k 4 8 will be s u m marize d b y  ra n d o mize d treat me nt gr o u p, se paratel y f or 
eac h s pecific me dical hist or y. In a d diti o n, t he n u m ber a n d pr o p orti o n of par tici pa nts w h o 
ha ve i ncrease d or decrease d t heir d ose of t hese me dicati o ns will als o be s u m marize d b y
ra n d o mize d treat me nt gr o u p, a n d t he n u m ber of partici pa nts wit h 0, 1, 2, 3, 4, 5 or > 5 of 
t hese s pecific me dicati o ns 
 will be s u m marize d.  All o t her c o nc o mita nt 
me dicati o ns will be s u m marize d b y  ra n d o mize d treat me nt gr o u p.
6. 6. S afet y S u m m aries a n d A n al yses
All s afety a n alyses will be perf or me d o n t he s afety p o p ul ati o n. T hese will be prese nte d i n 
t a b ul ar a n d/ or gr a p hic al f or m at a n d s u m m arize d descri ptively a n d will f oll o w Pfizer 
st a n d ar ds as a p pr o pri ate. F urt her details are pr o vi de d bel o w.
6. 6. 1. A d verse E ve nts
Me d D R A will be use d t o classif y  all A Es wit h res pect t o s yste m or ga n class a n d preferre d 
ter m. S u m maries of A Es will i ncl u de treat me nt-e mer ge nt A Es acc or di n g t o treat me nt gr o u p. 
F urt her m ore, a 3 -tier a p pr o ac h will be use d t o s u m m arize A Es. Tier-1 c o nsists of pre -
s pecifie d a dverse eve nts  
 a n d will i ncl u de A Es or c ollecti o ns of A Es rel ate d t o 
i de ntifie d a dverse dr u g re acti o ns i n t his pr o gr a m rel ate d t o eit her D G A T 2i or A C Ci. Where 
av ail a ble, st a n d ar d Me d D R A q ueries will be use d t o p o ol differe nt A E ter ms t h at are rel ate d 
t o t he Tier- 1 A Es. T he precise A E ter ms t h at will c o ntri b ute t o t he Tier-1 e n d p oi nts will be 
deter mi ne d pri or t o u n bli n di n g. F or t hese eve nts, t he perce nt a ge of p artici p a nts wit h i nci de nt 
A E, t he risk differe nce (usi n g a n u nc o n diti o nal e xact test t o c o m pare eac h acti ve treat me nt ar m 
vs place b o) , its 9 5 % c o nfi de nce i nterv al, a n d p-v al ue will be pr ovi de d. T he c o nfi de nce 
i nterv als a n d p-v al ues are n ot a dj uste d f or m ulti plicity a n d are pr ovi de d f or scree ni n g 
p ur p oses o nly. 
Tier -2 A Es a re t h ose t h at are n ot Tier-1, b ut are c o m m o n, occ urri n g i n at le ast 4 p artici p a nts 
i n a ny tre at me nt ar m. T he c ut- off of at le ast 4 eve nts w as c h ose n bec a use t he 9 5 % c o nfi de nce 
i nterv al f or t he bet wee n-gr o u p differe nce i n perce nt i nci de nce will al w ays i ncl u de zer o w he n 
tre at me nt gr o u ps of e q u al size e ac h h ave less t h a n 4 eve nts a n d s o a d ds little t o t he 
i nter pret ati o n of p ote nti ally me a ni n gf ul differe nces. F or t hese eve nts, t he perce nt a ge of 
p artici p a nts wit h i nci de nt A E, t he risk differe nce a n d its 9 5 % c o nf i de nce i nterv al will be 
pr ovi de d. T he CIs are f or esti m ati o n p ur p oses o nly. 
F or Tier 1 a n d Tier 2 A Es, T E A Es, b y  preferre d ter m, will be s orte d i n desce n di n g p oi nt 
esti mate of ris k differe nce. F or ta ble/ gra p hic o ut p ut, t he f oll o wi n g f o ot n otes will be i ncl u de d t o 
pr o vi de pr o per i nter pretati o n of p -val ues a n d/ or c o nfi de nce i nter vals, a n d t o descri be h o w 
c o m paris o n is c o n d ucte d. E. g. P -val ues a n d c o nfi de nce i nter vals are n ot a dj uste d f or m ulti plicit y 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 6
T M F D oc I D: 9 8. 0 3
a n d s h o ul d be use d f or scree ni n g p ur p ose o nl y. 9 5 % C o nfi de nce i nter vals are pr o vi de d t o hel p 
ga u ge t he precisi o n of t he esti mates f or Ris k Differe nce. Ris k Differe nce is c o m p ute d as < Acti ve 
treat me nt vers us Place b o >.
Tier -3 A Es are all ot her A Es ( neit her Tier -1 n or Tier -2). 
It s h o ul d be rec o g nize d t hat m ost st u dies are n ot desi g ne d t o relia bly de m o nstrate a ca usal 
relati o ns hi p bet wee n t he use of a p har mace utical pr o d uct a n d a n a d verse e ve nt or a gr o u p of 
a d verse e ve nts. E xce pt f or select e ve nts i n u ni q ue sit uati o ns, st u dies d o n ot e m pl o y  f or mal 
a dj u dicati o n pr oce d ures f or t he p ur p ose of e ve nt classificati o n. As s uc h, safet y  a nalys is is 
ge nerall y c o nsi dere d as a n e x pl orat or y  a nalys is a n d its p ur p ose is t o ge nerate h yp ot heses f or 
f urt her i n vesti gati o n. T he 3 -tier a p pr oac h facilitates t his e x pl orat or y anal y sis.
6. 6. 2. L a b or at or y D at a
La b orat or y para meters will be s u m marize d descri pti vel y  o ver ti me, a n d as descri be d i n 
Secti o n 3. 5. 2 . I ndi vi d ual p l ots of abs ol ute v al ues i n Platelet C o u nt, a P T T, I N R vs t i me f or 
partici pa nts wit h P latelet C o u nt <1 0 0, 0 0 0/ m m 3 after Da y 1 t o Wee k 4 8
will be pr o d uce d as 
well as i n di vi d ual p l ots of abs ol ute v al ues i n T G, F P G, F PI, A p o C 3 vs time f or partici pa nts 
wit h Fasti n g T G ≥4 0 0 m g/ d L after Da y 1 t o Wee k 4 8 .
6. 6. 3. Vit al Si g ns
C h a n ges fr o m b aseli ne i n syst olic bl o o d press ure, di ast olic bl o o d press ure a n d p ulse r ate 
will be s u m m arize d by tre at me nt a n d ti me. T he n u m ber ( %) of p artici p a nts wit h m axi m u m 
i ncre ases fr o m b aseli ne will be t a b ul ate d by tre at me nt as defi ne d i n S ecti o n 3. 5. 3 . N u m bers
a n d perce nt a ges of p artici p a nts meeti n g t he c ate g oric al criteri a will be pr ovi de d a n d 
i n divi d u al v al ues liste d i n t he st u dy re port. N o f or m al i nfere nti al st atistics will be a p plie d t o 
t he vit al si g ns d at a.
6. 6. 4. Electr oc ar di o gr a m s
C h a n ges fr o m b aseli ne f or t he E C G p ar a meters Q T i nterv al, he art r ate, Q Tc F i nterv al, P R 
i nterv al, a n d Q R S i nterv al will be s u m m arize d by tre at me nt a n d ti me. For p ur p oses of 
re p orti n g st u dy-level res ults, Q Tc F i nterv al will be derive d usi n g Fri derici a’s he art r ate 
c orrecti o n f or m ul a a p plie d t o d at a b ase d Q T i nterv al, a n d R R i nterv al . T he n u m ber ( %) of 
p artici p a nts wit h m axi m u m i ncre ases fr o m b aseli ne will be t a b ul ate d by tre at me nt as defi ne d 
i n S ecti o n 3. 5. 3 . N u m bers a n d perce nt a ges of p artici p a nts meeti n g t he c ate g oric al criteri a 
will be pr ovi de d a n d i n divi d u al v al ues liste d i n t he st u dy re p ort. N o f or m al i nfere nti al 
st atistics will be a p plie d t o t he E C G d at a.
7. I N T E RI M A N A L Y S E S
7. 1. I ntr o d ucti o n
I nteri m a n alyses (I As) will be perf or me d t o assess s afety after a p pr oxi m ately 3 3 %, 6 7 %, a n d 
1 0 0 % of t he pl a n ne d t ot al s a m ple size h as bee n r a n d o mize d i n t he st u dy
(a n d t hese w o ul d 
pri maril y  be f or E xter nal Data M o nit ori n g C o m mittee ( E- D M C ) safety re vie ws w hile t he 
st u d y is o n g oi n g).  If re q uire d, interi m a n alysis res ults fr o m a si n gle I A m ay be use d f or
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 7
T M F D oc I D: 9 8. 0 3
ot her p ur p oses s uc h as: i nter n al b usi ness decisi o ns re g ar di n g f ut ure st u dy pl a n ni n g, 
c o n d ucti n g a s a m ple size re -esti m ati o n, a d a pti n g t he s afety -rel ate d e n d p oi nts i n t he st u dy 
after t he i nteri m a n aly sis, or e arly u n bli n di n g t o f acilit ate P o p ul ati o n P K/ P D m o del 
devel o p me nt .  Bef ore a ny i nteri m a n alysis is i nsti g ate d, t he det ails of t he o bjectives, decisi o n 
criteri a, disse mi n ati o n pl a n, a n d met h o d of m ai nt ai ni n g t he st u dy bli n d as per Pfizer’s S O Ps 
will be d oc u me nte d a n d a p pr ove d i n a n E -D M C c h arter or a se parate i nteri m a nal ysis pla n as 
nee de d .
7. 2. I nteri m A n al yses a n d S u m m aries
A n y  a nalys es a n d s u m maries t o be i ncl u de d i n t he E -D M C re vie ws will be d oc u me nte d i n 
t he E-D M C C harter or a se parate i nteri m a nal y sis pla n.  
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 8
T M F D oc I D: 9 8. 0 3
8. R E F E R E N C E S
T h o mas N, S wee ne y  K, S o ma yaji V. Meta -a nal ysis of cli nical d ose res p o nse i n a lar ge dr u g
de vel o p me nt p ortf oli o. Statistics i n Bi o p har mace utical Researc h 2 0 1 4; 6( 4): 3 0 2 - 1 7.
T h o mas N, R o y  D. A nal ysis of cli nical d ose-res p o nse i n s mall- m olec ule dr u g de vel o p me nt: 
2 0 0 9 -2 0 1 4. Statistics i n Bi o p har mace utical Researc h 2 0 1 7; 9( 2): 1 3 7 - 4 6.
W u J, Ba nerjee A, Ji n B et al. Cli nical d ose – res p o nse f or a br oa d set of bi ol o gical pr o d ucts:
A m o del - base d meta-a nal ysis. Stat Met h o ds i n Me d Res 2 0 1 8; 2 7( 9): 2 6 9 4- 2 7 2 1
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 5 9
T M F D oc I D: 9 8. 0 3
9. A P P E N DI C E S
A p pe n di x 1. S u m m ar y o f Effic ac y A n al yses
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
Pri mar y : Pr o p orti o n of 
partici pa nts ac hie vi n g 
ce ntrall y a dj u dicate d 
res ol uti o n of N A S H 
wit h o ut w orse ni n g of 
fi br osis or i m pr o ve me nt 
i n fi br osis b y ≥1 sta ge 
wit h o ut w orse ni n g of 
N A S H, or b ot h, at Wee k 
4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 1.1)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be n o n -
res p o n ders. All data c ollecte d 
at or after wi t h dra wal fr o m 
treat me nt f or ot her reas o ns 
( n ot relate d t o lac k of efficac y 
or t olerati o n) will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
Se nsiti vit y  A nalys es
E val ua ble
Sa me as mai n a nal ys is, b ut 
ma y  utilize alter nati ve pri or 
distri b uti o ns f or Ba yesia n 
E ma x m o delli n g .
Ba yesia n E ma x 
f or D R
S u p ple me ntar y  a nalys is
( Esti ma n d 1. 2)
E val ua ble
All data c ollecte d bef ore or at 
t he ti me of treat me nt 
wit h dra wal will be i ncl u de d.
E n d p oi nt data c ollecte d after 
treat me nt wit h dra wal will be 
ce ns ore d. A nal ys is will be 
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 0
T M F D oc I D: 9 8. 0 3
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
carrie d o ut u n der t he 
ass u m pti o n t hat missi n g 
bi o psies at Wee k 4 8 are 
missi n g at ra n d o m c o n diti o nal 
o n d ose a n d t he strata f or me d 
b y  t he c o variates (fi br osis 
stat us a n d T 2 D M stat us).
Sec o n dar y : Pr o p orti o n of 
partici pa nts ac hie vi n g 
ce ntrall y a dj u dicate d 
res ol uti o n of N A S H 
wit h o ut w orse ni n g of 
fi br osis at Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 2. 1)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be n o n -
res p o n ders. All data c ollecte d 
at or after wit h dra wal fr o m 
treat me nt f or ot her reas o ns 
( n ot relate d t o lac k of efficac y 
or t olerati o n) will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
Se nsiti vit y  A nalys es
E val ua ble
Sa me as mai n a nal ys is, b ut 
ma y  utilize alter nati ve pri or 
distri b uti o ns f or Ba y esia n 
E ma x m o delli n g.
Ba yesia n E ma x 
f or D R
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 1
T M F D oc I D: 9 8. 0 3
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
Sec o n dar y : Pr o p orti o n of 
partici pa nts ac hie vi n g 
ce ntrall y a dj u dicate d 
i m pr o ve me nt i n fi br osis 
b y  ≥1 sta ge wit h o ut 
w orse ni n g of N A S H at 
Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 2. 2)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be n o n -
res p o n ders. All data c ollec te d 
at or after wit h dra wal fr o m 
treat me nt f or ot her reas o ns 
( n ot relate d t o lac k of efficac y 
or t olerati o n) will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
Se nsiti vit y  A nalys es
E val ua ble
Sa me as mai n a nal ys is, b ut 
ma y  utilize alter nati ve pri or 
distri b uti o ns f or Ba y esia n 
E ma x m o delli n g.
Ba yesia n E ma x 
f or D R
Sec o n dar y : Pr o p orti o n of 
partici pa nts ac hie vi n g 
ce ntrall y a dj u dicate d 
i m pr o ve me nt i n fi br osis 
b y  ≥2 sta ges wit h o ut 
w orse ni n g of N A S H at 
Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 2. 3)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be n o n -
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 2
T M F D oc I D: 9 8. 0 3
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
res p o n ders. All data c ollecte d 
at or after wit h dra wal fr o m 
treat me nt f or ot her reas o ns 
( n ot relate d t o lac k of efficac y 
or t olerati o n) will be i ncl u de d.
Se nsiti vit y  A nalys es
E val ua ble
Sa me as mai n a nal ys is, b ut 
utilize alter nati ve pri or 
distri b uti o ns f or Ba y esia n 
E ma x m o delli n g.
Ba yesia n E ma x 
f or D R
Sec o n dar y : Pr o p orti o n of 
partici pa nts ac hie vi n g 
ce ntrall y a dj u dicate d 
i m pr o ve me nt of ≥2 
p oi nts i n T otal N A F L D 
Acti vit y  Sc ore ( N A S) 
wit h o ut w orse ni n g of 
fi br osis at Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 2. 4)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be n o n -
res p o n ders. All data c ollecte d 
at or after wit h dra wal fr o m 
treat me nt f or ot her reas o ns 
( n ot relate d t o lac k of efficac y 
or t olerati o n) will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 3
T M F D oc I D: 9 8. 0 3
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
Se nsiti vit y  A nalys es
E val ua ble
Sa me as mai n a nal ys is, b ut 
utilize alter nati ve pri or 
distri b uti o ns f or Ba y esia n 
E ma x m o delli n g.
Ba yesia n E ma x 
f or D R
Sec o n dar y : Perce nta ge 
c ha n ge i n li ver fat 
(assesse d via M RI-
P D F F) at Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 2. 5)
E val ua ble
All data c ollecte d bef ore or at 
t he ti me of wit h dra wal will be 
i ncl u de d. E n d p oi nt data 
c ollecte d after treat me nt 
wit h dra wal will be ce ns ore d. 
Missi n g data at Wee k 4 8 will 
n ot be i m p ute d. M M R M will 
be use d t o o btai n L S mea n 
esti mate at Wee k 4 8 f or eac h 
d ose, w hic h will t he n be use d 
i n fitti n g t he Ba yesia n E ma x 
m o del .
Ba yesia n E ma x 
f or D R, 
A N C O V A f or 
pair wise 
c o m paris o ns
Se nsiti vit y  A nalys es
E val ua ble
Sa me as mai n a nal ys is, b ut 
utilize alter nati ve pri or 
distri b uti o ns f or Ba y esia n 
E ma x m o delli n g.
Ba yesia n E ma x 
f or D R
S u m mar y
E val ua ble
O bser ve d data.
N/ A
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 4
T M F D oc I D: 9 8. 0 3
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
E x pl orat or y : Pr o p orti o n 
of partici pa nts ac hie vi n g 
i m pr o ve me nt i n fi br osis 
b y  ≥1 sta ge i n de pe n de nt 
of c ha n ges i n N A S, at 
Wee k 4 8
Mai n a nal ys is
( Est ma n d 3. 2)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be n o n -
res p o n ders. All data c ollecte d 
at or after wit h dra wal fr o m 
treat me nt f or ot her reas o ns 
( n ot relate d t o lac k of efficac y 
or t olerati o n) will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
E x pl orat or y : Pr o p orti o n 
of partici pa nts ac hie vi n g 
res ol uti o n of N A S H 
wit h o ut w orse ni n g of 
fi br osis a n d 
i m pr o ve me nt i n fi br osis 
b y  ≥1 sta ge wit h o ut 
w orse ni n g of N A S H, at 
Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Est ma n d 3. 3)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be n o n -
res p o n ders. All data c ollecte d 
at or after wit h dra wal fr o m 
treat me nt f or ot her reas o ns 
( n ot relate d t o lac k of efficac y 
or t olerati o n) will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 5
T M F D oc I D: 9 8. 0 3
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
E x pl orat or y : Pr o p orti o n 
of partici pa nts wit h 
W orse ni n g of ≥2 p oi nts 
i n T otal N A S ( defi ne d as 
a n i ncrease of at least 2 
p oi nts i n T otal N A S 
c o m pare d t o baseli ne) 
i n de pe n de nt of c ha n ges 
i n fi br osis at Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 3. 1)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be res p o n ders 
(i.e. t he y will be ass u me d t o 
ha ve w orse ne d). All data
c ollecte d at or after 
wit h dra wal fr o m treat me nt f or 
ot her reas o ns ( n ot relate d t o 
lac k of efficac y or t olerati o n) 
will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
E x pl orat or y : Pr o p orti o n 
of partici pa nts wit h 
pr o gressi o n of fi br osis 
b y  ≥1 sta ge ( defi ne d as 
a n i ncrease of at least 1 
sta ge i n t he Br u nt-
Klei ner scale c o m pare d 
t o baseli ne) i n de pe n de nt 
of c ha n ges i n N A S at 
Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Est ma n d 3. 1)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be res p o n ders 
(i.e. t he y will be ass u me d t o 
ha ve w orse ne d). All data 
c ollecte d at or after 
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 6
T M F D oc I D: 9 8. 0 3
E n d p oi nt
A n al ysis T y pe
P o p ul ati o n
D at a I ncl usi o n a n d R ules f or 
H a n dli n g I nterc urre nt E ve nts a n d 
Missi n g D at a 
A n al ysis M o del
wit h dra wal fr o m treat me nt f or 
ot her reas o ns ( n ot relate d t o 
lac k of efficac y or t olerati o n) 
will be i ncl u de d.
E x pl orat or y : Pr o p orti o n 
of partici pa nts wit h 
pr o gressi o n of fi br osis 
b y  ≥1 sta ge a n d 
w orse ni n g of ≥2 p oi nts 
i n T otal N A S at Wee k 4 8
S u m mar y
E val ua ble
O bser ve d data.
N/ A
Mai n a nal ys is
( Esti ma n d 3. 1)
E val ua ble
Partici pa nts w h o disc o nti n ue 
treat me nt or fr o m t he st u d y 
d ue t o lac k of efficac y  or 
t olerati o n pri or t o Wee k 4 8 or 
if t he y d o n ot ha ve e val ua ble 
Wee k 4 8 Bi o ps y data, will be 
c o nsi dere d t o be res p o n ders 
(i.e. t he y will be ass u me d t o 
ha ve w orse ne d). All data
c ollecte d at or after 
wit h dra wal fr o m treat me nt f or 
ot her reas o ns ( n ot relate d t o 
lac k of efficac y or t olerati o n) 
will be i ncl u de d.
Ba yesia n E ma x 
f or D R, L o gistic 
Re gressi o n f or 
pair wise 
c o m paris o ns
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 7
T M F D oc I D: 9 8. 0 3
A p pe n di x 2. D at a Deri v ati o n Det ails
A p pe n di x 2. 1. Defi niti o n a n d U se of V isit W i n d o ws i n R e p orti n g
Eac h c ollecte d assess me nt will be ma p pe d t o its act ual visit wi n d o w acc or di n g t he f oll o wi n g 
al g orit h m descri be d i n t he ta ble bel o w:
Visit l a bel 
Pr ot oc ol defi ne d 
Wi n d o w ( d a ys)
Visit 
Visit wi n d o w as p art of fi n al re p orti n g*
F or effic ac y, P D, P K a n d s afet y e n d p oi nts
Pr e -Q ualificati o n 
N /A 
1 
N /A 
Scree n 1 
N /A 
2 
N /A 
Scree n 2 
N /A 
3 
N /A 
R u n -I n 
N /A 
3 
N /A
Wee k -2 
-1 4 ± 4
4 
• Bet wee n Wee k 0 a n d Wee k -2, data are use d t o defi ne 
baseli ne 
• B aseli ne will be res ult cl osest pri or t o d osi n g o n 
ra n d o mize d re gi me n o n Da y 1 [ Visit 5] 
• Wi n d o w f or baseli ne meas ure me nts is fr o m Da y - 2 2 t o 
Da y  1 [ Visit 5] pre-d ose ( T he o nl y e xce pti o n is f or 
Hei g ht, f or w hic h a n y meas ure me nt fr o m Pre Q t o Da y 1 
pre -d ose ca n be use d , a n d f or Fi br oscan ® f or w hic h t he 
last e val ua ble meas ure me nt fr o m S C R 1 t o Da y 1 pre -
d ose ca n be use d )
• La bel as ‘ B A S E LI N E’
Wee k 0 
1
5
Wee k 2 
1 4 ± 4 
6 
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 8, 2 1]; ie, -
6 da ys t o + 7 da y s 
Wee k 4 
2 8 ± 4 
7 
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 2 2, 3 5]; ie, 
-6 da y s  t o + 7 da ys 
Wee k 6 
4 2 ± 4 
8 
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 3 6, 4 9]; ie, 
-6 da y s t o + 7 da ys 
Wee k 8 
5 6 ± 4 
9 
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 5 0, 7 0]; ie, 
-6 da y s t o + 1 4 da ys 
Wee k 1 2 
8 4 ± 4 
1 0 
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 7 1, 9 8]; ie, 
-1 3 da ys t o + 1 4 da ys 
Wee k 1 6 
1 1 2 ± 4 
1 1 
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 9 9, 1 4 0]; ie, 
-1 3 da ys t o + 2 8 da ys 
Wee k 2 4
1 6 8 ± 4
1 3
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 1 4 1, 1 9 6] ;
ie, -2 7 da ys t o + 2 8 da ys
Wee k 3 2
2 2 4 ± 4
1 5
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 1 9 7, 2 5 2] ;
ie, -2 7 da ys t o + 2 8 da ys 
Wee k 3 6 * *
2 5 2 ± 4
1 6
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [1 9 7 , 3 0 8 ];
ie, -5 5 da ys t o +5 6 da ys 
Wee k 4 0
2 8 0 ± 4
1 7
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 2 5 3, 3 0 8] ;
ie, -2 7 da ys t o + 2 8 da ys 
Wee k 4 8
3 3 6 ± 4
1 9
‘ Date of assess me nt’ – ‘ Baseli ne date’ + 1 = [ 3 0 9, 3 4 3 ]; 
ie, -2 7 da ys t o +7 da ys 
Wee k 5 0 ( 1st 
F oll o w -u p visit) 
2 0
‘ Date of assess me nt’ – ‘ Date of last d ose’ + 1 = [ 7, 2 7]; 
ie, a n y ti me after 7 da ys a n d u p t o 2 8 da ys after last d ose. 
Wee k 5 2 ( 2 n d 
F oll o w -u p visit) 
≥2 8 - a n d ≤3 5 - da ys 
p ost last d ose at 
‘ Date of assess me nt’ – ‘ Date of last d ose + 1 ≥ 2 8; 
ie, a n y ti me after 2 8 da ys after last d ose
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 8
T M F D oc I D: 9 8. 0 3
Visit l a bel 
Pr ot oc ol defi ne d 
Wi n d o w ( d a ys)
Visit 
Visit wi n d o w as p art of fi n al re p orti n g*
F or effic ac y, P D, P K a n d s afet y e n d p oi nts
Wee k 4 8 visit i n 
t he pr ot oc ol
N ote: * per mitte d t o be w i der t ha n wi n d o w defi ne d i n pr ot oc ol f or p ur p oses of re p orti n g data b y n o mi nal 
visit.
* * T his visit wi n d o w will o nl y be use d f or Patie nt Re p orte d O utc o mes re p orte d at Wee k 3 6. T he ot her p ost -
baseli ne visits at w hic h t hese data are c ollecte d are Wee k s 1 2 , 2 4 a n d 4 8, t heref ore t he Wee k 3 2 a n d Wee k 
4 0 a nal ysis wi n d o w s ha ve n ot bee n a dj uste d t o all o w  f or t he Wee k 3 6 a nal ysis wi n d o w.
S pecial c o nsi derati o ns : 

F or partici pa nt s wit h dra w n earl y, t he 1 st f ollo w- u p visit wi n d o w ( F/ U) will i ncl u de data 
u p t o 4 da y s after t he last d ose of st u d y me dicati o n, a n d t he visit la bel is defi ne d i n 
acc or da nce wit h t he n o mi nal la bel as rec or de d o n t he “ E _ T E R M/ F O L L O W _ U P” 
A d mi nistrati o n C R F. 

Data fr o m pla n ne d a n d u n pla n ne d visits will be wi n d o we d, as well as data o n st u d y  dr u g 
a n d f or partici pa nt s w h o ma y ha ve disc o nti n ue d st u d y me dicati o n b ut are c o nti n ui n g i n 
t he st u d y.

If 2 or m ore o bser vati o ns fall wit hi n t he visit wi n d o w f or Wee k N (re gardless of w het her 
t he y are pla n ne d or u n pla n ne d), t he o bser vati o n use d will be t he o ne cl osest t o Da y 7 N 
(ra n d o mizati o n da y is Da y 1). If t he 2 cl osest o bser vati o ns are e q ui dista nt fr o m Da y 7 N, 
t he earlier o bser vati o n will be use d. 

A n assess me nt is c o nsi de re d ‘ o n treat me nt’ if t he f oll o wi n g is tr ue: 
o
‘ Date (ti me w he n data base d) of assess me nt’ > ‘ Baseli ne date (ti me)’ a n d ≤‘ Last 
d ose date (ti me)’ 

F or Li ver Bi o ps y, M RI a n d Fi br osca n ® assess me nts, a n y Wee k 4 8 
assess me nts w o ul d 
be c o nsi dere d t o be e val ua ble, re gar dless of w he n t he y were perf or me d relati ve t o t he last 
d ose .

I n a d diti o n, t he Fi br osca n® e n d p oi nt of C A P T M a n d V C T E T M will re q uire c o n d uct of 
Fi br o Sca n ®
f oll o wi n g a fast of at least 4 h o urs a n d b ase d o n ≥1 0 vali d meas ure me nts, 
t o be e val ua ble f or a nalysis , a n d a n a d diti o nal criteri o n s h o ul d be a p plie d f or li ver 
stiff ness ( V C T ET M ) o nl y:

F or me dia n stiff ness ( k Pa) ≥7. 1 k Pa:
o
I nter q uartile stiff ness Ra n ge ( k Pa) di vi de d by me dia n stiff ness ( k Pa) x 1 0 0 
s h o ul d be ≤3 0 % 
o
T his nee ds t o be deri ve d fr o m t h e I nter q uartile stiff ness Ra n ge ( k Pa) a n d 
Me dia n stiff ness ( k Pa) as rec or de d i n t he data base

F or me dia n stiff ness ( k Pa) < 7. 1 k Pa
o
a n y Inter q uartile stiff ness Ra n ge ( k Pa) res ult is acce pta ble, s o t his a d diti o nal 
criteri o n d oes n ot nee d t o be a p plie d t o t hese val ues
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 6 9
T M F D oc I D: 9 8. 0 3

Asses me nt of e val ua ble C A P T M ( d B/ m) res ult will n ot use I nter q uartile atte nt uati o n 
Ra n ge ( d B/ m ). 

F or Fi br osca n ® Baseli ne deri vati o n, t he last e val ua ble meas ure me nt fr o m S C R 1 t o 
D a y  1 pre-d ose ca n be use d (i.e. cl osest res ults o btai ne d pri or t o d osi n g o n Da y  1 
( Visit 5)).

Patie nt Re p orte d O utc o mes: All P R O e n d p oi nts will be a nal yz e d acc or di n g t o t he 
a nal ys is wi n d o ws a b o ve (a n d t he Wee k 3 6 a nalys is wi n d o w will o nl y be use d f or t he 
P R Os c o m plete d at Wee k 3 6) . N ote t hat o nl y  the dail y  assess me nts rec or de d i n t he e-
Diar y  pri or t o d osi n g o n Da y 1 [ Visit 5] will be i ncl u de d i n t he deri vati o n of Baseli ne 
N A S H S y m pt o m Diar y  sc ores. A ny dail y  assess me nts ca pt ure d i n t he e-Diar y  o n Da y 1 
or later will be e xcl u de d fr o m t he Baseli ne sc ores. F or P GI-S, as t his is rec or de d t wice at 
eac h visit, t he rec or ds will be selecte d base d o n t he bel o w met h o d:
Cl osest t o T ar get (first) – Selects t he rec or d cl osest t o t he tar get. If t w o rec or ds are 
e q ui-dista nt fr o m t he tar get ( bef ore a n d after), select t he 1 st rec or d.

F or t he f oll o wi n g assess me nts, t he a b o ve visit wi n d o ws will n ot be use d:
o
Li ver Bi o ps y:
F or li ver bi o ps y assess me nts, a n y pre-ra n d o mizati o n bi o ps y data will be 
c o nsi dere d t o be ‘ Baseli ne’, a n d a n y p ost -ra n d o mizati o n bi o ps y  data c ollecte d o n 
or after t he Wee k 2 4 visit will be c o nsi dere d t o be ‘ Wee k 4 8/ E n d of St u d y ’. T his 
is s o t hat a n y li ver bi o psies perf or me d at t he ‘earl y ter mi nati o n’ visit, w hic h will 
be a n u n pla n ne d visit (after Wee k 2 4), ca n be wi n d o we d a p pr o priat el y  s o t hat 
data will be s u m marize d a n d i ncl u de d i n t he a nal ysis as re q uire d.
o
M RI : All M RI
e n d p oi nts will be a nal yz e d acc or di n g t o t he n o mi nal visit t o w hic h 
t he y relate.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 0
T M F D oc I D: 9 8. 0 3
A p pe n di x 2. 2. E n d p oi nt Deri v ati o ns
A p pe n di x 2. 2. 1.
% Li ver F at usi n g M RI -P D F F a n d 
F or eac h partici pa nt i n t he Ima gi n g s u bst u d y  p o p ulati o n, t he W h ole L i ver P D F F ( W LP D F F 
i n %) will be calc ulate d fr o m t he pre -defi ne d i n di vi d ual se g me ntal P D F F ( S P D F F i n %) 
meas ure d i n Se g me nt I, II, III, I Va, I V b, V, VI, VII a n d VIII as f oll o ws:
W L P D F F = ( S P D F F Se g me nt II + S P D F F Se g me nt III + S P D F F Se g me nt I Va + S P D F F Se g me nt I V b + 
S P D F F Se g me nt V + S P D F F Se g me nt VI + S P D F F Se g me nt VII + S P D F F Se g me nt VIII + ( 0. 3 6 * 
S P D F F Se g me nt I )) / 8. 3 6 (if all se g me nts are assesse d a n d n o t missi n g/ ma p pi n g at Baseli ne, a n d 
o n Wee k 6 , Wee k 2 4 , a n d Wee k 4 8 ).
N ote: If data f or all se g me nts is n ot i ncl u de d, t he n a dj ust t he de n o mi nat or acc or di n gly. T his 
s h o ul d be t he n u m ber of all se g me nts c o ntri b uti n g t o t he n u merat or, e xce pt if t his i ncl u des 
Se g me nt 1, t he n a d d 0. 3 6 i nstea d of 1). F or e xa m ple, if t he o nl y  se g me nt n ot i ncl u de d is 
Se g me nt 1 t he n t he de n o mi nat or = 8, if se g me nt 2 is n ot i ncl u de d t he n t he de n o mi nat or = 7. 3 6 
(( 7 x 1) + 0. 3 6) etc. 
C alc ul ati o n R ule f or % Li ver F at w he n Assesse d wit h M RI -P D F F:
W L P D F F will be calc ulate d o n ma p pi n g n o n- missi n g se g m e nts at Baseli ne, a n d at Wee k 6 , 
Wee k 2 4 , a n d Wee k 4 8 .
F or i nsta nce, if res ults are re p orte d f or all se g me nts at Baseli ne, a n d at Wee k 6 , Wee k 2 4 , 
a n d Wee k 4 8 (see bel o w), t he n u m ber of se g me nts assesse d is e q ual t o 9.
                    
If at Baseli ne, all se g me nt data are a vaila ble b ut, at Wee k 6 , or Wee k 2 4 , or Wee k 4 8 , o nl y 7 
se g me nts ha ve res ults re p orte d, W L P D F F will be calc ulate d at Baseli ne, a n d at Wee k 6 , 
Wee k 2 4 , a n d Wee k 4 8 a n d usi n g t he matc hi n g i n di vi d ual se g me nts pr o vi di n g val ues o n all 
wee ks. F or i nsta nce, base d o n t he sc he ma bel o w, se g me nt II a n d Se g me nt V will n ot be use d 
t o calc ulate W L P D F F o n a n y  of t he ti me p oi nts re p orte d. I n t his case, W LP D F F will be
calc ulate d usi n g data i n t he 7 se g me nts re p orte d at all n o n -missi n g visits. A mi ni m u m of 5 
se g me nts nee d t o be a vaila ble at B aseli ne a n d at least o ne p ost -baseli ne visit i n or der t o 
calc ulate W LP D F F a n d t he partici pa nt s h o ul d ha ve a faste d stat us of ‘ Yes’ (i.e. faste d f or a 
d urati o n of at least 4 h o urs) . If a visit has fe wer t ha n 5 se g me nts or t he partici pa nt was n ot 
faste d, t he n t he w h ole visit w o ul d be c o nsi dere d ‘ missi n g’.
Baseli ne
Wee k 6
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 1
T M F D oc I D: 9 8. 0 3
                   
W L P D F F a n d i n di vi d ual % li ver fat meas ure d i n eac h i n di vi d ual se g me nt will be i ncl u de d i n 
s o urce data. W L P D F F will be s u m marize d b y  ra n d o mize d ar m a n d Week.
N ote: If baseli ne at t he i n di vi d ual se g me nt le vel is zer o b y  itself or after i m p utati o n, %
c ha n ge fr o m baseli ne a n d relati ve c ha n ge at i n di vi d ual se g me nt le vel will be re p orte d as “.”
( because n ot calc ula ble) wit h a f o ot n ote e x plai ni n g t hat t he val ue at baseli ne was zer o or 
i m p ute d t o zer o.
A si milar deri vati o n will be utilize d t o deter mi ne  
 ( val ues of w hic h will be pr o vi de d 
f or eac h se g me nt), w hic h reflects t he prese nce of 
 a n d t h us is 
reflecti ve of 
 (c o m bi nati o n of li ver 
 a n d 
).
A p pe n di x 2. 2. 2. M RI -deri ve d Li ver V ol u me
N o a d diti o nal deri vati o n is re q uire d f or M RI -deri ve d Li ver V ol u me – a si n gle val ue ( per 
partici pa nt per visit) f or li ver v ol u me (i n m L) will be rec or de d o n t he data base.
A p pe n di x 2. 2. 3. M RI -deri ve d 
N o a d diti o nal deri vati o n is re q uire d f or M RI -deri ve d 
– a si n gle val ue ( per 
partici pa nt per visit) f or 
 (i n m L) will be rec or de d o n t he data base.
A p pe n di x 2. 2. 4. F asti n g Pl as m a Gl uc ose a n d F asti n g Pl as m a I ns uli n ( T 2 D M 
P artici p a nt s O nl y)
F P G a n d F PI val ues will be assesse d at ti me p oi nts descri be d i n t he Sc he d ule of Acti vit y of 
t he pr ot oc ol.  
N ote: if plas ma gl uc ose c o nce ntrati o ns are re p orte d i n m m ol/ L , tra nsf or m t he val ue i n m g / d L 
usi n g t he f oll o wi n g e q uati o n :
Gl uc ose ( m g/ d L) = 1 8 * Gl uc ose ( m m ol/ L)
A p pe n di x 2. 2. 5. H o me ost atic M o del Assess me nt f or I ns uli n Resist a nce ( T 2 D M
P artici p a nt s O nl y)
T he H O M A- I R will be deri ve d usi n g fasti n g plas ma gl uc ose val ues a n d fasti n g plas ma 
i ns uli n val ues at ti me p oi nts descri be d i n t he Sc he d ule of Acti vit y of t he pr ot oc ol.
T he f or m ula use d t o deri ve H O M A -I R is as f oll o ws:
H O M A -I R = ( Gl uc oseFasti n g C o nce ntrati o n x I ns uli n Fasti n g C o nce ntrati o n ) / 4 0 5
w here plas ma gl uc ose c o nce ntrati o ns is re p orte d i n m g/ d L a n d plas ma i ns uli n is re p orte d i n 
m U/ L . As s uc h, H O M A-I R is u nit-less.
Baseli ne
Wee k 6
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 2
T M F D oc I D: 9 8. 0 3
A p pe n di x 2. 3. D at a Deri v ati o n f or P atie nt Re p orte d O utc o mes
A p pe n di x 2. 3. 1. N A S H -C H E C K
T he N A S H -C hec k is a N A S H -s pecific healt h-relate d q ualit y of life meas ure t hat was 
de vel o pe d base d o n q ualitati ve partici pa nt i n p ut. I t c o nsists of 3 1 ite ms t hat meas ure 3 
d o mai ns: s y m pt o ms ( 1 1 -p oi nt N R S), da y -t o-d a y  acti vities ( 5- p oi nt V R S), a n d e m oti o ns a n d 
lifest yle ( 4-p oi nt V R S), o ver t he past 7 da y s.
N A S H -C H E C K S y m pt o m Sc ale Sc ores
Si n gle S y m pt o m Ite m Sc ales 
Fi ve of t he s ym pt o m scale sc ores are si n gle ite ms ( a b d o mi n al p ai n , ite m 1; a b d o mi n al 
bl o ati n g , ite m 2; f ati g ue, ite m 3; slee p, ite m 4; itc h y s ki n, ite m 9). Eac h ite m has a n 1 1-
p oi nt n u merical rati n g scale wit h res p o nse a nc h ors ra n gi n g fr o m n o s y m pt o m (sc ore d 0) t o 
w or st p ossi ble or e xtre me s ym pt o m (sc ore d 1 0), wit h a hi g her sc ore i n dicati n g m ore se vere 
s ym pt o ms. T he ite m sc ore is use d as t he c orres p o n di n g s y m pt o m scale sc ore a n d t he ite m 
m ust be c o m plete d f or t hat s y m pt o m scale sc ore t o be deri ve d.
S y m pt o m scale sc ores ra n ge 0 t o 1 0, wit h hi g her sc ores i n dicati n g m ore se vere sy m pt o ms.
C o g niti ve S y m pt o m Sc ale 
N A S H -C H E C K has 4 ite ms assessi n g c o g niti ve s y m pt o ms (ite ms 5 – 8). Eac h ite m has a n 1 1 -
p oi nt n u merical rati n g scale wit h res p o nse a nc h ors ra n gi n g fr o m n o s y m pt o m (s c ore d 0) t o 
w orst p ossi ble or e xtre me s y m pt o m (sc ore d 1 0), wit h a hi g her sc ore i n dicati n g m ore se vere 
s ym pt o ms. 
T he c o g niti ve s y m pt o ms ra w sc ore is calc ulate d as t he mea n of t he n o n- missi n g ite m sc ores 
f or ite ms 5 t o 8 (i.e., t he s u m of ite ms 5– 8 di vi de d b y  t he n u m ber of n o n-missi n g ite ms). A 
mi ni m u m of 3 c o g niti ve s y m pt o ms ite ms nee d t o be a ns were d f or a ra w sc ore t o be deri ve d; 
s pecifically, if a res p o n de nt misses 2 or m ore of t hese ite ms, t hat pers o n’s c o g niti ve 
s ym pt o ms sc ore is set t o missi n g. T he ra w sc ore is use d as t he fi nal scale sc ore. T he f or m ulas 
f or t he ra w a n d scale sc ores are as f oll o ws:
C o g niti ve s y m pt o ms ra w sc ore = s u m of n o n-missi n g sc ores f or ite ms 5 t o 8 / 
    n u m ber of n o n -missi n g ite ms 
C o g niti ve s y m pt o ms sc ale sc ore = c o g niti ve s y m p t o ms ra w sc ore 
C o g niti ve s y m pt o ms scale sc ores ra n ge 0 t o 1 0, wit h hi g her sc ores i n dicati n g m ore se vere 
s ym pt o ms.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 3
T M F D oc I D: 9 8. 0 3
N A S H -C H E C K H R Q O L Sc ale Sc ores
Acti vit y Li mit ati o ns Sc ale 
N A S H -C H E C K has 8 ite ms assessi n g acti vit y  li mitati o ns d ue t o N A S H (ite ms 1 0– 1 7). E ac h 
ite m has a 5-p oi nt ver bal rati n g scale ra n gi n g fr o m " n o diffic ult y"  (sc ore d 0) t o " u na ble t o 
d o" (sc ore d 4), wit h a hi g her sc ore i n dicati n g greater pr o ble ms. 
T he acti vit y  li mitati o ns ra w sc ore is calc ulate d as t he mea n of t he n o n- missi n g ite m sc ores 
f or ite ms 1 0 t o 1 7 (i.e., t he s u m of ite ms 1 0 –1 7 di vi de d b y  t he n u m ber of n o n-missi n g ite ms). 
A mi ni m u m of 5 acti vit y  li mitati o ns ite ms nee d t o be a ns were d f or a ra w sc ore t o be deri ve d; 
s pecifically, if a res p o n de nt misses 4 or m ore of t hese ite ms, t hat pe rs o n’s acti vit y li mitati o ns 
sc ore is set t o missi n g. Fi nall y, t he ra w sc ore is tra nsf or me d t o ra n ge 0 t o 1 0 t o f or m t he fi nal 
scale sc ore. T he f or m ulas f or t he ra w a n d scale sc ores are as f oll o ws:
Acti vit y  li mitati o ns ra w sc ore = s u m of n o n- missi n g sc ores f or ite ms 1 0 t o 1 7 / 
     n u m ber of n o n - missi n g ite ms
Acti vit y li mit ati o ns sc ale sc ore = (acti vit y li mitati o ns ra w sc ore / 4) * 1 0
Acti vit y  li mitati o ns scale sc ores ra n ge 0 t o 1 0, wit h hi g her sc ores i n dicati n g greater acti vit y 
li mitati o ns.  
E m oti o n al I m p act Sc ale 
N A S H -C H E C K has 4 ite ms assessi n g e m oti o nal i m pact d ue t o N A S H (ite ms 1 8 – 2 1). Eac h 
ite m has a 4-p oi nt ver bal rati n g scale ra n gi n g fr o m " n ot at all" (sc ore d 0) t o " ver y  m uc h" 
(sc ore d 3), wit h a hi g her sc ore i n dicati n g greater pr o ble ms. 
T he e m oti o nal i m pact ra w sc ore is calc ulate d as t he mea n of t he n o n -missi n g ite m sc ores f or 
ite ms 1 8 t o 2 1 (i.e., t he s u m of ite ms 1 8 –2 1 di vi de d b y t he n u m ber of n o n - missi n g ite ms). All 
4 e m oti o nal i m pact ite ms nee d t o be a ns were d f or a ra w sc ore t o be deri ve d ; s pecifically, if a 
res p o n de nt misses 1 or m ore of t hese ite ms, t hat pers o n’s e m oti o nal i m pact sc ore is set t o 
missi n g. Fi nall y, t he ra w sc ore is tra nsf or me d t o ra n ge 0 t o 1 0 t o f or m t he fi nal scale sc ore. 
T he f or m ulas f or t he ra w a n d scale sc ores are as f oll o ws:
E m oti o nal i m pact ra w sc ore = s u m of n o n -missi n g sc ores f or ite ms 1 8 t o 2 1 / 
  n u m ber of n o n -missi n g ite ms
E m oti o n al i m p act sc ale sc ore = (e m oti o nal i m pact ra w sc ore / 3) * 1 0
E m oti o nal i m pact scale sc ores ra n ge 0 t o 1 0, wit h hi g her sc ores i n dicat i n g greater e m oti o nal 
i m pact. 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 4
T M F D oc I D: 9 8. 0 3
S oci al I m p act Sc ale 
N A S H -C H E C K has 7 ite ms assessi n g s ocial i m pact d ue t o N A S H (ite ms 2 2 – 2 8). Eac h ite m 
has a 4 -p oi nt ver bal rati n g scale ra n gi n g fr o m " n ot at all" (sc ore d 0) t o " ver y  m uc h" (sc ore d 
3), wit h a hi g her sc ore i n dicati n g greater pr o ble ms.
T he s ocial i m pact ra w sc ore is calc ulate d as t he mea n of t he n o n -missi n g ite m sc ores f or 
ite ms 2 2 t o 2 8 (i.e., t he s u m of ite ms 2 2 –2 8 di vi de d b y t he n u m ber of n o n -missi n g ite ms). A 
mi ni m u m of 5 s ocial i m pact ite ms nee d t o be a n s were d f or a ra w sc ore t o be deri ve d; 
s pecifically, if a res p o n de nt misses 3 or m ore of t hese ite ms, t hat pers o n’s s ocial i m pact sc ore 
is set t o missi n g. Fi nall y, t he ra w sc ore is tra nsf or me d t o ra n ge 0 t o 1 0 t o f or m t he fi nal scale 
sc ore. T he f or m ulas f or t he ra w a n d scale sc ores are as f oll o ws:
S ocial i m pact ra w sc ore = s u m of n o n - missi n g sc ores f or ite ms 2 2 t o 2 8 / 
n u m ber of n o n -missi n g ite ms
S oci al i m p act sc ale sc ore = (s ocial i m pact ra w sc ore / 3) * 1 0
S ocial i m pact scale sc ores ra n ge 0 t o 1 0, wit h h i g her sc ores i n dicati n g greater s ocial i m pact.

N A S H -C hec k 3 1 -Ite m Versi o n a n d 2 8-Ite m Versi o n ite m m a p pi n g:
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 5
T M F D oc I D: 9 8. 0 3
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 6
T M F D oc I D: 9 8. 0 3
A p pe n di x 2. 3. 2. P R O MI S F ati g ue C ust o m 9 -Ite m Versi o n
T he P R O MI S Fati g ue is a self -re p orte d meas ure t hat assesses a ra n ge of sy m pt o ms i n t he 
past 7 da y s fr o m mil d s u bjecti ve feeli n gs of tire d ness t o a n o ver w hel mi n g, de bilitati n g, a n d 
s ustai ne d se nse of e x ha usti o n t hat li kel y decreases o ne’s a bilit y t o e xec ute dail y acti vities 
a n d f u ncti o n n or mall y i n fa mil y  or s ocial r oles.
T he s h ort f or m c o nsists of 9 ite ms t hat partici pa nts will be as ke d t o rate fr o m 1: “ Ne ver” t o 5: 
“ Al wa ys”. A gl o bal ra w sc ore ra n gi n g fr o m 9 t o 4 5 is calc ulate d a n d ca n be tra nslate d i nt o a 
T- sc ore ( Mea n = 5 0, S D = 1 0) usi n g eit her t he a p plica ble sc ore c o n versi o n ta ble pr o vi de d b y 
t he de vel o per (see bel o w) or usi n g o nli n e sc ori n g ser vice
(htt p:// w w w. healt h meas ures. net/sc ore -a n d -i nter pret/calc ulate-sc ores/sc ori n g-i nstr ucti o ns).
B ot h t he gl o bal ra w sc ore a n d t he T -sc ore will be s u m marize d, a n d o nl y if all ite ms ha ve 
bee n a ns were d ( n o missi n g res p o nses are all o we d) .
A p pe n di x 2. 3. 3. N A S H S y m pt o m Di ar y
T he N A S H S y m pt o m Diar y  is a daily, self -a d mi nistere d q uesti o n naire t hat meas ures 
s ym pt o ms of N A S H. T his meas ure was de vel o pe d b y  Pfizer base d o n q ualitati ve partici pa nt 
i n p ut as well as re vie w of ot her data s o urces (ie, literat ure a n d ot her e xisti n g meas ures). T he 
meas ure c o nsists of a t otal of 5 ite ms t hat as k partici pa nts t o rate t he se verit y  of t heir 
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 7
T M F D oc I D: 9 8. 0 3
a b d o mi nal s ym pt o ms ( pai n a n d bl oati n g [ 2 ite ms]), fati g ue ( 1 ite m), slee p dist ur ba nce 
( 1 ite m), a n d da yti me slee pi ness ( 1 ite m), i n t he past 2 4 -h o urs o n a n 1 1 -p oi nt N R S t hat 
ra n ges fr o m 0 t o 1 0. T he N A S H dail y  sy m pt o m diar y  e ntries will be i de ntifie d fr o m eac h 
date /ti me-sta m pe d (Refer t o Date/ Ti me of C ollecti o n i n Secti o n 3. 1 1 of t he D T S ).
N A S H S y m pt o m Di ar y Sc ori n g
N A S H S y m pt o m D iar y is a ne wly de vel o pe d meas ure. T he c urre nt sc ori n g al g orit h m is 
preli mi nar y . T he fi nal sc ori n g al g orit h m will be de vel o pe d base d o n psyc h o metric e val uati o n 
of t he meas ure o nce C 2 5 4 1 0 1 3 data is a vaila ble.

Eac h ite m is sc ore d i n di vi d uall y

T he sc ore f or eac h ite m is defi ne d as t he a vera ge of dail y data o ver t he assess me nt 
peri o d ( 1 4 c o nsec uti ve da y s)
o
Assess me nt peri o d is defi ne d i n t he st u d y  pr ot oc ol ( Secti o n 8. 1. 3, Ta ble 4) 
o
Mi n of 5 0 % of dail y data ( mi n of 7 da ys , a n d t hese d o n ot nee d t o be 
c o nsec uti ve b ut m ust be wit hi n t he sa me 1 4 da y  peri o d) d uri n g t he assess me nt 
peri o d is re q uire d t o calc ulate t he sc ore
o
If < 7 da ys of sc ores d uri n g assess me nt peri o d, t he n a vera ge dail y sc ore s h o ul d 
be set t o missi n g
o
A nal y se C ha n ge fr o m Baseli ne i n ( 1) Pai n. ( 2) Bl oati n g. ( 3) F ati g ue. ( 4) S lee p 
dist ur ba nce , a n d ( 5) Da yti me slee pi ness a vera ge dail y sc ore.
A p pe n di x 2. 4. D at a Deri v ati o n f or N o n St a n d ar d S afet y E n d p oi nts
A p pe n di x 2. 4. 1. E L F Test 
E L F sc ore ( hi g hli g hte d bel o w) will be calc ulate d usi n g t he La b C or p re p orte d se nsiti ve res ults 
f or f oll o wi n g 3 para meters assa ye d usi n g t he Ce nta ur ( R O W) or Ce nta ur X P ( C hi na) 
c he mil u mi nesce nce assa y fr o m Sie me ns –
1.
Ser u m h y al ur o nic aci d ( H A) – re p orte d i n n g/ m L
o
assa y ra n ge = 1. 6 t o 1 0 0 0 n g/ m L
2.
Ser u m a mi n o- ter mi nal pr o pe pti de of t ype III pr oc olla ge n ( PIII N P) – re p orte d i n n g/ m L
o
assa y ra n ge = 0. 5 t o 1 5 0 n g/ m L
3.
Ser u m tiss ue i n hi bit or of metall o pr otei nases 1 ( TI M P -1) – re p orte d i n n g/ m L
o
assa y ra n ge = 3. 5 t o 1 0 0 0 n g/ m L
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 8
T M F D oc I D: 9 8. 0 3
T he a b o ve hi g hli g hte d f or m ula s h o ul d be a d de d as a pr o gra m mi n g f o oter f or t he res pecti ve 
o ut p uts, as f oll o ws:
“ E L F Sc ore usi n g Ce nta ur a n d Ce nta ur X P assa y  deri ve d as 2. 2 7 8 + 0. 8 5 1 l n( CH A ) + 0. 7 5 1 
l n( CP 3 N P ) + 0. 3 9 4 l n( CTI M P 1 ), w here c o nce ntrati o ns ( C) of eac h assa y are i n n g/ ml.”
A p pe n di x 2. 4. 2. M E L D sc ore 
T he M E L D sc ore f or all t he partici pa nt s t o be deri ve d usi n g t he bel o w me nti o ne d f or m ula:-
I nitial M E L D(i) sc ore = 0. 9 5 7 x Lo g e(creati ni ne m g/ d L) + 0. 3 7 8 x Lo g e( bilir u bi n m g/ d L) + 
1. 1 2 0 x L o g e(I N R) + 0. 6 4 3
N ote: La b orat or y  val ues < 1. 0 will be set t o 1. 0 w he n calc ulati n g t h e i nitial M E LD (i) sc ore.
T he ma xi m u m M E L D sc ore is 4 0. T he M E L D sc ore deri ve d fr o m t his calc ulati o n will be 
r o u n de d t o t he te nt h deci mal place a n d t he n m ulti plie d b y 1 0.
If t he i nitial M E L D (i) sc ore is greater t ha n 1 1, t he n t he sc ore s h o ul d be re-calc ulate d usi n g t he 
bel o w f or m ula: -
M E L D = M E L D (i) + 1. 3 2 *( 1 3 7 -Na) – [ 0. 0 3 3 * M E L D(i)*( 1 3 7 -Na)]
N otes: -
1. If t he creati ni ne val ue is > 4. 0 m g/ d L t he n set t his t o 4. 0.
2. If S o di u m ( Na i n t he sec o n d e q uati o n) is < 1 2 5 m m ol/ L t he n set t his t o 1 2 5.
3. If S o di u m ( Na i n t he sec o n d e q uati o n) is > 1 3 7 m m ol/ L t he n set t his t o 1 3 7.
4. All u nits s h o ul d be i n C o n ve nti o nal U nits (c o n versi o ns s h o w n i n ta ble bel o w)
T o be i ncl u de d i n A dj u dicate d E ve nts listi n g, ( M E L D) sc ore m ust i ncrease fr o m ≤1 2 at 
baseli ne t o ≥1 5 o n at least 2 c o nsec uti ve occasi o ns at least 4 wee ks a part a n d wit h o ut a n 
i nter me diate sc ore < 1 5.
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 7 9
T M F D oc I D: 9 8. 0 3
C o n versi o n of SI u nits t o c o n ve nti o n al u nits:
L a b or at or y p ar a meter ( u nit i n M E L D -
N a)
SI res ult 
c o n ve nti o n al u nit res ult 
Ser u m creati ni ne ( m g/ d L)
µ m ol/ L  x 0. 0 1 1 3 
res ult i n m g/ d L 
Ser u m s o di u m ( m E q/ L )
m m ol/ L  res ult x 1 = res ult i n m E q/ L
T otal bilir u bi n ( m g/ d L)
µ m ol/ L  x 0. 0 5 8 5 
res ult i n m g/ d L 
I N R ( U nitless para meter)
Res ult i n SI  u nit x 1 = res ult i n c o n ve nti o nal 
u nit
S o urce f or c o nversi o ns : htt ps:// w w w.la bc or p.c o m/res o urce/si -u nit -c o n versi o n -ta ble
A p pe n di x 2. 4. 3. Esti m ate d Gl o mer ul ar Filtr ati o n R ate 
T h e Esti mate d Gl o mer ular Filtrati o n Rate ( e G F R ) will be calc ulate d usi n g c ystati n- C, as 
f oll o ws:
If c ystati n-C > 0. 8 m g/ L:
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 3 3 x (c y stati n-C/ 0. 8) -1. 3 2 8 x 0. 9 9 6 A ge
( m ulti pl y w h ole e q uati o n b y 0. 9 3 2 if fe male)
If c ystati n- C ≤0. 8 m g/ L:
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 3 3 x (c ystati n-C/ 0. 8) -0. 4 9 9 x 0. 9 9 6 A ge
( m ulti pl y w h ole e q uati o n b y 0. 9 3 2 if fe male)
W here A ge is t he partici pa nt’s a ge at scree ni n g (c ollecte d at S C R 1 visit) i n years.
F or t he e ntire st u d y  p o p ulati o n, e G F R will be s u m marize d b y ra n d o mize d ar m.
Ref: I n ker L A, Sc h mi d C H, Ti g hi o uart H, et al. Esti mati n g Gl o mer ular Filtrati o n Rate fr o m 
Ser u m Creati ni ne a n d C ystati n C. N E n gl J Me d 2 0 1 2; 3 6 7: 2 0 - 9.
A p pe n di x 2. 4. 4. A U DI T T ot al Sc ore 
T h e A U DI T t otal sc ore is calc ulate d as t he s u m of sc ores pr o vi de d f or eac h of t he 1 0 
q uesti o ns of t he A U DI T q uesti o n naire. T he ra n ge of p ossi ble A U DI T t otal sc ores is fr o m 0 t o 
4 0 . 
N ot all q uesti o ns i n t he A U DI T q uesti o n naire ha ve t o be a ns were d (see bel o w), h o we ver, it is 
n ot p ossi ble t o s ki p q uesti o ns i n t he e Diar y (if t he y s h o ul d be a ns were d). Theref ore t here 
s h o ul d n o t be a n y missi n g res p o nses ( ot her t ha n t h ose t hat are all o we d t o be missi n g base d 
o n t he re s p o nses t o Qs 1, 2 a n d 3).
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 8 0
T M F D oc I D: 9 8. 0 3
Ref : Ba b or T F, Hi g gi ns-Bi d dle J C, Sa n u ders J B, M o nteir o M G. A U DI T – t he alc o h ol use
dis or ders i de ntificati o n test – g ui deli nes f or use i n pri mar y  care – 2 n d e diti o n. W orl d
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 8 1
T M F D oc I D: 9 8. 0 3
Healt h Or ga nizati o n; De part me nt of Me ntal Healt h a n d S u bsta nce De pe n de nce – 2 0 0 1.
A p pe n di x 2. 5. Defi niti o n of Pr ot oc ol De vi ati o ns T h at Rel ate t o St atistic al 
A n al yses/ P o p ul ati o ns
A p pe n di x 2. 5. 1. C o m pli a nce
C o m plia nce wit h d o u ble- bli n de d st u d y  me dicati o n will be calc ulate d usi n g data ca pt ure d o n 
the D o u ble Bli n de d treat me nt C R Fs .
C o m plia nce bet wee n a n y t w o visits i n t he st u d y  will be calc ulate d as: 
% C o m plia nce = # of pills act uall y ta ke n si nce t he pre vi o us visit x 1 0 0
    # of pills e x pecte d t o be ta ke n si nce t he pre vi o us visit
T he # of pills act u all y t a ke n si nce t he pre vi o us visit will be ta ke n directly fr o m t he “ Act ual 
D ose” fiel d i n t he D o u ble Bli n de d treat me nt C R Fs (sites will be i nstr ucte d t o e nter t he total 
n u m ber of ta blets t hat t he partici pa nt has c o ns u me d si nce t he last o n-site visit).
T he # of pills e x p ecte d t o be t a ke n si nce t he pre vi o us visit = ( Date of c urre nt visit – Date 
of pre vi o us visit) * 6
C o m plia nce acr oss t he o verall st u d y  treat me nt peri o d will be calc ulate d as:
% C o m plia nce =  # of pills act uall y ta ke n d uri n g t he d o u ble - bli n d treat me nt p hase x 1 0 0
      
     # of pills e x pecte d t o be ta ke n d uri n g t he d o u ble -bli n d treat me nt p hase
T he # of pills act u all y t a ke n d uri n g t he d o u ble - bli n d tre at me nt p h ase = s u m of all 
“ Act ual d ose” fiel ds f or all visits d uri n g t he d o u ble-bli n d treat me nt p hase (i.e. t he s u m of t he 
t otal n u m ber of ta blets t hat t he partici pa nt has c o ns u me d d uri n g t he d o u ble-bli n d treat me nt 
p hase )
T he # of pills e x pecte d t o be t a ke n d uri n g t he d o u ble - bli n d tre at me nt p h ase = ( Wee k 4 8 
( V 1 9) or Earl y Ter m visit date – Baseli ne visit date ( V 5) + 1 ) * 6
A p pe n di x 3. D at a Set Descri pti o ns
N ot a p plica ble
A p pe n di x 4. St atistic al Met h o d ol o g y Det ails
N ot a p plica ble
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 8 2
T M F D oc I D: 9 8. 0 3
A p pe n di x 5. List o f A b bre vi ati o ns
A b bre vi ati o n
Ter m
% C D T
P erce nt car b o h y drate deficie nt tra nsferri n relati ve t o t otal tra nsferr i n
A C Ci
A cet yl -C o A car b o x y lase i n hi bit or ( P F-0 5 2 2 1 3 0 4)
A E
A d verse e ve nt
A L P
Al kali ne p h os p hatase
A L T
A la ni ne a mi n otra nsferase 
A N C O V A
A nal y sis of c o varia nce
a P T T
A cti vate d partial t hr o m b o plasti n ti me
A S T 
A s partate a mi n otra nsferase 
A U DI T
Alc o h ol use dis or ders i de ntificati o n test
BI D
B is i n die (t wice-a-d a y )
B L Q
B el o w t he li mit of q ua ntitati o n
B MI
B o d y mass i n de x
B P M
B eats per mi n ute
C A P T M
C o ntr olle d atte n uati o n para meter
Ca P S
C DI S C a n d Pfizer sta n dar ds
C B L
C ha n ge fr o m baseli ne
C DI S C
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m
C D T
Car b o h y drate deficie nt tra nsferri n
CI
C o nfi de nce i nter val
C K 1 8 -M 3 0
C yt o kerati n -1 8 -M 3 0
fra g me nt
C K 1 8 -M 6 5
C yt o kerati n -1 8 -M 6 5
fra g me nt
C K D -E PI
C hr o nic Ki d ne y  Disease E pi de mi ol o g y C olla b orati o n e q uati o n
C R F
C ase re p ort f or m
DI LI
D r u g-i n d uce d li ver i nj ur y
D G A T 2i
D iac yl gl ycer ol ac yltra nsferase 2 i n hi bit or ( P F-0 6 8 6 5 5 7 1)
D R
D ose res p o nse
D T S
Data Tra nsfer S pecificati o n
E C
E t hics C o m mittee
E C G
E lectr ocar di o gra m
E -D M C
E xter nal data m o nit ori n g c o m mittee 
e G F R
E sti mate d gl o mer ular filtrati o n rate
E L F
E n ha nce d Li ver Fi br osis
E R
E x p os ure res p o nse
F A S
F ull a nal ys is set
F P G
Fasti n g plas ma gl uc ose
F PI
Fasti n g plas ma i ns uli n
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
Healt h A ut h orit y
H b A 1 C
Gl y cate d he m o gl o bi n
H D L -C
H i g h de nsit y li p o pr otei n c h olester ol
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 8 3
T M F D oc I D: 9 8. 0 3
A b bre vi ati o n
Ter m
HI V
H u ma n i m m u n o deficie nc y vir us
H O M A -I R
H o me ostatic M o del Assess me nt f or I ns uli n Resista nce
H R Q o L
H ealt h-relate d q ualit y of life
hs -C R P
Hi g h -se nsiti ve C-reacti ve pr otei n
I A
I nteri m A nalys is
I C D
Inf or me d c o nse nt d oc u me nt
I M E
I mp orta nt Me dical E ve nt
I N R
Inter nati o nal n or malize d rati o
I P V
I ntra-pat h ol o gist varia bilit y
I RB
Instit uti o nal R e vie w B oar d
L D L -C
L o w de nsit y  li p o pr otei n-c h olester ol
L F T
L i ver f u ncti o n test
L L Q
L o wer li mit of q ua ntificati o n
L S M
L east-s q uares mea n
M A C E
M aj or a d verse car di o vasc ular e ve nt
M C H
M ea n c or p usc ular he m o gl o bi n
M C H C
M ea n c or p usc ular he m o gl o bi n c o nce ntrati o n
M C V
M ea n c or p usc ular v ol u me
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M E L D
M o del of e n d -sta ge li ver disease
M M R M
M i xe d-effects m o del wit h re peate d meas ures
M RI
M a g netic res o na nce i ma gi n g
M RI -P D F F
Ma g netic res o na nce i ma gi n g usi n g pr ot o n de nsit y  fat fracti o n 
ac q uisiti o n 
N/ A
N ot a p plica ble
N A F L D
N o nalc o h olic fatt y li ver disease
N A S
N A F L D Acti vit y  Sc ore
N A S H
N o nalc o h olic steat o he patitis
N D
N ot d o ne
N R S
N u meric rati n g scale
N S
N o sa m ple
P C C
P ote ntial C li nical C o ncer n
P C S K 9
P r o pr otei n c o n vertase s u btilisi n/ ke xi n t ype 9
P D
P har mac o d y na mic(s)
P GI -C
Patie nt Gl o bal I m pressi o n of C ha n ge
P GI -S
Patie nt Gl o bal I m pressi o n of Se verit y
P K
P har mac o ki netic(s)
P R O
P atie nt-re p orte d o utc o me
P R O MI S
Patie nt -Re p orte d Meas ure me nt O utc o me I nf or mati o n S y ste m
Pr o C 3
N -ter mi nal pr o pe pti de of t ype III  pr oc olla ge n
Pr o C 6
C -ter mi nal fra g me nt of α 3 c hai n of pr oc olla ge n t y pe VI  
P B L
P erce nt c ha n ge fr o m baseli ne
PI II N P
A mi n o -ter mi nal pr o pe pti de of t ype III pr oc olla ge n
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)


P F -0 6 8 6 5 5 7 1 ( D G A T 2i) a n d P F -0 6 8 6 5 5 7 1 + P F -0 5 2 2 1 3 0 4 ( D G A T 2i + A C Ci)
Pr ot oc ol C 2 5 4 1 0 1 3 Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 5. 0 Statistical A nal ysis Pla n Te m plate 0 5 -Dec -2 0 1 9
P FI Z E R C O N FI D E N TI A L 
Pa ge 8 4
T M F D oc I D: 9 8. 0 3
A b bre vi ati o n
Ter m
P R
P eri o d of ti me fr o m t he o nset of t he P wa ve t o t he be gi n ni n g of t he 
Q R S c o m ple x o n a n electr ocar di o gra m
P T
P referre d ter m
Q D
Q ua q ue die ( o nce -a-da y )
Q R S
C o m bi nati o n of Q -, R- a n d S - wa ve o n a n electr ocar di o gra m 
re prese nti n g ve ntric ular de p olarizati o n
Q Tc
C orrecte d Q T
Q Tc F
C orrecte d Q T ( Fri dericia met h o d)
R B C
R e d bl o o d cell
R C
Relatice c ha n ge
R C B L
R elati ve c ha n ge fr o m baseli ne
R N A
R i b o n ucleic aci d
R O W
Rest of W orl d
R R
Res pirat or y  rate
S A E
S eri o us a d verse e ve nt
S A P
S tatistical a nal ysis pla n
S D
Sta n dar d de viati o n
S E
Sta n dar d err or
SI
S y stè me i nter nati o nal
S O P
S ta n dar d o perati n g pr oce d ure
S P D F F
S e g me ntal P D F F
T 2 D M
T y p e 2 dia betes mellit us
T E A E
Treat me nt E mer ge nt A d verse E ve nt
T D D
T otal Dail y  D ose
TI M P -1
T iss ue i n hi bit or of metall o pr otei nases 1
U A
Uri nal y sis
U L N
U p per li mit of n or mal
U L Q
U p per li mit of q ua ntificati o n
V C T E T M
Vi brati o n -C o ntr olle d Tra nsie nt Elast o gra p h y
V L D L
V er y l o w-de nsit y  li p o pr otei n
V R S
Ver bal rati n g scale
W B C
W hite bl o o d cell
W L P D F F
W h ole L i ver P D F F
0 9 0 1 7 7 e 1 a 0 9 a b 3 7 4\ A p pr o v e d\ A p pr o v e d O n: 0 6- M a y- 2 0 2 4 1 5: 0 3 ( G M T)
C CI