Clinical trial NCT05113940
Conditions: Healthy Participants
Keywords: PF-07258669 multiple dose melanocortin-4 receptor MC4R healthy participants safety tolerability pharmacokinetics
Sponsor: Pfizer
Start date: 2021-11-08; Completion date: 2023-07-27
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Part A of this study is to evaluate safety, tolerability, and pharmacokinetics (PK) of PF-07258669 after administration of multiple ascending oral doses to healthy adult participants. Optional cohorts of healthy adult Japanese participants and/or older adult participants may also be evaluated if results in other cohorts support further evaluation. Part B of this study is a 2-period, fixed-sequence, multiple-dose, open-label design to evaluate the effect of PF-07258669 on midazolam PK in healthy adult participants. Part B will be conducted if the results of Part A support further evaluation of PF-07258669.

Detailed description:

Arms: arm 1: Dose level 1: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Carbohydrate High Calorie (HCHC) arm 2: Dose level 2: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: HCHC arm 3: Dose level 3: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: HCHC arm 4: Dose level 4: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: Standard Diet (SD) arm 5: Dose level 5: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD arm 6: Multiple dose administration of PF-07258669 and placebo over 14 days in Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD arm 7: Drug-drug interaction assessment of pharmacokinetics interaction in PF-07258669 and midazolam Dietary allocation: SD arm 8: Multiple dose administration of PF-07258669 and placebo over 14 days in older adult participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD arm 9: Dose level 6: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD arm 10: Dose level 7: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD arm 11: Dose level 8: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD arm 12: Dose Level 9: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Fat High Calorie (HFHC) arm 13: Dose Level 10: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Fat High Calorie (HFHC)
Interventions: intervention 1: PF-07258669 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days intervention 2: Placebo will be administered as tablets; Q8H or Q12H over 14 days intervention 3: Single doses of Midazolam will be administered as oral solution alone and in combination with PF-07258669

Protocol documents:
Prot_000.pdf: 
P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1
A P H A S E 1, R A N D O MI Z E D, D O U B L E -B LI N D, S P O N S O R -O P E N, 
P L A C E B O -C O N T R O L L E D S T U D Y T O I N V E S TI G A T E T H E S A F ET Y, 
T O L E R A BI LI T Y, P H A R M A C O KI N E TI C S, A N D P H A R M A C O KI N E TI C 
I N T E R A C TI O N WI T H MI DA Z O L A M O F  M U L TI P L E A S C E N DIN G O R A L D O S E S 
O F P F -0 7 2 5 8 6 6 9 I N H E A L T H Y N O N -J A P A N E S E , J A P A N E S E , A N D O L D E R
A D U L T P A R TI CI P A N T S
St u d y I nter ve nti o n N u m ber :
P F -0 7 2 5 8 6 6 9
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 5 3 7 9 7
E u dr a C T N u m ber:
2 0 2 1 -0 0 4 0 3 7 -3 6
Cli nic al Tri als. g o v I D:  
N/ A
Pr ot oc ol N u m ber:
C 4 5 4 1 0 0 3
P h ase:
1
Brief Title: A P hase 1 St u d y  of M ulti ple Asce n di n g D oses of P F-0 7 2 5 8 6 6 9 i n Healt h y  
A d ult Partici pa nts
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 nt s, yo 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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2
D oc u me nt Hist or y
D oc u me nt
Versi o n D ate
A me n d me nt 4
0 9 N o ve m ber 2 0 2 2
A me n d me nt 3
0 9 Marc h 2 0 2 2
A me n d me nt 2
1 3 Ja n uar y 2 0 2 2
A me n d me nt 1
1 2 Oct o ber 2 0 2 1
Ori gi nal pr ot oc ol
2 4 A u g ust 2 0 2 1
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d I R Bs/ E Cs a n d a n y gl o bal pr ot oc ol a d mi nistrati ve 
clarificati o n letter.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3
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 4 ( 0 9 N o ve m ber 2 0 2 2 )
O ver all R ati o n ale f or t he A me n d me nt: T h e pr ot oc ol is bei n g a me n de d t o all o w 
partici pa nts t o be all ocate d t o 1 of 3 diets (e g, sta n dar d, H C H C, or H F H C) , wit h opti o nal 
a d diti o nal c o h orts of partici pa nts all ocate d t o t he H F H C diet ( wit h a lar ger sa m ple size).
T hese a d diti o nal o pti o nal c o h orts ma y all o w f or better c haracterizati o n of safety, t olera bilit y,
or cli nical bi o mar ker of i nterest (e g, b o d y wei g ht). T he f oll o wi n g c ha n ges t o C 4 5 4 1 0 0 3 
pr ot oc ol are n o w pr o p ose d:
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
S u bst a nti al or 
N o ns u bst a nti al
1. 1 ( S y n o psis), 1. 2 
( Sc he ma, Fi g ure 1), 
4. 1. 1 ( Part A), 4. 2. 1 
( Rati o nale f or Part 
A), 9. 3. 4 
( Tertiar y/ E x pl orat or
y E n d p oi nts), a n d 
9. 5. 1 ( Sa m ple Size 
Deter mi nati o n)
O pti o nal c o h orts 
of partici pa nts 
all ocate d t o t he 
H F H C diet were 
a d de d ( wit h a 
lar ger sa m ple 
size).
T hese c o h orts ma y  all o w 
f or better c haracter izati o n 
of safety, t olera bilit y, or 
cli nical bi o mar ker of 
i nterest (e g, b o dy wei g ht).
S u bsta ntial
1. 1 ( S y n o psis), 1. 2 
( Sc he ma), 2. 3. 1 
( Ris k Assess me nt), 
4. 1 ( O verall 
Desi g n), 4. 1. 1 ( Part 
A), 4. 1. 2 ( Part B), 
4. 2. 1 ( Rati o nale f or 
Part A), 4. 2. 2 
( Rati o nale for Part 
B), 5. 3. 1 ( Meals a n d 
Dietar y  
Restricti o ns), 9. 3. 3. 3 
[ Statistical Met h o ds 
f or P F-0 7 2 5 8 6 6 9 P K 
Data ( Part A o nl y) , 
9. 3. 4 
( Tertiar y/ E x pl orat or
y E n d p oi nts), a n d 
9. 5. 1 ( Sa m ple Size 
Deter mi nati o n)
C o h orts will be 
all ocate d t o 1 of 3 
diets (ie, sta n dar d, 
H C H C, or H F H C).
Partici pa nts i n Part 
B will o nl y  be 
all ocate d t o 
sta n dar d diet.
T he i nfl ue nce of diet o n 
safety a n d t olera bilit y 
(e g, li ver f u ncti o n tests, 
tri glyceri des) has bee n 
re p orte d i n p u blis he d 
literat ure i n healt hy 
partici pa nts resi de nt i n a 
C R U. All ocati o n t o 1 of 3 
diets will facilitate a m ore 
c o m pre he nsi ve 
assess me nt of safet y, 
t olera bilit y, P K, a n d 
e x pl orat or y e n d p oi nts.
S u bsta ntial
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
S u bst a nti al or 
N o ns u bst a nti al
1. 3. 1 ( Part A –
O verall Sc he d ule of 
Acti vities) a n d te xt 
t hr o u g h o ut 
d oc u me nt
U p date d 
n u m beri n g of 
A p pe n dices 8- 1 5.
A d diti o n of Ki d ne y  Safet y 
M o nit ori n g G ui deli nes 
( A p pe n di x 7) re q uire d 
s u bse q ue nt a p pe n dices t o 
be re -n u m bere d.
N o ns u bsta ntial
2. 2. 6 ( Cli nical 
O ver vie w)
A d de d s u m mar y  of 
safety, t olera bilit y, 
a n d P K data 
o bser ve d t o date i n 
t he c urre nt st u d y.
Pr o vi de s t he m ost u p t o 
date s u m mar y  of cli nical 
safety, t olera bilit y, a n d 
P K data f or P F -0 7 2 5 8 6 6 9.
N o ns u bsta ntial
4. 3. 3. 1 ( Part A 
P F -0 7 2 5 8 6 6 9 D ose 
Selecti o n
A d de d rati o nale 
f or d ose selecti o n 
f or partici pa nts 
all ocate d t o H F H C 
diet.
D oses a d mi nistere d t o 
all ocate d t o t he H F H C 
diet (if e nr olle d) will be 
less t ha n or e q ual t o t he 
hi g hest safe a n d well 
t olerate d d ose e val uate d i n 
healt h y  a d ult n o n -
Ja pa nese partici pa nts
all ocate d t o sta n dar d diet
i n Part A.
N o ns u bsta ntial
1 0. 2 ( A p pe n di x 2: 
Cli nical L a b orat or y 
Tests )
A d de d c y stati n C 
t o c he mistr y 
la b orat or y 
assess me nts.
Ali g ns wit h c urre nt best 
practice f or cli nical safet y 
assess me nts i n m ulti ple 
asce n di n g d ose st u dies.
N o ns u bsta ntial
1 0. 7 ( A p pe n di x 7: 
Ki d ne y  Safety:  
M o nit ori n g 
G ui deli nes)
A d de d ki d ne y  
safety m o nit o ri n g 
g ui deli nes as a n 
a p pe n di x.
Ali g ns wit h c urre nt best 
practice f or cli nical safet y 
assess me nts i n m ulti ple 
asce n di n g d ose st u dies.
N o ns u bsta ntial
1 0. 1 4 ( A p pe n di x 1 4: 
Pr ot oc ol 
A me n d me nt 
Hist or y )
M o ve d S u m mar y  
of C ha n ges ta ble 
f or A me n d me nt 3 
fr o m be gi n ni n g of 
pr ot oc ol t o t he 
a p pe n di x.
M o ve d t o hi g hli g ht 
c ha n ges f or A me n d me nt 4 
at t he be gi n ni n g of t he 
pr ot oc ol.
N o ns u bsta ntial
1 0. 1 5 ( A p pe n di x 1 5: 
A b bre viati o ns)
A d de d ne w 
a b bre viati o ns.
Ne w a b bre viati o ns were 
a d de d t o pr ot oc ol te xt.
N o ns u bsta ntial
1 1 ( Refere nces)
A d de d ne w 
refere nces.
T o s u p p ort rati o nale f or 
dietar y  all ocati o ns, 
c ystati n C, a n d ki d ne y 
safety m o nit ori n g.
N o ns u bsta ntial
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
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 1
LI S T O F FI G U R E S .................................................................................................................1 1
1. P R O T O C O L  S U M M A R Y...................................................................................................1 2
1. 1. S y n o psis ..................................................................................................................1 2
1. 2. Sc he ma ....................................................................................................................1 6
1. 3. Sc he d ule of Acti vities .............................................................................................1 7
1. 3. 1. Part A – O verall Sc he d ule of Acti vities .....................................................1 7
1. 3. 2. Part A – Sc he d ule a n d Pr oce d ures f or Da y s 1 a n d 1 4 O nl y ( u nless 
ot her wise n ote d) ...............................................................................................2 0
1. 3. 3. Part B – O verall Sc he d ule of Acti vities ......................................................2 2
2. I N T R O D U C TI O N ...............................................................................................................2 4
2. 1. St u d y  Rati o nale .......................................................................................................2 4
2. 2. Bac k gr o u n d .............................................................................................................2 4
2. 2. 1. M C 4 R a n d Geriatric A n ore xia.................................................................... 2 4
2. 2. 2. N o ncli nical P har mac ol o g y ..........................................................................2 4
2. 2. 3. N o ncli nical P har mac o ki netics a n d Meta b olis m ......................................... 2 5
2. 2. 4. Bi o p har mace utics .......................................................................................2 5
2. 2. 5. S u m mar y of N o ncli nical T o xic ol o g y  St u dies.............................................2 6
2. 2. 6. Cli nical O ver vie w .......................................................................................2 6
2. 3. Be nefit/ Ris k Assess me nt................................ .........................................................2 8
2. 3. 1. Ris k Assess me nt......................................................................................... 3 0
2. 3. 2. Be nefit Assess me nt .....................................................................................3 4
2. 3. 3. O verall Be nefit/ Ris k C o ncl usi o n ................................................................3 4
3. O BJ E C TI V E S A N D E N D P OI N T S .....................................................................................3 4
4. S T U D Y D E SI G N .................................................................................................................3 6
4. 1. O verall Desi g n .........................................................................................................3 6
4. 1. 1. Part A.......................................................................................................... 3 6
4. 1. 2. Part B.......................................................................................................... 3 7
4. 2. Scie ntifi c Rati o nale f or St u d y Desi g n.....................................................................3 8
4. 2. 1. Rati o nale f or Part A.................................................................................... 3 8
4. 2. 2. Rati o nale f or Part B.................................................................................... 4 1
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6
4. 2. 3. C h oice of C o ntrace pti o n/ Barrier Re q uire me nts ......................................... 4 3
4. 2. 4. C ollecti o n of Retai ne d Researc h Sa m ples .................................................. 4 3
4. 3. J ustificati o n f or D ose ..............................................................................................4 3
4. 3. 2. H u ma n E x p os ure St o p pi n g L i mits..............................................................4 4
4. 3. 3. Rati o nale f or D ose Selecti o n ...................................................................... 4 4
4. 3. 3. 1. Part A P F -0 7 2 5 8 6 6 9 D ose Selecti o n ......................................... 4 4
4. 3. 3. 2. Part B D ose Selecti o n ................................................................ 4 7
4. 4. E n d of St u d y  Defi niti o n .......................................................................................... 4 8
5. S T U D Y P O P U L A T I ON ...................................................................................................... 4 8
5. 1. I ncl usi o n Criteria ..................................................................................................... 4 8
5. 2. E xcl usi o n Criteria .................................................................................................... 5 0
5. 3. L ifest yle C o nsi derati o ns.......................................................................................... 5 3
5. 3. 1. Meals a n d Dietar y  Restricti o ns................................................................... 5 3
5. 3. 2. Caffei ne, Alc o h ol, a n d T o bacc o ................................................................. 5 5
5. 3. 3. Acti vit y ....................................................................................................... 5 6
5. 3. 4. Dail y  Me dicati o n ( O pti o nal C o h ort of Ol der Partici pa nts O nl y) ............... 5 6
5. 3. 5. C o ntrace pti o n ..............................................................................................5 7
5. 4. Scree n Fail ures ........................................................................................................ 5 7
6. S T U D Y I N T E R V E N TI O N S( S) A ND C O N C O MI T A N T T H E R A P Y............................... 5 7
6. 1. St u d y  Inter ve nti o n(s) A d mi nistere d ........................................................................ 5 7
6. 1. 1. A d mi nistrati o n ............................................................................................ 5 7
6. 2. Pre parati o n, Ha n dli n g, St ora ge, a n d Acc o u nta bilit y ............................................... 5 9
6. 2. 1. Pre parati o n a n d Dis pe nsi n g ........................................................................ 6 0
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 ..................................... 6 0
6. 3. 1. All ocati o n t o St u d y I nter ve nti o n ................................................................ 6 0
6. 3. 2. Brea ki n g t he Bli n d ...................................................................................... 6 1
6. 4. St u d y  Inter ve nti o n C o m plia nce ............................................................................... 6 1
6. 5. D ose M o dificati o n ................................................................................................... 6 2
6. 5. 1. D ose Escalati o n a n d St o p pi n g R ules ..........................................................6 2
6. 6. C o nti n ue d Access t o St u d y  Inter ve nti o n After t he E n d of t he St u d y ...................... 6 3
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7
6. 7. Treat me nt of O ver d ose............................................................................................ 6 3
6. 7. 1. O ver d ose of P F- 0 7 2 5 8 6 6 9 ..........................................................................6 3
6. 7. 2. O ver d ose of Mi daz ola m ............................................................................. 6 4
6. 8. C o nc o mita nt T hera p y ..............................................................................................6 5
6. 8. 1. O pti o nal C o h ort of Ol der A d ult Partici pa nts O nl y ..................................... 6 5
6. 8. 2. Resc ue Me dici ne ......................................................................................... 6 6
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 ........................................................................... 6 6
7. 1. Disc o nti n uati o n of St u d y  Inter ve nti o n .................................................................... 6 6
7. 1. 1. E C G C ha n ges ..............................................................................................6 7
7. 1. 2. P ot e ntial Cases of Ac ute Ki d ne y I nj ur y ..................................................... 6 7
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 8
7. 2. 1. Wit h dra wal of C o nse nt ............................................................................... 6 8
7. 3. L ost t o F oll o w u p .................................................................................................... 6 9
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 9
8. 1. Efficac y  Assess me nts..............................................................................................7 1
8. 2. Safet y Assess me nts ................................................................................................. 7 1
8. 2. 1. P h y sical E xa mi nati o ns ................................................................................ 7 1
8. 2. 2. Ne ur ol o gical E xa mi nati o ns ( Part A o nl y ) .................................................. 7 1
8. 2. 3. Vital Si g ns .................................................................................................. 7 2
8. 2. 3. 1. Res pirat or y  Rate........................................................................ 7 3
8. 2. 3. 2. Oral B o d y Te m perat ure ............................................................. 7 3
8. 2. 4. Electr ocar di o gra ms ..................................................................................... 7 3
8. 2. 4. 1. C o nti n u o us Car diac M o nit ori n g b y Tele metr y  ( Part A 
o nl y )................................................................................................... 7 4
8. 2. 5. C o nti n u o us P ulse O xi metr y  ( Part B O nl y) ................................................. 7 4
8. 2. 8. Cli nical Safet y  La b orat or y Assess me nts.................................................... 7 5
8. 2. 9. C O VI D -1 9 Relate d Meas ures .....................................................................7 5
8. 2. 1 1. S uici dal I deati o n a n d Be ha vi or Ris k M o nit ori n g .....................................7 6
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8
8. 2. 1 1. 1. C ol u m bia S uici de Se verit y Rati n g Scale ( Part A O nl y) ......... 7 6
8. 2. 1 1. 2. Rater Q ualificati o ns ................................................................. 7 7
8. 3. A d verse E ve nts, Seri o us A d verse E ve nts, a n d Ot her Safet y Re p orti n g ................. 7 7
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 8
8. 3. 1. 1. Re p orti n g S A Es t o Pfizer Safet y ............................................... 7 8
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 9
8. 3. 2. Met h o d of Detecti n g A Es a n d S A Es .......................................................... 7 9
8. 3. 3. F oll o w -U p of A Es a n d S A Es ...................................................................... 7 9
8. 3. 4. Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es........................................... 7 9
8. 3. 5. E n vir o n me ntal E x p os ure, 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 ..................................................... 8 0
8. 3. 5. 1. E x p os ure D uri n g Pre g na nc y ...................................................... 8 0
8. 3. 5. 2. E x p os ure D uri n g Breastfee di n g ................................................ 8 2
8. 3. 5. 3. Occ u pati o nal E x p os ure ............................................................. 8 2
8. 3. 6. Car di o vasc ular a n d Deat h E ve nts ...............................................................8 2
8. 3. 7. Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot 
Q ualif y i n g as A Es or S A Es .............................................................................. 8 2
8. 3. 8. A d verse E ve nts of S pecial I nterest............................................................. 8 2
8. 3. 8. 1. Lac k of Efficac y ........................................................................ 8 3
8. 3. 9. Me dical De vice Deficie ncies ......................................................................8 3
8. 3. 1 0. Me dicati o n Err ors ..................................................................................... 8 3
8. 4. P har mac o ki netics .................................................................................................... 8 4
8. 4. 1. Plas ma f or A nal ys is of P F-0 7 2 5 8 6 6 9 C o nce ntrati o ns ( Part A O nl y) ......... 8 4
8. 4. 2. Uri ne f or A nal ys is of P F-0 7 2 5 8 6 6 9 C o nce ntrati o ns ( Part A O nl y) ...........8 5
8. 4. 3. Plas ma f or Q ualitati ve Meta b olite Pr ofili n g ( Part A o nl y).........................8 5
8. 4. 4. Plas ma f or A nal ys is of Mi daz ola m C o nce ntrati o ns ( Part B o nly) ............. 8 5
8. 5. P har mac o d y na mics .................................................................................................. 8 6
8. 5. 1. B o d y Wei g ht ...............................................................................................8 6
8. 6. Ge netics ................................................................................................................... 8 8
8. 6. 1. S pecifie d Ge netics ...................................................................................... 8 8
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9
8. 6. 2. Retai ne d Researc h Sa m ples f or Ge netics................................................... 8 8
8. 7. Bi o mar kers .............................................................................................................. 8 8
8. 7. 2. Plas ma f or Deter mi nati o n of 4 -H y dr o x y c h olester ol/ C h olester ol 
Rati o ................................................................................................................. 8 8
8. 7. 3. Uri ne f or Det er mi nati o n of 6-H y dr o x yc o rtis ol/ C ortis ol Rati o................. 8 8
8. 7. 4. E xtracell ular Vesicle A nal ys is of C Y P 3 A I n d ucti o n ................................. 8 9
8. 7. 5. Bi o mar kers Sa m ple Ha n dli n g ..................................................................... 8 9
8. 7. 6. S pecifie d Ge ne E x pressi o n ( R N A) Researc h ............................................. 8 9
8. 7. 7. S pecifie d Pr otei n Researc h ......................................................................... 9 0
8. 7. 8. S pecifie d Meta b ol o mic Researc h ...............................................................9 0
8. 7. 9. Retai ne d Researc h Sa m ples f or Bi o mar kers ............................................... 9 0
8. 8. I m m u n o ge nicit y Assess me nts ................................................................................. 9 0
8. 9. Healt h Ec o n o mics ................................................................................................... 9 0
9. S T A TI S TI C A L C O N SI D E R A TI O N S ................................................................................ 9 0
9. 1. Statistical H y p ot heses ............................................................................................. 9 0
9. 2. A nal y sis Sets ........................................................................................................... 9 1
9. 3. Statistical A nal y ses ................................................................................................. 9 1
9. 3. 1. Ge neral C o nsi derati o ns ...............................................................................9 1
9. 3. 2. Safet y E n d p oi nts ......................................................................................... 9 2
9. 3. 2. 1. Electr ocar di o gra m A nal y ses...................................................... 9 2
9. 3. 3. P K E n d p oi nts ..............................................................................................9 3
9. 3. 3. 1. Deri vati o n of P F -0 7 2 5 8 6 6 9 P K Para meters ( Part A O nl y) ....... 9 3
9. 3. 3. 2. Deri vati o n of Mi daz ola m P K Para meters ( Part B O nl y) ........... 9 4
9. 3. 3. 3. Statistical Met h o ds f or P F -0 7 2 5 8 6 6 9 P K Data ( Part A 
o nl y )................................................................................................... 9 4
9. 3. 3. 4. Statistical Met h o ds f or Mi daz ola m P K Data ( Part B o nl y) ....... 9 5
9. 3. 4. Tertiar y / E x pl orat or y E n d p oi nt(s) ...............................................................9 6
9. 3. 5. Ot her A nal ys e(s) ......................................................................................... 9 6
9. 4. I nteri m A nal ys es ..................................................................................................... 9 6
9. 5. Sa m ple Size Deter mi nati o n ..................................................................................... 9 6
9. 5. 1. Part A Sa m ple Size ..................................................................................... 9 6
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0
9. 5. 2. Part B Sa m ple Size .....................................................................................9 7
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 9
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 9
1 0. 1. 1. Re g ulat or y a n d Et hical C o nsi derati o ns ....................................................9 9
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 9
1 0. 1. 2. Fi na ncial Discl o s ure ...............................................................................1 0 0
1 0. 1. 3. I nf or me d C o nse nt Pr ocess ......................................................................1 0 0
1 0. 1. 4. Data Pr otecti o n .......................................................................................1 0 1
1 0. 1 . 5. C o m mittees Str uct ure .............................................................................1 0 1
1 0. 1. 5. 1. Data M o nit ori n g C o m mittee .................................................1 0 1
1 0. 1. 6. Disse mi nati o n of Cli nical St u d y  Data ....................................................1 0 1
1 0. 1. 7. Data Q ualit y Ass ura nce ..........................................................................1 0 3
1 0. 1. 8. S o urce D oc u me nts ..................................................................................1 0 4
1 0. 1. 9. St u d y  a n d Site Start a n d Cl os ure ............................................................1 0 4
1 0. 1. 1 0. P u blicati o n P olic y .................................................................................1 0 5
1 0. 1. 1 1. S p o ns or’s Q ualifie d Me dical Pers o n nel ...............................................1 0 6
1 0. 2. A p pe n di x 2: Cli nical La b orat or y  Tests...............................................................1 0 7
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 9
1 0. 3. 1. Defi niti o n of A E .....................................................................................1 0 9
1 0. 3. 2. Defi niti o n of a n S A E ..............................................................................1 1 0
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 D uri n g 
t he Acti ve C ollecti o n Peri o d..........................................................................1 1 1
1 0. 3. 4. Re p orti n g of S A Es.................................................................................. 1 1 5
1 0. 4. A p pe n di x 4: C o ntrace pti ve a n d Barrier G ui da nce ..............................................1 1 6
1 0. 4. 1. Male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria.................................. 1 1 6
1 0. 4. 2. Fe male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria ...............................1 1 6
1 0. 4. 3. W o ma n of C hil d beari n g P ote nt ial ..........................................................1 1 6
1 0. 4. 4. C o ntrace pti o n Met h o ds ...........................................................................1 1 7
1 0. 5. A p pe n di x 5: Ge netics ..........................................................................................1 1 9
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 2 0
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1
1 0. 7. A p pe n di x 7: Ki d ne y  Safet y: M o nit ori n g G ui deli nes .......................................... 1 2 2
1 0. 7. 1. La b orat or y  Assess me nt of C ha n ge i n Ki d ne y F u ncti o n a n d 
Detecti o n of Ki d ne y  Inj ur y ............................................................................ 1 2 2
1 0. 7. 2. A ge -S pecific Ki d ne y  F u ncti o n Calc ulati o n Rec o m me n dati o ns............. 1 2 2
1 0. 7. 2. 1. A d ults ( 1 8 Years a n d A b o ve) — 2 0 2 1 C K D -E PI 
E q uati o ns 3 3 ...................................................................................... 1 2 2
1 0. 7. 3. A d verse E ve nt Gr a di n g f or Ki d ne y Safety La b orat or y  
A b n or malities ................................................................................................. 1 2 2
1 0. 8. A p pe n di x 8: E C G Fi n di n gs of P ote ntial Cli nical C o ncer n ................................. 1 2 3
1 0. 1 3. A p pe n di x 1 3: Pr o hi bite d C o nc o mita nt Me dicati o ns T hat Ma y  Res ult i n 
D DI .......................................................................................................................... 1 3 4
1 0. 1 4. A p pe n di x 1 4: Pr ot oc ol A me n d me nt Hist or y ..................................................... 1 3 6
1 0. 1 5. A p pe n di x 1 5: A b bre via ti o ns ............................................................................. 1 4 7
1 1. R E F E R E N C E S ................................................................................................................ 1 5 2
LI S T O F T A B L E S
Ta ble 1.
Si n gle -D ose P F -0 7 2 5 8 6 6 9 P K Para meters i n C 4 5 4 1 0 0 1 ......................... 2 7
Ta ble 2.
Pre dicte d P F -0 7 2 5 8 6 6 9 Stea d y -State E x p os ures ...................................... 4 5
Ta ble 3.
Deri vati o n of P F -0 7 2 5 8 6 6 9 P K Para meters............................................. 9 3
Ta ble 4.
Deri vati o n of Mi daz ola m P K Para meters ................................................. 9 4
Ta ble 5.
E x pecte d Wi dt hs of t he 9 0 % CI s ( wit h 8 0 % C o vera ge Pr o ba bilit y) 
f or Differe nt P ossi ble Esti mate d Effects f or A U Ci nf a n d C ma x ................. 9 7
Ta ble 6.
Pr ot oc ol Re q uire d Safet y L a b orat or y Assess me nts................................1 0 7
LI S T O F FI G U R E S
Fi g ure 1.
Part A: M ulti ple Asce n di n g D ose E val uati o n .......................................... 1 6
Fi g ure 2.
Part B: D DI Assess me nt ........................................................................... 1 6
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2
1. P R O T O C O L S U M M A R Y 
1. 1. S y n o psi s 
Brief Title: A P hase 1 St u d y  of M ulti ple Asce n di n g D oses of P F-0 7 2 5 8 6 6 9 i n Healt h y  A d ult 
Partici pa nts
R ati o n ale : T his st u d y  will be t he first ti me m ulti ple asce n di n g d oses of P F-0 7 2 5 8 6 6 9 are 
a d mi nistere d t o h u ma ns. T he safet y, t olera bilit y , a n d P K of m ulti ple asce n di n g d oses of 
P F - 0 7 2 5 8 6 6 9 will be e val uate d i n Part A. The effect of P F -0 7 2 5 8 6 6 9 o n m i daz ola m P K will 
be e val uate d i n Part B if res ults fr o m Part A s u p p ort f urt her de vel o p me nt of P F- 0 7 2 5 8 6 6 9.
O bjecti ves a n d E n d p oi nts :
O bjecti ves
E n d p oi nts
P art A
Pri m ar y: 
Pri m ar y: 

T o e val uate t he safet y a n d t olera bilit y of m ulti ple, 
asce n di n g, oral d oses of P F -0 7 2 5 8 6 6 9 i n healt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult 
partici pa nts (if e nr olle d).

A ssess me nt of ad verse e ve nts, cli nical safet y 
la b orat or y tests, vital si g ns , c o nti n u o us car diac 
m o nit ori n g, 1 2 -lea d E C Gs, res pirat or y rate, oral b o d y 
te m perat ure, p h ysical e xa mi nati o ns, ne ur ol o gical 
e xa mi nati o n fi n di n gs, C- S S R S,
 
.
Sec o n d ar y: 
Sec o n d ar y: 

T o e val uate t he plas ma a n d uri ne P K of si n gle a n d 
m ulti ple oral d oses of P F - 0 7 2 5 8 6 6 9 i n h ealt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult
partici pa nts (if e nr olle d). 

P F - 0 7 2 5 8 6 6 9 plas ma P K o n Da ys 1 a n d 1 4 : C ma x, 
A U C t a u, T ma x , d ose -n or malize d C ma x , a n d 
d ose -n or malize d A U C t a u.

P F - 07 2 5 8 6 6 9 uri ne P K o n Da y 1 4: Ae t a u, Ae t a u% , a n d 
C L r (if data per mit ).
Terti ar y/ E x pl or at or y: 
Terti ar y/ E x pl or at or y: 

T o e val uate a d diti o nal P K para meters of 
P F -0 7 2 5 8 6 6 9 f oll o wi n g si n gle a n d m ulti ple oral 
d oses t o healt h y n o n -Ja pa nese, Ja pa nese (if e nr olle d), 
a n d ol der a d ult partici pa nts (if e nr olle d).

P F -0 7 2 5 8 6 6 9 plas ma P K o n Da y 1 4 : C L/ F, C m i n, C a v, 
P T R, R ac, R ac, C ma x, t½ , a n d V z/ F (if data per mit).

T o e val uate t he effect of m ulti ple, asce n di n g d oses of 
P F -0 7 2 5 8 6 6 9 a d mi nistere d f or 1 4 da ys i n healt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult 
partici pa nts (if e nr olle d) o n b o d y wei g ht .

C ha n ge fr o m baseli ne i n b o d y wei g ht o n Da ys 7 
a n d 1 4.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3


 
 

 

T o e val uate t he p ote ntial f or i n d ucti o n of C Y P 3 A
wit h a d mi nistrati o n of m ulti ple , asce n di n g d oses of
P F -0 7 2 5 8 6 6 9 a d mi nistere d f or 1 4 da ys i n healt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult 
partici pa nts (if e nr olle d).

C ha n ge fr o m baseli ne o n Da y 1 4:

Uri nar y 6 -h y dr o x yc orti s ol/c ortis ol rati o;

Plas ma 4 -h y dr o x yc h olester ol/c h olester ol rati o ;

Ser u m e xtracell ular vesicles (if a nal yze d).

T o c o n d uct e x pl orat or y pr ofili n g f or plas ma 
meta b olites of P F - 0 7 2 5 8 6 6 9 i n stea d y-state plas ma 
sa m ples i n healt h y n o n-Ja pa nese, Ja pa nese (if 
e nr olle d), a n d ol der a d ult partici pa nts (if e nr olle d) .

Q ualitati ve plas ma le vels of p ote ntial meta b olites of
P F - 0 7 2 5 8 6 6 9 at stea d y-state.
P art B 
Pri m ar y: 
Pri m ar y: 

T o e val uate t he effects of P F -0 7 2 5 8 6 6 9 o n 
mi daz ola m P K i n healt h y a d ult partici pa nts .

Mi daz ola m plas ma P K para meters
al o ne a n d i n 
c o m bi nati o n wit h P F -0 7 2 5 8 6 6 9 o n Peri o d 1/ Da y 1, 
Peri o d 2/ Da y 2, a n d Peri o d 2/ Da y 1 0 : C ma x, A U C last, 
a n d A U C i nf (if data per mit).
Sec o n d ar y: 
Sec o n d ar y: 

T o e val uate t he safet y a n d t olera bilit y of mi daz ola m
al o ne a n d i n c o m bi nati o n wit h P F - 0 7 2 5 8 6 6 9 w he n 
a d mi nistere d t o healt h y a d ult partici pa nts.

A d verse e ve nts, vital si g ns meas ure me nts, c o nti n u o us
p ulse o xi metr y, 1 2 -lea d E C Gs, p h ysical e xa mi nati o n 
fi n di n gs, a n d cli nical safet y la b orat or y me as ure me nts.
Terti ar y/ E x pl or at or y : 
Terti ar y/ E x pl or at or y : 

T o e val uate t he effects of P F - 07 2 5 8 6 6 9 o n a d diti o nal 
P K para meters of mi daz ola m i n healt h y a d ult 
partici pa nts.

Mi daz ola m plas ma P K para meters al o ne a n d i n 
c o m bi nati o n wit h P F -0 7 2 5 8 6 6 9 o n Peri o d 1/ Da y 1, 
Peri o d 2/ Da y 2, a n d Peri o d 2/ Da y 1 0: T ma x, C L/ F , 
V z/ F, a n d t½ (if data per mit).

T o e val uate t he p ote ntial f or i n d ucti o n of C Y P 3 A
wit h a d mi nistrati o n of m ulti ple d oses of
P F - 0 7 2 5 8 6 6 9 i n healt h y a d ult partici pa nts.

C ha n ge fr o m baseli ne:
Uri nar y 6 -h y dr o x yc ortis ol/c ortis ol rati o o n Da y 7
(if a nal yze d);
Plas ma 4 -h y dr o x yc h olester ol/c h olester ol rati o o n 
Da y 1 0 ;
Ser u m e xtracell ular vesicles o n Da y 1 0
(if a nal yze d).
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4
Brief S u m m ar y: Part A of t his st u d y  is a ra n d o mize d, i n vesti gat or- a n d partici pa nt -bli n d , 
s p o ns or-o pe n , place b o-c o ntr olle d e val uat i o n of t he safety, t olera bilit y , a n d P K of 
P F -0 7 2 5 8 6 6 9 after a d mi nistrati o n of m ulti ple asce n di n g oral d oses t o healt h y  a d ult 
partici pa nts. U p t o 3 differe nt dietar y  all ocati o ns (ie, sta n dar d, H C H C , a n d H F H C diets) m a y
be e m pl o y e d i n t his st u d y. O pti o nal c o h ort s of healt h y  a d ult Ja pa nese partici pa nts a n d/ or 
ol der a d ult partici pa nts ma y als o be e val uate d if res ults i n ot her c o h orts s u p p ort f urt her 
e val uati o n . Preca uti o nar y se nti nel d osi n g will be use d i n eac h c o h ort of Part A i n w hic h 
P F -0 7 2 5 8 6 6 9 e x p os ures ( C ma x a n d/ or A U C 2 4) are pr ojecte d t o be hi g her t ha n t he e x p os ures 
e val uate d i n t he si n gle asce n di n g d ose cli nical st u d y C 4 5 4 1 0 0 1 or at t he discreti o n of t he 
i n vesti gat or i n res p o nse t o safety si g nals o bser ve d i n a pre vi o us c o h ort. If t he pr ojecte d 
e x p os ures ha ve bee n e val uate d i n a pre vi o us c o h ort of t he c urre nt st u d y , se nti nel d osi n g m a y  
be o mitte d . W he n se nti nel d osi n g is e m pl o ye d, 2 partici pa nts ( 1 recei vi n g P F -0 7 2 5 8 6 6 9 a n d 
1 recei vi n g place b o) will be d ose d bef ore t he re mai ni n g partici pa nts of t hat c o h ort are d ose d. 
Safet y  a n d t olera bilit y data t hr o u g h at least 4 8 h o urs after t he first d ose of st u d y  i nter ve nti o n 
f or t he se nti nel partici pa nts will be re vie we d pri or t o d osi n g t he re mai ni n g partici pa nts of t hat 
c o h ort.
Part B of t his st u d y  is a 2-peri o d, fi xe d- se q ue nce, m ulti ple-d ose, o pe n -la bel desi g n t o 
e val uate t he effect of P F -0 7 2 5 8 6 6 9 o n mi daz ola m P K i n healt h y  a d ult partici pa nts. Part B 
will be c o n d ucte d if t he res ults of Part A s u p p ort f urt her e val uati o n of P F -0 7 2 5 8 6 6 9. A ll 
partici pa nts i n Part B will be all ocate d t o sta n dar d diet. Preca ut i o nar y se nti nel d osi n g ma y be 
use d i n Part B if a ut oi n hi biti o n of P F -0 7 2 5 8 6 6 9 P K is o bser ve d i n Part A of t he st u d y , or at 
t he discreti o n of t he i n vesti gat or. Base d o n p ote ntial ti me-de pe n de nt i n hi biti o n of C Y P 3 A 4/ 5 
at hi g h d oses of P F 0 7 2 5 8 6 6 9, near ma xi m al i n hi biti o n of C Y P 3 A 4/ 5 is pre dicte d t o occ ur o n 
Peri o d 2/ Da y  2. T heref ore, if se nti nel d osi n g is e m pl o ye d, 2 partici pa nts will be d ose d, a n d if 
n o u nt o war d effects are o bser ve d t hr o u g h at least 2 4 h o urs after mi daz ola m d osi n g i n Peri o d 
2/ Da y  2 f or t he se nti nel partici pa nts, t he re mai ni n g partici pa nts of t hat c o h ort will t he n be 
d ose d. If u nt o war d effects are o bser ve d, a l o wer d ose of P F -0 7 2 5 8 6 6 9 ma y be e val uate d i n 
a n ot her c o h ort. If t he P F - 0 7 2 5 8 6 6 9/ mi daz ola m c o m bi nati o n use d i n t he first c o h ort of Part B 
is well t olerate d, se nti nel d osi n g ma y n ot be use d i n s u bse q ue nt c o h orts if t he P F-0 7 2 5 8 6 6 9 
d ose use d i n a n y a d diti o nal c o h ort of Part B is less t ha n t he P F - 0 7 2 5 8 6 6 9 d ose e val uate d i n 
t he first c o h ort of Part B.
N u m ber of P artici p a nts: A p pr o xi matel y  1 3 8 healt h y  a d ult partici pa nts ma y  be e nr olle d i n 
Part A of t his st u d y , of w ho m a p pr o xi matel y 8 m a y be Ja pa nese a n d a p pr o xi matel y 8- 1 0 m a y  
be ol der a d ult partici pa nts . A p pr o xi matel y  1 2 healt h y  a d ult par tici pa nts will be e nr olle d i n 
Part B. A d diti o nal o pti o nal c o h orts ma y be e nr olle d i n Part A t o re peat a d ose or t o e x pa n d 
t he d ose/e x p os ure ra n ge or better c haracterize a partic ular safety or t olera bilit y  si g nal or 
cli nical bi o mar ker of i nterest (e g, b o d y wei g ht). Si milarl y , a d diti o nal o pti o nal c o h orts ma y  
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 5
be e nr olle d i n Part B t o e val uate t he effect of a d diti o nal d ose le vels of P F-0 7 2 5 8 6 6 9 o n 
mi daz ola m P K.
T he o pti o nal c o h ort of ol der a d ult partici pa nts, if e nr olle d, will be c o n d ucte d after t he res ults 
of Part B are a vaila ble.
N ote: “E nr olle d ” mea ns a partici pa nt ’s a gree me nt t o partici pate i n a cli nical st u d y f oll o wi n g 
c o m pleti o n of t he i nf or me d c o nse nt pr ocess a n d scree ni n g. A partici pa nt will be c o nsi dere d 
e nr olle d if t he i nf or me d c o nse nt is n ot wit h dra w n pri or t o partici pati n g i n a n y  st u d y acti vit y 
after scree ni n g. P ote ntial partici pa nts w h o are scree ne d f or t he p ur p ose of deter mi ni n g 
eli gi bilit y f or t he st u d y, b ut d o n ot partici pate i n t he st u d y, are n ot c o nsi dere d e nr olle d, u nless 
ot her wise s pecifie d b y t he pr ot oc ol.
I nter ve nti o n Gr o u ps a n d D ur ati o n : Partici pa nts of Part A of t his st u d y will recei ve
m ulti ple d oses of P F -0 7 2 5 8 6 6 9 or place b o f or 1 4 da ys. I n Peri o d 1 of Part B, p artici pa nts 
will recei ve a si n gle d ose of mi daz ola m . In Peri o d 2 of Part B , partici pa nts will recei ve 
m ulti ple d oses of P F -0 7 2 5 8 6 6 9 f or 1 0 d a y s. Mi daz ola m will be c o-a d mi nistere d wit h 
P F -0 7 2 5 8 6 6 9 o n Da ys 2 a n d 1 0 of Part B. P F -0 7 2 5 8 6 6 9 a n d place b o will be a d mi nistere d as 
ta blets. Mi daz ola m will be a d mi nistere d as a n oral s ol uti o n.
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 : N o
St atistic al Met h o ds : T he sa m ple size has bee n c h ose n base d o n t he nee d t o mi ni mize
e x p os ure t o h u ma ns of a ne w c he mical e ntit y w hile all o wi n g a de q uate c haracterizati o n of 
safety, t olera bilit y, a n d P K data at eac h d ose le vel . F or t he o pti o nal H F H C c o h orts, t he 
sa m ple size was selecte d t o pr o vi de acce pta ble o perati n g c haracteristics t o assess c ha n ge 
fr o m baseli ne i n b o d y wei g ht. All safet y a nal ys es will be perf or me d o n t he S afet y Anal ys is 
S et, w hic h is defi ne d as all partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n a n d w h o 
recei ve at least 1 d ose of st u d y i nter ve nti o n. Partici pa nts will be a nal yze d acc or di n g t o t he 
st u d y i nter ve nti o n t he y act uall y recei ve d. Safet y data will be p rese 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 vel y , w here a p pr o priate. T he P K para meters f or 
P F ‑ 0 7 2 5 8 6 6 9 a n d mi daz ola m will be deri ve d fr o m t he plas ma c o nce ntrati o n‑ti me pr ofiles. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 6
P K para meters a n d c o nce ntrati o ns of P F -0 7 2 5 8 6 6 9 a n d midaz ola m wi ll be descri pti vely 
s u m marize d b y d ose, dietar y  all ocati o n, a n d n o mi nal ti me, as a p pr o priate.
1. 2. Sc he m a
Fi g ure 1.
P art A: M ulti ple Asce n di n g D ose E v al u ati o n
Fi g ure 2.
P art B: D DI Assess me nt
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 7
1. 3. S c he d ule of Acti v ities
T he S o A ta ble pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures. Refer t o t he S T U D Y A S S E S S M E N T S A N D 
P R O C E D U R E S secti o n 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 hed ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d in t he S o A ta ble, i n or der t o c o n d uct 
e val uati o ns or assess me nts re q uire d t o pr otect t he well -bei n g of t he partici pa nt .
1. 3. 1. P art A – O ver all Sc he d ule of Acti vities
Visit I de ntifier
See A p pe n di x 1 5 f or ab bre viati o ns i n t his ta ble
Scree ni n g
St u d y D a y [ all acti vities at 0 h (pri or t o d osi n g ) u nless ot her wise s pecifie d ]
F oll o w -U p
E T/ 
D C
D a ys Rel ati ve t o D a y 1 a
D a y -2 8 t o 
D a y - 3
- 2
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
Visit :
2 1 -2 4 b
C o nt act :
4 2 -4 9 b
I nf or me d c o nse nt a n d de m o gra p h y
X
O ut patie nt visit
X
X
I n patie nt sta y at C R U
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

X c
Re vie w i ncl usi o n/e xcl usi o n criteria
X
X
Me dical/ me dicati o n hist or y
X
X
Hist or y of alc o h ol, t o bacc o, a n d ille gal dr u g use
X
X
C o ntrace pti o n c hec k
X
X
X
X
X
X
C O VI D -1 9 relate d meas ures d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
P h ysical e xa mi nati o n e (b o d y wei g ht a n d hei g ht 
at Scree ni n g o nl y)
X  
X
X
Ne ur ol o gical e xa mi nati o n
X
X f
X f
X
Re vie w c o nc o mita nt treat me nts
X
X
X
X
X
Seri o us/ n o n -seri o us A E m o nit ori n g
X  
X
 
 
 
 
 
 
 
 
 
 
 
 

 
 

X  
X  
X  
X
(i ncl u di n g b o d y 
wei g ht)
X  
X
X
X  
X  
X
X
C -S S R S g
X
X
Refer t o  Secti o n 1. 3. 2
X f
Refer t o  Secti o n 1. 3. 2
X
X
Res pirat or y rate
X h
X i
X i
X i
X h
X
Oral b o d y te m perat ure
X h
X i
X i
X i
X h
X
S u pi ne 1 2 -Lea d E C G j
X
X h
X i
X i
X i
X h
X
X
X
Tri plicate s u pi ne B P a n d P R
Ort h ostatic (s u pi ne a n d sta n di n g) B P a n d P R
X
X h
X i
X i
X i
X h
X
X
X
C o nti n u o us car diac tele metr y k
X
X
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 8
Visit I de ntifier
See A p pe n di x 1 5 f or ab bre viati o ns i n t his ta ble
Scree ni n g
St u d y D a y [ all acti vities at 0 h (pri or t o d osi n g ) u nless ot her wise s pecifie d ]
F oll o w -U p
E T/ 
D C
D a ys Rel ati ve t o D a y 1 a
D a y -2 8 t o 
D a y - 3
- 2
- 1
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
Visit :
2 1 -2 4 b
C o nt act :
4 2 -4 9 b
Bli n de d st u d y i nter ve nti o n a d mi nistrati o n p
X
X
X
X
X
X
X
X
X
X
X
X
Bl o o d s a m pli n g f or:
Ser u m F S H q
X
H b c A b, Hb s A g, Hb s A b, H C V A b, HI V testi n g
X
Cli nical safet y la b orat or y tests , i ncl u di n g 
c o m pre he nsi ve li pi d pa nelr
X  
X
Refer t o  Secti o n 1. 3. 2
X  
X
X
X
Refer t o  Secti o n 1. 3. 2
X  
X
X
Retai ne d researc h sa m ple: bi o mar kers ( Pre p B 1)
Retai ne d researc h sa m ple : bi o mar kers ( Pre p B 2 )
Retai ne d researc h sa mple : g e netics (Pre p D 1. 5 )
Ser u m e xtracell ular vesicles
P F -0 7 2 5 8 6 6 9 plas ma P K
X h
X
X
X
X h
X s
X
4 -h y dr o x yc h olester ol/c h olester ol
Meta b olite pr ofili n g
X h
Uri ne s a m pli n g f or:
Uri ne dr u g test
X
X
Cli nical safet y la b orat or y tests r
X
X
Secti o n 
1. 3. 2
X
X
X
X
Secti o n 
1. 3. 2
X
X
X
P F -0 7 2 5 8 6 6 9 P K
6 -h y dr o x yc ortis ol/c ortis ol rati ot
X
X h
a.
Da y relati ve t o start of d osi n g of bli n de d st u d y i nter ve nti o n ( Da y 1).
b.
O n -site f oll o w-u p visit t o occ ur 7 -1 0 da ys after a d mi nistrati o n of t he fi nal d ose of st u d y i nter ve nti o n. F oll o w - u p c o ntact ma y occ ur via tele p h o ne c o ntact a n d m ust occ ur 
2 8 -3 5 da ys after a d mi nistrati o n of t he fi nal d ose of st u d y i nter ve nti o n.
c.
Disc har ge fr o m C R U. Ja pa nese partici pa nts ma y re mai n i n -h o use u ntil t he f oll o w -u p visit.
d.
Per C R U pr oce d ure s. 
e.
C o m plete p h ysical e xa mi nati o n m ust eit he r be c o n d ucte d at Scree ni n g or Da y -2. Brief p h ysical e xa mi nati o n ma y be perf or me d o n Da y -2 if a c o m plete p h ysical e xa mi nati o n 
is perf or me d at Scree ni n g. Brief p h ysical e xa mi nati o ns ma y be perf or me d as a p pr o priate at ot her ti mes at t he i n vesti gat or’s discreti o n if t here are fi n di n gs d uri n g t he pre vi o us 
e xa mi nati o n or ne w/ o pe n a d verse e ve nts.
f.
C o n d ucte d at a p pr o xi matel y 2 h o urs p ost m or ni n g d ose.
g.
Baseli ne/ Lifeti me assess me nt t o be perf or me d at Scree ni n g; “ Si nce last visit” assess me nts s h o ul d be perf or me d at ot her ti me p oi nts. 
h.
T hese assess me nts o n Da y 2 a n d Da y 1 5 are c ollecte d 2 4 h o urs after t he pre vi o us da y’s m or ni n g d ose a n d are desi g nate d as 2 4 H sa m ples f or Da ys 1 a n d 1 4 i n Secti o n 1. 3. 2 .
i.
C o n d ucte d pri or t o m or ni n g d ose a n d at a p pr o xi matel y 1 h o ur ( T ma x) p ost m or ni n g d ose.
j.
Si n gle 1 2 -lea d E C G at Scree ni n g, disc har ge, E T/ D C, a n d f oll o w-u p visit; all ot her ti mes m ust c ollect tri plicate E C Gs per n o mi nal ti me p oi nt.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 9
k.
Baseli ne c o nti n u o us car diac tele metr y will be rec or de d f or at least 2 h o urs o n Da y -1. O n Da ys 1, 7, a n d 1 4, c o nti n u o us car diac tele metr y will be gi n at least 3 0 mi n utes pri or 
t o m or ni n g d ose a n d c o nti n ue f or 8 h o urs after t he m or ni n g d ose.
l.
Da y - 1: T o be c o n d ucte d as ti me -matc he d baseli ne [ie, 0 H (a p pr o xi matel y 1 5 mi n bef ore brea kfast), 1. 5 H, 4 H (a p pr o xi matel y 1 5 mi n bef ore l u nc h), a n d 1 0 H (a p pr o xi matel y 
1 5 mi n bef ore di n ner) . 0 H meas ure me nt o n Da y 1 als o ser ves as 2 4 H Da y -1 baseli ne meas ure me nt. 0 H o n Da y -1 is a p pr o xi matel y 2 4 h o urs pri or t o a d mi nistrati o n of t he first 
d ose of st u d y i nter ve nti o n.
m.
Da ys 4, 7, a n d 1 0 : T o be c o n d ucte d at 0 H (a p pr o xi matel y 1 5 mi n bef ore brea kfast), 1. 5 H, 4 H (a p pr o xi matel y 1 5 mi n bef ore l u nc h), 1 0 H (a p pr o xi matel y 1 5 mi n bef ore 
di n ner), a n d 2 4 H (a p pr o xi matel y 1 5 mi n bef ore brea kfast o n Da ys 5, 8, a n d 1 1, res pecti vel y ).
n.
Da y - 1: T o be c o n d ucte d as ti me -matc he d baseli ne [ie, 0 H ( a p pr o xi matel y 1 5 mi n after brea kfast; ser ves as 2 4 H basel i ne meas ure me nt), 4 H (a p pr o xi matel y 1 5 mi n after 
l u nc h), a n d 1 0 H (a p pr o xi matel y 1 5 mi n after di n ner). 0 H o n Da y -1 is a p pr o xi matel y 2 4 h o urs pri or t o a d mi nistrati o n of t he first d ose of st u d y i nter ve nti o n.
o.
Da ys 4, 7, a n d 1 0 : T o be c o n d ucte d at 4 H (a p pr o xi matel y 1 5 mi n after l u nc h), 1 0 H (a p pr o xi matel y 1 5 mi n after di n ner), a n d 2 4 H (a p pr o xi matel y 1 5 mi n after brea kfast o n 
Da ys 5, 8, a n d 1 1, res pecti vel y ).
p.
St u d y i nter ve nti o n t o be a d mi nistere d Q 8 H or Q 1 2 H (as o utli ne d i n Secti o n 1. 3. 2 ) wit h t he e xce pti o n of Da y 1 4 i n w hic h o nl y a m or ni n g d ose will be a d mi nistere d.
q.
Fe males w h o ha ve bee n a me n orr heic f or at least 1 2 m o n t hs.
r.
Partici pa nts s h o ul d fast f or at least 1 2 h o urs pri or t o sa m ple c ollecti o n.
s.
Da y 1 6 P K sa m ple t o be c ollecte d at 4 8 h o ur after t he fi nal d ose of st u d y i nter ve nti o n o n Da y 1 4.
t.
O n Da y -1, uri ne c ollecti o n f or 6 - h y dr o x yc ortis ol/c ortis ol t o occ ur o ver 0-2 4 h o urs. T he e n d of t he 2 4 -h o ur c ollecti o n ti me will occ ur pri or t o d osi n g o n t he m or ni n g of
Da y 1.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 0
1. 3. 2. P art A – S c he d ule a n d Pr oce d ures f or D a ys 1 a n d 1 4 O nl y ( u nless ot her wise n ote d)
H o urs Rel ati ve t o D osi n g at 0 H
0
0. 2 5
0. 5
1
1. 5
2
4
6
8
1 0
1 2
1 6
1 8
2 4
C o nti n ue d i n patie nt sta y at C R U
 
 
 
 
 
 
 
 
 
 
 
 
 

Seri o us/ n o n -seri o us A E m o nit ori n g
 
 
 
 
 
 
 
 
 
 
 
 
 

C -S S R S ( Da y 1 4 o nl y)
X
R es pirat or y rate
X
X
X
X
X a
Oral b o d y te m perat ure
X
X
X
X
X a
Tri plicate s u pi ne 1 2 -lea d E C G 
X b
X
X
X
X
X
X
X
X
X a
Tri plicate s u pi ne B P a n d P R
X
X
X
X
X
X
X
Ort h ostatic (s u pi ne a n d sta n di n g) B P a n d P R c
X
X
X
X
X a
C o nti n u o us car diac tele metr y d
X
 
 
 
 
 
 

X
Bl o o d s a m pli n g f or:
Cli nical safet y la b orat or y tests , i ncl u di n g c o m pre he nsi ve li pi d pa nel ( Da y 1 4 
o nl y) e
X
Retai ne d researc h sa m ple f or bi o mar kers ( Pre p B 1) [ Da y 1 o nl y ]f
X
Retai ne d researc h sa m ple f or bi o mar kers ( Pre p B 2 ) [Da y 1 o nl y ]f
X
Retai ne d researc h sa mple f or g e netics (Pre p D 1. 5 ) [Da y 1 o nl y ]f
X
Ser u m e xtracell ular vesicles
X
P F -0 7 2 5 8 6 6 9 P K g
X
X
X
X
X
X
X
X
X
X
X a
4 -h y dr o x yc h olester ol/c h olester ol
X
Meta b olite pr ofili n g (0 H o n Da y 1 a n d all i n dicate d ti me p oi nts o n Da y 1 4)
X
X
X
X
X
X a
Uri ne s a m pli n g f or:
Cli nical safet y la b orat or y test s ( Da y 1 4 o nl y) e
X
P K pre d ose s p ot uri ne bla n k ( Da y 1 o nl y)
X
P F -0 7 2 5 8 6 6 9 P K ( Da y 1 4 o nl y)
X
 
 
 
 
 
 

X h

X h
6 -h y dr o x yc ortis ol/c ortis ol rati o ( Da y 1 4 o nl y)i
X
 
 
 
 
 
 
 
 
 
 
 

X a
Bli n de d st u d y i nter ve nti o n a d mi nistr ati o n
If Q 8 H re gi me nj
X
X
X
If Q 1 2 H re gi me nj
X
X
a.
T he 2 4 H assess me nts f or Da ys 1 a n d 1 4 occ ur pri or t o m or ni n g d osi n g o n Da y 2 a n d 2 4 h o urs after Da y 1 4 m or ni n g d osi n g , res pecti vel y.
b.
Da y 1 o nl y: At -1 H, -0. 5 H, a n d 0 H pri or t o t he m or ni n g d ose, tri plicate 1 2 lea d E C Gs will be o btai ne d at eac h ti me p oi nt. T he a vera ge of t he tri plicate E C G meas ure me nts
o ver t he 3 pre -d ose meas ure me nt ti mes (t otal of 9 E C G meas ure me nts) c ollecte d bef ore m or ni n g d ose a d mi nistrati o n o n Da y 1 will se r ve as eac h partici pa nt’s baseli ne Q Tc 
val ue.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 1
c.
W he n ti mi n g of ort h ostatic assess me nts c oi nci des wit h ti mi n g of tri plicate s u pi ne assess me nts, t he last of t he tri plicate s u p i ne rea di n gs will be use d as t he s u pi ne rea di n g f or 
t he ort h ostatic assess me nt.
d.
C o nti n u o us car diac tele metr y t o c o m me nce at least 3 0 mi n utes pri or t o m or ni n g d ose a n d c o nti n ue f or 8 h o urs after m or ni n g d ose.
e.
Partici pa nts s h o ul d fast f or at least 1 2 h o urs pri or t o sa m ple c ollecti o n.
f.
Pre p B 1, B 2, a n d D 1. 5 Retai ne d Researc h Sa m ples: If n ot c ollecte d o n t he desi g nate d c ollecti o n da y, c ollect at t he ne xt a vaila ble ti me p oi nt w he n bi os peci me ns are bei n g 
c ollecte d i n c o nj u ncti o n wit h a partici pa nt visit.
g.
T he P K sa m pli n g sc he me is s u bject t o c ha n ge pe n di n g o bser ve d data i n pre vi o us c o h orts. Sa m pl i n g ti mes a n d/ or d urati o n of sa m pli n g ma y be m o difie d a n d/ or e xte n de d if 
data ge nerate d i n pre vi o us c o h orts i n dicate t hat t he t ½ is l o n ger t ha n e x pecte d.
h.
O n Da y 1 4, uri ne c ollecti o n f or P K t o occ ur o ver 0 -, acc or di n g t o d osi n g fre q ue nc y (ie, 0-8 H f or Q 8 H ; 0-1 2 H f or Q 1 2 H).
i.
O n Da y 1 4, uri ne c ollecti o n f or 6 - h y dr o x yc ortis ol/c ortis ol
t o occ ur o ver 0-2 4 h o urs p ost m or ni n g d ose. T he e n d of t he 2 4 -h o ur 
c ollecti o n ti me f or Da y - 1 will occ ur t he m or ni n g o n Da y 1 pri or t o d osi ng.
j.
St u d y i nter ve nti o n t o be a d mi nistere d Q 8 H or Q 1 2 H wit h t he e xce pti o n of Da y 1 4 i n w hic h o nl y a m or ni n g d ose will be a d mi nistere d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 2
1. 3. 3. P art B – O ver all Sc he d ule of Acti vities
Visit I de ntifier
Scree ni n g
Peri o d 1
Peri o d 2
F oll o w -U p
E T/ D C
D a y Rel ati ve t o D a y 1 a
D a y - 2 8 t o 
D a y - 2
- 1
1
2
1
2
3
4
5
6
7
8
9
1 0
1 1
V isit:
1 7 -2 0 b
C o nt act:
3 8 -4 5 b
I nf or me d co nse nt a n d de m o gra p h y
X
O ut patie nt visit
X
X
I n patie nt sta y at C R U
X
 
 
 
 
 
 
 
 
 
 
 

X c
Re vie w i ncl usi o n/ excl usi o n criteria
X
X
Me dical/ me dicati o n hist or y
X
X
Hist or y of alc o h ol, t o bacc o, a n d ille gal dr u g use 
X
X
C o ntrace pti o n c hec k
X
X
X
X
X
X
C O VI D -1 9 relate d meas ures d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
P h ysical e xa mi nati o n e ( b o d y wei g ht a n d hei g ht at 
scree n o nl y)
X
X
X
Re vie w c o nc o mita nt treat me nts
X  
X
X
X  
X
Seri o us/ n o n -seri o us AE m o nit ori n g
X  
X
 
 
 
 
 
 
 
 
 
 
 

X
X
X  
X
 (i ncl u di n g b o d y 
wei g ht)
X f
X f
X f
X f
X
X
R es pirat or y rate
X f
X g
X g
X g
X g
X
O ral b o d y te m perat ure
X f
X g
X g
X g
X g
X
S u pi ne 1 2 -Lea d E C G
X h
X i
X j
X j
X j
X j
X h
X h
X h
S u pi ne vital si g ns ( B P a n d P R)
X i
X j
X j
X j
X j
O rt h ostatic (s u pi ne a n d sta n di n g) B P a n d P R
X h
X i
X j
X j
X j
X j
X h
X h
X h
C o nti n u o us p ulse o xi metr y
X k
X k
X k
Mi daz ola m d osi n g
X
X l
X l
P F -0 7 2 5 8 6 6 9 d osi n g m
X
X
X
X
X
X
X
X
X
X
Bl o o d s a m pli n g f or:
Cli nical safet y la b orat or y tests , i ncl u di n g 
c o m pre he nsi ve li pi d pa neln
X  
X  
X  
X  
X
X
X  
X  
X
X
Ser u m F S H o
X
H Bc A b, H Bs A g, H Bs A b, H C V A b, HI V testi n g
X
Retai ne d researc h sa m ple f or bi o mar kers ( Pre p B 1) p
X f
Retai ne d researc h sa m ple f or bi o mar kers ( Pre p B 2 )p
X f
Retai ne d researc h sa mple f or g e netics (Pre p D 1. 5 )p
X f
M i daz ola m plas ma P K
X q
X r
X q
X r
X q
X r
X
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 3
Visit I de ntifier
Scree ni n g
Peri o d 1
Peri o d 2
F oll o w -U p
E T/ D C
D a y Rel ati ve t o D a y 1 a
D a y - 2 8 t o 
D a y - 2
- 1
1
2
1
2
3
4
5
6
7
8
9
1 0
1 1
V isit:
1 7 -2 0 b
C o nt act:
3 8 -4 5 b
Ser u m e xtracell ular vesicles
X f
X f
4 -h y dr o x yc h olester ol/c h olester ol
X f
X f
Uri ne s a m pli n g f or:
Uri ne dr u g test
X
X
Cli nical safet y la b orat or y tests n
X
X
X
X
X
X
X
X
X
X
6 -h y dr o x yc ortis ol/c ortis ol rati o
X  
X s
X  
X s
a.
Da y relati ve t o start of d osi n g of bli n de d st u d y i nter ve nti o n ( Da y 1).
b.
O n -site f oll o w-u p visit t o occ ur 7 -1 0 da ys after a d mi nistrati o n of t he fi nal d ose of st u d y i nter ve nti o n. F oll o w -u p c o ntact ma y occ ur via tele p h o ne c o ntact a n d m ust occ ur 
2 8 -3 5 da ys after a d mi nistrati o n of t he fi nal d ose of st u d y i nter ve nti o n.
c.
Disc har ge fr o m C R U.
d.
Per C R U pr oce d ures. 
e.
C o m plete p h ysical e xa mi nati o n m ust eit her be c o n d ucte d at Scree ni n g or Da y -1. Brief p h ysical e xa mi nati o n ma y be perf or me d o n Da y -1 if a c o m plete p h ysical e xa mi nati o n 
is perf or me d at Scree ni n g. Brief p h ysical e xa mi nati o ns ma y be perf or me d as a p pr o priate at ot her ti mes at t he i n vesti gat or’s discreti o n if t here are fi n di n gs d uri n g t he pre vio us 
e xa mi nati o n or ne w/ o pe n a d verse e ve nts.
f.
P ri or t o m or ni n g d osi n g. Da y 1 1
t o occ ur bef ore brea kfast.
g.
C o n d ucte d pri or t o m or ni n g d ose a n d at a p pr o xi matel y 1 h o ur p ost m or ni n g d ose of P F -0 7 2 5 8 6 6 9 .
h.
Si n gle 1 2 -lea d E C G a n d vital si g ns at Scree ni n g, disc har ge, f oll o w- u p visit, a n d E T/ D C. 
i.
Tri plicate 1 2 -lea d E C G a n d vital si g ns o n Da y 1 of Peri o d 1 pri or t o d osi n g a n d a p pr o xi matel y 1 h o ur p ost mi daz ola m d ose. W he n ti mi n g of ort h ostatic assess me nts c oi nci des 
wit h ti mi n g of tri plicate s u pi ne assess me nts, t he last of t he tri plicate s u pi ne rea di n gs will be use d as t he s u pi ne rea di n g f or t he ort h ostatic assess me nt .
j.
Tri plicate 1 2 -lea d E C G a n d vital si g ns o n Da ys 1, 4, 7, a n d 1 0 of Peri o d 2 pri or t o d osi n g a n d a p pr o xi matel y 1 h o ur p ost m or ni n g d ose of P F - 0 7 2 5 8 6 6 9. W he n ti mi n g of 
ort h ostatic assess me nts c oi nci des wit h ti mi n g of tri plicate s u pi ne assess me nts, t he last of t he tri plicate s u pi ne rea di n gs wi ll be use d as t he s u pi ne rea di n g f or t he ort h ostatic 
assess me nt .
k.
C o nti n u o us p ulse o xi metr y t o be gi n 3 0 mi n utes pri or t o mi daz ola m d osi n g a n d t o c o nti n ue u ntil at least 6 h o urs after mi daz ola m d osi n g .
l.
O n da ys of c o -a d mi nistrati o n of mi daz ola m a n d P F -0 7 2 5 8 6 6 9 ( Da y 2 a n d Da y 1 0 of Peri o d 2), mi daz ola m will be a d mi nistere d wit hi n 5 mi n utes after t he m or ni n g d ose of 
P F - 0 7 2 5 8 6 6 9.
m.
T he d ose a n d d ose re gi me n of P F -0 7 2 5 8 6 6 9 will be deter mi ne d base d o n t he res ults of Part A of t his st u d y.
n.
Partici pa nts s h o ul d fast f or at least 1 2 h o urs pri or t o sa m ple c ollecti o n.
o.
Fe males w h o ha ve bee n a me n orr heic f or at least 1 2 m o nt hs.
p.
Pre p B 1, B 2, a n d D 1. 5 Retai ne d Researc h Sa m ples: If n ot c ollecte d o n t he desi g nate d c ollecti o n da y, c ollect at t he ne xt a vaila ble ti me p oi nt w he n bi os peci me ns are bei n g 
c ollecte d i n c o nj u ncti o n wit h a partici pa nt visit.
q.
Mi daz ola m P K bl o o d sa m ples t o be c ollecte d pri or t o d osi n g, a n d at 0. 5, 1, 2, 3, 4, 6, 8, 1 0, 1 2, a n d 1 6 h o urs p ost -d ose.
r.
Mi daz ola m P K bl o o d sa m ple t o be c ollecte d a t 2 4 h o urs after mi daz ola m d ose t hat was a d mi nistere d o n Peri o d 1/ Da y 1, Peri o d 2/ Da y 2, or Peri o d 2/ Da y 1 0.
s.
T hese assess me nts are t o occ ur o ver 0 -2 4 h o urs o n Da y - 1 a n d Da y 7. T he e n d of t he 2 4 -h o ur meas ure me nt ti me will occ ur o n t he m or ni n gs of Da y 1 a n d Da y 8, res pecti vel y .
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 4
2. I N T R O D U C TI O N
P F - 0 7 2 5 8 6 6 9 is a s mall m olec ule M C 4 R a nta g o nist
t hat is bei n g de vel o pe d f or t he treat me nt 
of meta b olic diseases wit h cata b olic i m bala nces ass ociate d wit h u ni nte n de d wei g ht l oss, s uc h 
as geriatric a n ore xia . Base d o n precli nical data, an ta g o nis m of M C 4 R ma y i ncrease a p petite, 
f o o d i nta ke, a n d b o dy wei g ht i n h u ma ns.
2. 1. St u d y R ati o n ale 
T his st u d y  will be t he first ti me m ulti ple asce n di n g d oses of P F-0 7 2 5 8 6 6 9 are a d mi nistere d 
t o h u ma ns. T he p ur p ose of Part A of t his st u d y is t o e val uate t he safety, t olera bilit y, a n d P K 
of m ulti ple asce n di n g d oses of P F - 0 7 2 5 8 6 6 9 i n healt h y  a d ult partici pa nts. Healt h y a d ult 
Ja pa nese a n d/ or ol der a d ult partici pa nts ma y  als o be e nr olle d i n Part A . Safet y, t olera bilit y, 
a n d P K res ults o btai ne d fr o m Ja pa nese a n d/ or ol der a d ult partici pa nts will be use d t o s u p p ort 
partici pati o n of Ja p a nese a n d/ or ol der a d ult partici pa nts i n f ut ure cli nical st u dies. T he 
p ur p ose of Part B of t his st u d y is t o e val uate t he effect of P F - 0 7 2 5 8 6 6 9 o n m i daz ola m P K i n 
healt h y  a d ult partici pa nts.
2. 2. B ac k gr o u n d 
2. 2. 1. M C 4 R a n d Geri atric A n ore xi a
Geriatric a n ore xia is t he l oss of a p petite or decrease d f o o d i nta ke i n later life1 a n d is 
ass ociate d wit h a d verse o utc o mes i ncl u di n g mal n utriti o n, sarc o pe nia, frailt y, a n d i nc rease d 
m ortalit y .2 -5 M C 4 R is a sti m ulat or y  G P C R pri maril y ex presse d i n t he brai n a n d is c o nsi dere d 
t he master re g ulat or of e ner g y bala nce a n d t h us pla ys a ke y r ole i n t he re g ulati o n of a p petite 
a n d b o d y wei g ht. 6 ,7 D o w nstrea m M C 4 R si g nali n g has bee n re p orte d t o be d ysre g ulate d i n 
b ot h el derl y  a d ults a n d a ge d r o de nts1 ,8 ,9 w here a n i m bala nce i n M C 4 R si g nali n g has bee n 
re p orte d i n a ge d rats wit h i ncrease d acti vit y or h yper se nsiti vit y of t he rece pt or, res ulti n g i n 
re d uce d f o o d i nta ke a n d wei g ht l oss.1 0 -1 2 I nhi biti o n of M C 4 R si g nali n g has als o c o nsiste ntl y  
bee n s h o w n t o i ncrease f o o d i nta ke a n d b o d y wei g ht i n m ulti ple precli nical m o dels of 
c hr o nic ill ness s uc h as i n d uce d cac he xia; li p o p ol ysacc hari de- i n d uce d a n ore xia,1 3 heart 
fail ure,1 4 c hr o nic ki d ne y disease,1 5 a n d ca ncer. 1 6 ,1 7 Ta ke n t o get her, t hese data s u g gest t hat 
a nta g o nis m of M C 4 R ma y i ncrease a p petite, f o o d i nta ke, 
 
.
2. 2. 2. N o ncli nic al P h ar m ac ol o g y
P F - 0 7 2 5 8 6 6 9 was s h o w n t o be a s pecific a nta g o nist of M C 4 R i n rats, d o gs, a n d h u ma ns 
 
. T he 
f u ncti o nal a nta g o nistic p ote nc y of P F-0 7 2 5 8 6 6 9 s h o we d s pecificit y  f or h u ma n M C 4 R ( Kd of 
n M) o ver t he ot her h u ma n rece pt or is of or ms, w here K d val ues were  
 n M f or 
h u ma n M C 1 R, M C 2 R, a n d M C 5 R a n d  
 n M f or h u ma n M C 3 R. 
 
 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 5
 
 
 
 
2. 2. 3. N o ncli nic al P h ar m ac o ki netics a n d Met a b olis m
2. 2. 4. Bi o p h ar m ace utics
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 6
2. 2. 5. S u m m ar y of N o ncli nic al T o xic ol o g y St u dies
P F -0 7 2 5 8 6 6 9 was e val uate d i n a series of safet y p har mac ol o g y  a n d t o xicit y st u dies i n rats 
a n d d o gs u p t o 1 m o nt h i n d urati o n, as well as i n a batter y  of ge netic t o xicit y st u dies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Details of t he 
n o ncli nical safet y pr o gra m are pr o vi de d i n t he i n vesti gat or’s br oc h ure. T he n o ncli nical s afet y 
pr ofile of P F -0 7 2 5 8 6 6 9 has bee n a de q uatel y c haracterize d t o s u p p ort pr o gressi o n i nt o 
cli nical trials of u p t o 4 wee ks.
2. 2. 6. Cli nic al O ver vie w
T he cli nical st u d y C 4 5 4 1 0 0 1 was t he first st u d y t o a d mi nister P F-0 7 2 5 8 6 6 9 t o h u ma ns a n d 
i n vesti gate d t he safety, t olera bilit y, a n d P K of si n gle asce n di n g d oses of P F - 0 7 2 5 8 6 6 9 a n d/ or 
place b o t o 2 9 healt h y  a d ult partici pa nts . T he st u d y was a ra n d o mize d, place b o -c o ntr olle d,
i n vesti gat or- a n d partici pa nt -bli n d, s p o ns or-o pe n , se q ue ntial desi g n. S afet y , t olera bilit y, a n d 
P K data ha ve bee n ge nerate d at si n gle d oses of place b o a n d P F - 0 7 2 5 8 6 6 9 ra n gi n g fr o m 
0. 1 m g t o 3 0 0 m g. P F -0 7 2 5 8 6 6 9 was well t olerate d wit h a n acce pta ble safet y  pr ofile, a n d 
t here were n o deat hs, S A Es , or seri o us A Es re p orte d. A t otal of 1 9 treat me nt-e mer ge nt 
a d verse e ve nts were re p orte d acr oss 1 4 of 2 9 partici pa nts . All a d verse e ve nts were gra de d as 
mil d i n se verit y . T here were n o re porte d disc o nti n uati o ns fr o m st u d y or fr o m st u d y  dr u g d ue 
t o A Es. Fi ve A Es were c o nsi dere d treat me nt -relate d b y t he i n vesti gat or ( 4 A Es i n 
P F - 0 7 2 5 8 6 6 9 gr o u ps a n d 1 A E i n place b o gr o u p). I nci de nce rates of A Es were si milar acr oss 
treat me nt gr o u ps: 7 of t he 1 9 A Es were re p orte d i n 6 partici pa nts recei vi n g place b o, a n d 
1 2 A Es were re p orte d i n 1 0 partici pa nts recei vi n g P F- 07 2 5 8 6 6 9 at 1 m g t o 3 0 0 m g. T here 
was n o e vi de nce of a n y  i ncrease d i nci de nce of A Es wit h i ncreasi n g d ose of P F- 0 7 2 5 8 6 6 9. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 7
T here were 4 A Es relate d t o as ym pt o matic ele vati o ns i n ser u m tri gl yc eri des re p orte d acr oss 
2 partici pa nts ( 2 A Es per partici pa nt ). T hree of t hese 4 A Es f oll o we d P F -0 7 2 5 8 6 6 9 ( 3 0 m g, 
1 0 0 m g, 2 0 0 m g) a n d t he re mai ni n g A E occ urre d f oll o wi n g place b o. Gi ve n t he cr oss o ver 
st u d y desi g n, t he fl uct uati o ns i n ser u m tri glyceri des o bser ve d i n t hese partici pa nts bef ore 
d osi n g, after place b o, a n d fl uct uati o ns i n tri gl yceri des d uri n g t he f oll o w -u p after c o m pl eti o n 
of d osi n g, a c o n vi nci n g ass ociati o n of P F -0 7 2 5 8 6 6 9 d osi n g wit h tri gl yc eri de ele vati o n was
n ot a p pare nt.  
Ot her t ha n t he A Es relate d t o ser u m tri gl yc eri des a b o ve, t here were n o cli nicall y sig nifica nt 
a d verse tre n ds n ote d i n safet y la b orat or y data. Wit h t he e xce pti o n of a n A E of as y m pt o matic 
ort h ostatic h y p ote nsi o n, n o cli nicall y  si g nifica nt a d verse c ha n ges i n vital si g ns were 
o bser ve d. T here were n o cli nicall y si g nifica nt a d verse tre n ds o bserve d i n E C G para meters.
F oll o wi n g a d mi nistrati o n of si n gle oral d oses of P F- 0 7 2 5 8 6 6 9 u n der faste d c o n diti o ns, 
me dia n T ma x ra n ge d fr o m 0. 7 5 t o 1. 2 5 h o urs acr oss t he d ose gr o u ps. T he mea n ter mi nal t½
ra n ge d fr o m 2.5 t o 1 3 h o urs. I n ge neral, bot h C ma x a n d A U C i nf i ncrease d i n a n a p pr o xi mate
d ose -pr o p orti o nal ma n ner acr oss t he d ose ra n ge e val uate d wit hi n eac h c o h ort ( 0. 1- 3 m g  i n 
C o h ort 1 a n d 1 0 -2 0 0 m g i n C o h ort 2) . H o we ver, less t ha n d ose pr o p orti o nal i ncreases of 
C ma x a n d A U C i nf were o bser ve d w he n c o m pari n g C o h ort 1 a n d C o h ort 2. A s u m mar y  of 
si n gle-d ose P F -0 7 2 5 8 6 6 9 P K para meters fr o m C 4 5 4 1 0 0 1 is prese nte d i n Ta ble 1.
T a ble 1.
Si n gle -D ose P F -0 7 2 5 8 6 6 9 P K P ar a meters i n C 4 5 4 1 0 0 1
C o h ort
D ose ( m g)
C m a x ( n g/ m L)
T m a x ( h)
A U C i nf ( n g• h/ m L)
Ter mi n al t ½ ( h)
1
0. 1
0. 8 4 3 9 ( 1 3 %)
1 ( 1 -1. 5)
2. 6 5 9 ( 14 %)
2. 5 0 8 ± 0. 9 2 4
0. 3
3. 0 5 3 ( 3 5 %)
1 ( 0. 5 -1)
8. 2 5 2 (2 8 %)
3. 8 2 8 ± 0. 9 2 3
1
1 0. 7 2 ( 4 0 %)
0. 7 5 ( 0. 5 -1)
2 8. 5 5 ( 28 %)
4. 5 7 2 ± 0. 9 3 4
3
2 6. 4 8 ( 3 5 %)
0. 7 5 ( 0. 5 -1)
7 6. 6 3 ( 2 8 %)
5. 0 1 3 ± 0. 5 2 8
2
1 0
5 3. 3 0 ( 2 4 %)
1 ( 0. 5 -1)
1 8 3. 0 ( 1 5 %)
5. 5 5 8 ± 0. 7 9 0
3 0 
1 8 8 . 1 ( 3 %)
1 ( 1 -1)
5 8 6. 9 (1 1 %)
6. 6 9 8 ± 1. 6 5 1
1 0 0 
5 7 3 . 4 ( 4 5 %)
1 ( 0. 5 - 1. 5)
2 1 5 6 ( 12 %)
6. 4 1 5 ± 1. 5 9 1
2 0 0 
1 1 7 3 ( 4 1 %)
1. 2 5 ( 1- 2)
4 0 3 3 (2 1 %)
6. 8 8 0 ± 1. 9 7 0
3
3 0 0
1 6 0 4 ( 6 4 %)
1 ( 0. 5 -1. 5)
6 0 3 6 ( 32 %)
1 2. 9 9 ± 1 0. 0 4 5
Data are prese nte d as ge o metric mea n ( % C V) f or C ma x a n d A U C i nf; me dia n (ra n ge) f or Tma x , a n d arit h metic 
mea n ± sta n dar d de viat io n f or ter mi nal t½ .
 
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 8
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As of Oct o ber 2 0 2 2, P F -0 7 2 5 8 6 6 9 d oses ha ve bee n escalate d fr o m 2 m g Q 8 H t o 2 0 m g Q 8 H. 
A t otal of 5 0 partici pa nts ha ve bee n e nr olle d i n t he c urre nt st u d y , recei vi n g eit her 
P F - 07 2 5 8 6 6 9 or place b o . Preli mi nar y draft C ma x a n d A U C ta u ha ve i ncrease d i n a n 
a p pr o xi mate d ose -pr o p orti o nal ma n ner. Me dia n T ma x ra n ge d fr o m 0. 5 t o 1 h o ur p ost-d ose. 
T he mea n t ½ ra n ge d fr o m 4. 8 t o 7. 7 h o urs acr oss t he d ose ra n ge e val uate d . All re p orte d 
a d verse e ve nts ha ve bee n mil d or m o derate ,
2. 3. Be nefit/ Ris k Assess me nt
St u d y  C 4 5 4 1 0 0 3 is t he first ti me t hat P F-0 7 2 5 8 6 6 9 will be a d mi nistere d as re peate d d oses t o 
h u ma n s. F or t he healt h y  partici pa nts partici pati n g i n t his m ulti ple , oral d ose st u d y , n o cli nical 
be nefit is e x pecte d. T he st u d y  is desi g ne d t o pr o vi de t he basis f or f urt her cli nical 
de vel o p me nt of P F -0 7 2 5 8 6 6 9 as a p ote ntial ne w, p har mac ol o gical a ge nt f or t he t reat me nt of 
geriatric a n ore xia. P ost ulate d ris ks base d o n n o ncli nical st u dies a n d cli nical data t o date are 
s u m marize d i n Secti o n 2. 2. 5 a n d Secti o n 2. 2. 6 . T he cli nical i m pact of t hese p ote ntial ris ks 
will b e mi ni mize d t hr o u g h t he pr o p ose d ca uti o us d ose escalati o n pr ocess, w herei n hi g her 
d oses of P F - 0 7 2 5 8 6 6 9 will be a d mi nistere d o nl y after l o wer d oses ha ve bee n f o u n d t o be safe 
a n d well t olerate d wit h a n acce pta ble safet y pr ofile. Pre defi ne d h u ma n e x p os ure st o p pi n g 
li mits will n ot be e xcee de d. I n a d diti o n, t his st u d y ma y use preca uti o nar y  se nti nel d osi n g (as 
o utli ne d i n Secti o n 4. 1. 1 a n d Secti o n 4. 1. 2 ) a n d i ncl u des sta n dar d, i nte nsi ve, i n patie nt 
m o nit ori n g of t he partici pa nt s d uri n g t he d osi n g peri o d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 2 9
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 d verse e ve nts of P F - 0 7 2 5 8 6 6 9 m a y  be f o u n d i n t he I B, w hic h is t he S R S D f or t his 
st u d y. T he S R S D f or mi daz ola m ma y  be f o u n d i n t he a p pr o ve d S m P C2 8 i n t he E ur o pea n 
U ni o n.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 0
2. 3. 1. Ris k Assess me nt
All st u d y  i nter ve nti o n ris ks are c o m m u nicate d t hr o u g h t he I B.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 1
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 2

St u d y I nter ve nti o n – Mi d az ol a m  
Decrease d res pirat or y 
rate
Res pirat or y de pressi o n is a rec o g nize d p ote ntial 
si de effect of mi daz ola m. Ot her p ote ntial si de 
effects i ncl u de h y p ote nsi o n a n d s o m n ole nc e. 

All partici pa nts i n Part B w ill be m o nit ore d cl osel y f or a n y si de effects 
o n da ys of mi daz ola m d osi n g as o utli ne d i n Secti o n 1. 3. 3 .

C o nti n u o us p ulse o xi metr y will be c o n d ucte d i n Part B starti n g 3 0 
mi n utes pri or t o eac h mi daz ola m d os e a n d c o nti n u i n g u ntil at least 6 
h o urs after eac h mi daz ola m d ose.

Preca uti o nar y se nti nel d osi n g ma y be e m pl o ye d as descri be d i n 
Secti o n 4. 1. 2 .
Ot her
Ris k C O VI D -1 9 
c o nta mi nati o n d uri n g 
st u d y
D uri n g t he pa n de mic, healt h y partici pa nts c o ul d be 
i nfecte d wit h t he S A R S- C o V-2 vir us t hr o u g h st u d y 
partici pati o n, w hic h c o ul d lea d t o i ncrease d healt h 
ris ks f or t his partici pa nt a n d ot hers i n t he st u d y.  
A d verse e ve nts c o ul d be c o nf o u n de d.

C O VI D -1 9 s pecific assess me nts acc or di n g t o t he S o A .
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 3
P ote ntial l a b orat or y 
c ha n ges, i ncl u di n g 
ele vati o ns i n li ver 
f u ncti o n tests a n d li pi d 
para meters, i n res p o nse 
t o u nrestricte d cal oric 
i nta ke
T he i nfl ue nce of diet o n safet y a n d t olera bilit y 
(e g, li ver f u ncti o n tests, tri gl yceri des) has bee n 
re p orte d i n p u blis he d literat ure of healt h y 
partici pa nts resi de nt i n a C R U.

U p t o 3 differ e nt dietar y all ocati o ns (ie, sta n dar d, hi g h 
car b o h y drate -hi g h cal orie, a n d hi g h fat -hi g h cal orie diets) ma y be 
e mpl o y e d i n t his st u d y t o per mit assess me nt of safet y a n d t olera bilit y i n 
t he setti n g of differe nt diets.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 4
2. 3. 2. Be nefit Assess me nt
T he partici pa nts i n t his st u d y  are n ot e x pecte d t o o btai n a n y s pecific be nefit be yo n d 
c o ntri b uti n g t o t he pr ocess of de vel o pi n g ne w t hera pies i n a n area of u n met nee d. T he y  will 
recei ve cl ose m o nit ori n g of t heir safet y via st u d y pr oce d ures u n derta ke n (e g, p h ysical 
e xa mi nati ons, 1 2 -lea d E C Gs, vital si g ns) w hic h will occ ur as o utli ne d i n t his pr ot oc ol.
2. 3. 3. O ver all Be nefit /Ris k C o ncl usi o n
Base d o n t he t otalit y of a vaila ble cli nical a n d n o ncli nical data, a n d ta ki n g i nt o acc o u nt t he 
meas ures t o mi ni mize r is k t o st u d y partici pa nts, t he o verall be nefit/ris k pr ofile s u p p orts 
cli nical testi n g of m ulti ple d oses of P F -0 7 2 5 8 6 6 9 i n t his st u d y as part of t he cli nical 
de vel o p m e nt f or a n i n dicati o n of geriatric a n ore xia .
3. O B J E C TI V E S A N D E N D P O I N T S
O bjecti ves
E n d p oi nts
P art A
Pri m ar y : 
Pri m ar y : 

T o e val uate t he safet y a n d t olera bilit y of m ulti ple, 
asce n di n g, oral d oses of P F -0 7 2 5 8 6 6 9 i n healt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult
partici pa nts (if e nr olle d).

A ssess me nt of ad verse e ve nts, cli nical safet y 
la b orat or y tests, vital si g ns , c o nti n u o us car diac 
m o nit ori n g, 1 2 -lea d E C Gs, res pirat or y rate, oral b o d y 
te m perat ure, p h ysical e xa mi nati o ns, n e ur ol o gical 
e xa mi nati o n fi n di n gs, C- S S R S,
 
.
Sec o n d ar y:
Sec o n d ar y : 

T o e val uate t he plas ma a n d uri ne P K of si n gle a n d 
m ulti ple oral d oses of P F - 0 7 2 5 8 6 6 9 i n h ealt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult
partici pa nts (if e nr olle d).

P F - 0 7 2 5 8 6 6 9 plas ma P K o n Da ys 1 a n d 1 4 : C ma x, 
A U C t a u, T ma x , d ose -n or malize d C ma x , a n d 
d ose -n or malize d A U C t a u.

P F - 07 2 5 8 6 6 9 uri ne P K o n Da y 1 4: Ae t a u, Ae t a u% , a n d 
C L r (if data per mit ).
Terti ar y/ E x pl or at or y: 
Terti ar y/ E x pl or at or y: 

T o e val uate a d diti o nal P K para meters of 
P F -0 7 2 5 8 6 6 9 f oll o wi n g si n gle a n d m ulti ple oral 
d oses t o healt h y n o n -Ja pa nese, Ja pa nese (if e nr olle d), 
a n d ol der a d ult partici pa nts (if e nr olle d).

P F -0 7 2 5 8 6 6 9 plas ma P K o n Da y 1 4 : C L/ F, C mi n , C a v, 
P T R, R ac, R ac, C ma x, t½ , a n d V z/ F (if data per mit).

T o e val uate t he effect of m ulti ple, asce n di n g d oses of 
P F - 0 7 2 5 8 6 6 9 a d mi nistere d f or 1 4 da ys i n healt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult
partici pa nts (if e nr olle d) o n b o d y wei g ht .

C ha n ge fr o m baseli ne i n b o d y wei g ht o n Da y s 7 
a n d 1 4 .
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 5

T o e val uate t he p ote ntial f or i n d ucti o n of C Y P 3 A
wit h a d mi nistrati o n of m ulti ple , asce n di n g d oses of
P F -0 7 2 5 8 6 6 9 a d mi nistere d f or 1 4 da ys i n healt h y 
n o n -Ja pa nese, Ja pa nese (if e nr olle d), a n d ol der a d ult
partici pa nts (if e nr olle d).

C ha n ge fr o m baseli ne o n Da y 1 4:

Uri nar y 6 -h y dr o x yc ortis ol/c ortis ol rati o ;

Plas ma 4 -h y dr o x yc h olester ol/c h olester ol rati o ;

Ser u m e xtracell ular vesicles (if a nal yze d).

T o c o n d uct e x pl orat or y pr ofili n g f or plas ma 
meta b olites of P F - 0 7 2 5 8 6 6 9 i n stea d y-state plas ma 
sa m ples i n healt h y n o n -Ja pa nese, Ja pa nese (if 
e nr olle d), a n d ol der a d ult partici pa nts (if e nr olle d).

Q ualitati ve p las ma le vels of p ote ntial meta b olites of
P F - 0 7 2 5 8 6 6 9 at stea d y-state.
P art B
Pri m ar y: 
Pri m ar y: 

T o e val uate t he effects of P F -0 7 2 5 8 6 6 9 o n 
mi daz ola m P K i n healt h y a d ult partici pa nts

Mi daz ola m plas ma P K para meters al o ne a n d i n 
c o m bi nati o n wit h P F -0 7 2 5 8 6 6 9 o n Peri o d 1/ Da y 1, 
Peri o d 2/ Da y 2, a n d Peri o d 2/ Da y 1 0 : C ma x, A U C last,
a n d A U C i nf (if data per mit).
Sec o n d ar y: 
Sec o n d ar y : 

T o e val uate t he safet y a n d t olera bilit y of mi daz ola m
al o ne a n d i n c o m bi nati o n wit h P F - 0 7 2 5 8 6 6 9 w he n 
a d mi nistere d t o healt h y a d ult partici pa nts

A d verse e ve nts, vital si g ns meas ure me nts, c o nti n u o us
p ulse o xi metr y , 1 2 -lea d E C Gs, p h ysical e xa mi nati o n 
fi n di n gs, a n d cli nical safet y la b orat or y me as ure me nts.
Terti ar y/ E x pl or at or y : 
Terti ar y/ E x pl or at or y : 

T o e val uate t he effects of P F - 07 2 5 8 6 6 9 o n a d diti o nal 
P K para meters of mi daz ola m i n healt h y a d ult 
partici pa nts

Mi daz ola m plas ma P K para meters al o ne a n d i n 
c o m bi nati o n wit h P F -0 7 2 5 8 6 6 9 o n Peri o d 1/ Da y 1, 
Peri o d 2/ Da y 2 , a n d Peri o d 2/ Da y 1 0: T ma x, C L/ F , 
V z/ F, a n d t½ (if data per mit).

T o e val uate t he p ote ntial f or i n d ucti o n of C Y P 3 A
wit h a d mi nistrati o n of m ulti ple d oses of
P F - 0 7 2 5 8 6 6 9 i n healt h y a d ult partici pa nts

C ha n ge fr o m baseli ne:
Uri nar y 6 -h y dr o x yc ortis ol/c ortis ol rati o o n Da y 7
(if a nal yze d);
Plas ma 4 -h y dr o x yc h olester ol/c h olester ol rati o o n 
Da y 1 0;
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 6
Ser u m e xtracell ular vesicles o n Da y 1 0
(if a nal yze d).
4. S T U D Y D E SI G N
4. 1. O ver all Desi g n
T h is st u d y c o nsists of 2 parts . Part A will e val uate t he safety, t olera bilit y , a n d P K of m ulti ple 
asce n di n g d oses of P F -0 7 2 5 8 6 6 9 . Part B will assess t he effects of P F -0 7 2 5 8 6 6 9 o n 
mi daz ola m P K . A t otal of u p t o a p pr o xi matel y 1 5 0 partici pa nts are pla n ne d t o be e nr olle d i n 
t his st u d y. Partici pa nts w h o disc o nti n ue pri or t o c o m pleti o n of t he st u d y  f or reas o ns u nrelate d 
t o safety ma y be re place d at t he discreti o n of t he i n vesti gat or a n d s p o ns or. Partici pa nts 
wit h dra w n f or safet y reas o ns will n ot be re place d.
4. 1. 1. P art A
Part A of t his st u d y  is a ra n d o mize d , i n vesti gat or- a n d partici pa nt -bli n d, s p o ns or -o pe n, 
place b o -c o ntr olle d eval uat i o n of t he safety, t olera bilit y , a n d P K of P F-0 7 2 5 8 6 6 9 after 
a d mi nistrati o n of m ulti ple asce n di n g oral d oses t o healt h y  a d ult partici pa nts. U p t o 
3 differe nt dietar y  all ocati o ns (ie, sta n dar d, hi g h car b o hy drate -hi g h cal orie, a n d hi g h fat -hi g h 
cal orie diets) m a y be e m pl o y e d. A n o pti o nal c o h ort of healt h y a d ult Ja pa nese partici pa nts 
ma y  als o be e val uate d if res ults i n n o n-Ja pa nese partici pa nts s u pp ort f urt her e v al uati o n. I n 
a d diti on, a n o pti o nal c o h ort of ol der a d ult partici pa nts ma y  als o be e val uate d if res ults i n 
y o u n ger partici pa nts s u p p ort f urt her e val uati o n. T he c o h ort of ol der partici pa nts will o nl y  be 
e val uate d after t he res ults of Part B of t his st u d y are a vaila ble. 
A p pr o xi matel y  1 3 8 healt h y  a d ult partici pa nts ma y be e nr olle d i n Part A, of w hic h 
a p pr o xi matel y 8 m a y be Ja pa nese a n d 8 - 1 0 m a y  be ol der partici pa nts. 
Preca uti o nar y  se nti nel d osi n g will be use d i n eac h c o h ort of Part A i n w hic h P F - 0 7 2 5 8 6 6 9 
e x p os ures ( C ma x a n d/ or A U C 2 4) are pr ojecte d t o be hi g her t ha n t he e x p os ures e val uate d i n t he 
si n gle asce n di n g d ose cli nical st u d y C 4 5 4 1 0 0 1 or at t he discreti o n of t he i n vesti gat or i n 
res p o nse t o safety si g nal s o bser ve d i n a pre vi o us c o h ort. If t he pr ojecte d e x p os ures ha ve bee n 
e val uate d i n a pre vi o us c o h ort of t he c urre nt st u d y, se nti nel d osi n g ma y be o mitte d . W he n 
se nti nel d osi n g is e m pl o ye d, 2 partici pa nts ( 1 recei vi n g P F -0 7 2 5 8 6 6 9 a n d 1 recei vi n g 
place b o) will be d ose d bef ore t he re mai ni n g partici pa nts of t hat c o h ort are d ose d. Safet y a n d 
t olera bilit y data t hr o u g h at least 4 8 h o urs after t he first d ose of st u d y  i nter ve nti o n f or t he 
se nti nel partici pa nts will be re vie we d pri or t o d osi n g t he re mai ni n g partici pa nts of t hat 
c o h ort.
A d diti o nal o pti o nal c o h orts ma y  be e nr olle d t o re peat a d ose or t o e x pa n d t he d ose/e x p os ure 
ra n ge or better c haracterize a partic ular safety or t ol era bilit y si g nal or cli nical bi o mar ker of 
i nterest (e g, b o d y  wei g ht). 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 7
F or a gi ve n partici pa nt, t he t otal st u d y d urati o n fr o m scree ni n g t o t he f oll o w - u p p h one call 
will be u p t o a p pr o xi matel y 1 1 wee ks. Scree ni n g will occ ur wit hi n 2 8 da y s pri or t o t he first 
d ose of bli n de d st u d y  i nter ve nti o n. Eli gi ble partici pa nts w h o meet t he e ntr y criteria will 
pr o gress t o a d missi o n t o t he C R U f or a 18 d a y  (a n d 17 ni g ht) i n patie nt sta y. W hile i n patie nt, 
st u d y i nter ve nti o n will be a d mi nistere d eit her Q 8 H or Q 1 2 H f or 1 4 c o nsec uti ve da ys wit h t he 
e xce pti o n of Da y 1 4 i n w hic h o nl y a si n gle m or ni n g d ose will be a d mi nistere d. Partici pa nts 
will re mai n i n patie nt f or a n a d diti o nal 4 8 h o urs after t he m or ni n g d ose o n Da y  1 4. F oll o wi n g 
disc har ge, partici pa nts will ret ur n f or a n o n -site f oll o w-u p visit 7 t o 1 0 da y s after 
a d mi nistrati o n of t he fi nal d ose of st u d y i nter ve nti o n. Ja pa nese partici pa nts, if e nr olle d, m a y  
re mai n i n-h o use u ntil t h e f oll o w-u p visit. T he f oll o w -u p c o ntact m a y  occ ur via a tele p h o ne 
call a n d will occ ur 2 8 t o 3 5 da y s after a d mi nistrati o n of t he fi nal d ose of st u d y i nter ve nti o n.
D ose le vels will be escalate d acr oss c o h orts t o brac ket t he e x pecte d cli nical d ose ra n ge, b ut
pr ojecte d e x p os ures will n ot e xcee d t he pre - defi ne d h u ma n e x p os ure li mits. D ose escalati o n 
i ncre me nts bet wee n c o h orts will be selecte d s uc h t hat u p t o se mi -l o garit h mic e x p os ures will 
be e x pecte d. 
At t he discreti o n of t he i n vesti gat or, n o n -se nti nel partici pa nts m a y  be gi n t heir sta y at t he 
C R U o n t he sa me da y as t he se nti nel partici pa nts i n or der t o sta n dar dize c o n diti o ns f or all 
partici p a nts of a gi ve n c o h ort. I n t hat case, a d missi o n a n d baseli ne acti vities ca n be starte d 
eit her o n t heir first da y i n t he C R U or o n Da y -2 of t heir sta y, a n d t hese partici pa nts w o ul d 
re mai n i n t he C R U f or u p t o a 2 0 d a y  (a n d 19 ni g ht) i n patie nt sta y .
4. 1. 2. P art B
Part B will be c o n d ucte d if t he res ults of Part A s u p p ort f urt her e val uati o n of P F - 0 7 2 5 8 6 6 9. 
Part B is a 2- peri o d , fi xe d-se q ue nce, m ulti ple-d ose, o pe n -la bel desi g n t o e val uate t he effect 
of P F -0 7 2 5 8 6 6 9 o n mi daz ola m P K i n healt h y  a d ult partici pa nts. A t otal of a p pr o xi matel y  
1 2 healt h y  a d ult partici pa nts per c o h ort will be e nr olle d i n Part B . All partici pa nts i n Part B 
will be all ocate d t o sta n dar d diet.
Preca uti o nar y  se nti nel d osi n g ma y be use d i n Part B 
 
 
 T heref ore, if se nti nel d osi n g 
is e m pl o ye d, 2 partici pa nts will be d ose d, a n d if n o u nt o war d effects are o bser ve d t hr o u g h at 
least 2 4 h o urs after m i daz ola m d osi n g i n Peri o d 2/ Da y 2 f or t he se nti nel partici pa nts, t he 
re mai ni n g partici pa nts of t hat c o h ort will t he n be d ose d. If u nt o war d effects are o bser ve d, a 
l o wer d ose of P F -0 7 2 5 8 6 6 9 ma y  be e val uate d i n a n ot her c o h ort. 
F or a gi ve n partici pa nt, t he t otal st u d y  d urati o n fr o m scree ni n g t o t he f oll o w-u p p h o ne call 
will be u p t o a p pr o xi matel y  1 1 wee ks. Scree ni n g will occ ur wit hi n 2 8 da y s pri or t o t he first 
d ose of st u d y  i nter ve nti o n. Eli gi ble partici pa nts w h o meet t he e ntr y  criteria will pr o gress t o 
a d missi o n t o t he C R U f or a 1 4 d a y  (a n d 13 ni g ht) i n patie nt sta y . W hile i n patie nt, partici pa nts 
will recei ve a si n gle d ose of mi daz ola m i n Peri o d 1. Peri o d 2 will f oll o w 2 da y s after 
a d mi nistrati o n of mi daz ola m i n Peri o d 1. I n Peri o d 2, partici pa nts will recei ve P F -0 7 2 5 8 6 6 9 
(d ose a n d d ose re gi me n t o be deter mi ne d base d o n res ults of Part A) f or 1 0 c o nsec uti ve da ys. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 8
S i n gle d oses of mi daz ola m will be c o -a d mi nistere d wit h i n 5 mi n utes after t he m or ni n g d ose 
of P F - 0 7 2 5 8 6 6 9 o n Da y s 2 a n d 1 0. Partici pa nts will re mai n i n patie nt f or 2 4 h o urs after t he 
fi nal d ose of mi daz ola m o n Da y 1 0. F oll o wi n g disc har ge, partici pa nts will ret ur n f or a n o n -
site f oll o w-u p visit 7 t o 1 0 da y s after a d mi nistrati o n of t he fi nal d ose of st u d y i nter ve nti o n. 
T he f oll o w -u p c o ntact ma y  o c c ur via a tele p h o ne call a n d will occ ur 2 8 t o 3 5 da y s after 
a d mi nistrati o n of t he fi nal d ose of st u d y  i nter ve nti o n.
I nitially, a P F - 0 7 2 5 8 6 6 9 d ose/e x p os ure le vel si milar t o t he M T D deter mi ne d i n Part A is 
pla n ne d t o be use d t o ma xi mize t he p ossi bilit y  of detecti n g a P K i nteracti o n wit h mi daz ola m
i n Part B. H o we ver, a l o wer d ose le vel ma y  be e val uate d base d o n t he res ults of Part A. 
A d diti o nal o pti o nal c o h orts ma y  be a d de d if it is necessar y t o e val uate t he effect of a d diti o nal 
d ose le vels of P F -0 7 2 5 8 6 6 9 o n m i daz ola m P K. If t he P F- 0 7 2 5 8 6 6 9/ mi daz ola m c o m bi nati o n
use d i n t he first c o h ort of Part B is well t olerate d, se nti nel d osi n g ma y n ot be use d i n 
s u bse q ue nt c o h orts if t he P F-0 7 2 5 8 6 6 9 d ose use d i n a n y  a d diti o nal c o h ort of Part B is less 
t ha n t he P F- 0 7 2 5 8 6 6 9 d ose e val uate d i n t he first c o h ort of Part B.
4. 2. Scie ntific R ati o n ale f or St u d y Desi g n
T he p o p ulati o n pla n ne d f or t his st u d y  will be healt h y a d ult males a n d fe males of 
n o nc hil d beari n g p ote ntial. Fe male partici pa nts will be c o nfir me d n ot t o be of c hil d beari n g 
p ote ntial beca use e m br y o- fetal de vel o p me ntal t o xicit y st u dies wit h P F-0 7 2 5 8 6 6 9 ha ve n ot 
bee n c o n d ucte d. I n males, a p pr o priate meas ures are e x pecte d t o be f oll o we d t o mi ni mize 
p ote ntial tra nsfer of P F -0 7 2 5 8 6 6 9 via se me n .
4. 2. 1. R ati o n ale f or P art A
Beca use t his is t he first ti me m ulti ple d oses of P F-0 7 2 5 8 6 6 9 will be a d mi nistere d t o h u ma ns, 
a se q ue ntial c o h ort, escalati n g oral d ose desi g n is pla n ne d wit h caref ul assess me nt a n d 
o n g oi n g re vie w of safet y,  t olera bilit y, a n d P K data of P F- 0 7 2 5 8 6 6 9. Preca uti o nar y  se nti nel
d osi n g m a y  als o be e m pl o ye d as descri be d i n Secti o n 4. 1. 1 .
At eac h d ose le vel pr o p ose d f or d ose- escalati o n c o h orts of healt h y a d ult n o n -Ja pa nese 
partici pa nts , a p pr o xi matel y 8 partici pa nts are pla n ne d t o recei ve P F -0 7 2 5 8 6 6 9 a n d 
a p pr o xi matel y 2 partici pa nts are pla n ne d t o recei ve place b o . T he pla n ne d d oses i n t he 
escalati o n se q ue nce (Ta ble 2 ) ma y be m o difie d or re peate d, as g ui de d by e mer gi n g safet y, 
t olera bilit y, a n d P K data b ut will f oll o w t he d ose -escalati o n r ules defi ne d i n Secti o n 6. 5. 1 .
A d diti o nal o pti o nal c o h orts of healt h y a d ult n o n -Ja pa nese partici pa nts ma y be e nr olle d t o 
re peat a d ose or t o e x pa n d t he d ose/e x p os ure ra n ge or better c haracterize t he safety a n d 
t olera bilit y pr ofile or cli nical bi o mar ker of i nterest (e g, b o d y  wei g ht). 
T he i nfl ue nce of diet o n safet y a n d t olera bilit y (e g, li ver f u ncti o n tests, tri gl yc eri des) has 
bee n re p orte d i n p u blis he d literat ure i n healt h y partici pa nts resi de nt i n a C R U. 3 2 C o h orts of 
healt h y  n o n-Ja pa nese partici pa nts will be all ocate d t o 1 of 3 differe nt dietar y all ocati o ns 
(ie, sta n dar d, H C H C, or H F H C diets) descri be d i n Secti o n 5. 3. 1 t o facilitate a m ore 
c o m pre he nsi ve assess me nt of safet y, t olera bilit y , P K, a n d e x pl orat or y e n d p oi nts. O pti o nal 
c o h orts of Ja pa n ese a n d/ or ol der a d ult partici pa nts will be all ocate d t o sta n dar d diet o nl y . 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 3 9
A lar ger sa m ple size will be use d f or t he a d diti o nal o pti o nal c o h orts of healt h y  a d ult n o n-
Ja pa nese partici pa nts recei vi n g t he H F H C diet. If c o n d ucte d, t he first c o h ort all ocate d t o t he 
H F H C diet will li kel y e val uate safety, t olera bilit y, P K, a n d P D at t he ma xi m u m t olerate d 
d ose of P F -0 7 2 5 8 6 6 9 i de ntifie d i n earlier d ose-escalati o n c o h orts all ocate d t o sta n dar d diet.
T his c o h ort will c o nsis t of a p pr o xi matel y 2 4 partici pa nts wit h a p pr o xi matel y 1 2 partici pa nts 
pla n ne d t o recei ve P F -0 7 2 5 8 6 6 9 a n d a p pr o xi matel y 1 2 partici pa nts pla n ne d t o recei ve 
place b o . A n o pti o nal sec o n d c o h ort all ocate d t o t he H F H C diet m a y  be e nr olle d t o e val uate 
safety, t ole ra bility, P K, a n d P D at a l o wer d ose/e x p os ure t o f urt her c haracterize t he 
d ose/ e x p os ure -res p o nse relati o ns hi p a n d i nf or m d ose selecti o n f or later cli nical st u dies. T his 
sec o n d c o h ort m a y  c o nsist of a p pr o xi matel y  1 6 partici pa nts wit h a p pr o xi matel y
1 2 partic i pa nts pla n ne d t o recei ve P F-0 7 2 5 8 6 6 9 a n d a p pr o xi matel y 4 partici pa nts pla n ne d t o 
recei ve place b o. Refer t o Secti o n 9. 5. 1 f or a d diti o nal details o n t he sa m ple size 
deter mi nati o n.
A n o pti o nal c o h ort of a p pr o xi matel y 8 healt h y  a d ult Ja pa nese partici pa nts (a p pr o xi matel y
6 recei vi n g P F-0 7 2 5 8 6 6 9 a n d a p pr o xi matel y 2 place b o) m a y be e nr olle d i n t h is st u d y t o 
c ollect safet y, t olera bility , a n d P K data of P F -0 7 2 5 8 6 6 9 t o s u p p ort e nr oll me nt of Ja pa nese 
partici pa nts i n f ut ure cli nical st u dies wit h P F -0 7 2 5 8 6 6 9 if res ults fr o m pre vi o us c o h orts 
s u p p ort f urt her cli nical de vel o p me nt of P F -0 7 2 5 8 6 6 9 . 
A n o pti o nal c o h ort of a p pr o xi matel y 8- 1 0 ol der a d ult partici pa nts (a p pr o xi matel y 
6- 8 recei vi n g P F-0 7 2 5 8 6 6 9 a n d a p pr o xi matel y place b o) ma y  be e nr olle d i n t his st u d y t o 
c ollect safet y, t olera bilit y, a n d P K data of P F-0 7 2 5 8 6 6 9 t o s u p p ort e nr oll me nt of ol der a d ults 
i n f ut ure cli nical st u dies wit h P F-0 7 2 5 8 6 6 9.
T o per mit a n u n biase d assess me nt of safet y, t he a d mi nistrati o n of b ot h P F -0 7 2 5 8 6 6 9 a n d 
place b o will be bli n de d t o b ot h site staff (e xce pt t h ose i n v ol ve d i n pre parati o n of d oses ) as 
well as all partici pa nts i n Part A.
S erial plas ma P K sa m ples will be c ollecte d o n Da y s 1 a n d 1 4 t o c haracterize si n gle-d ose a n d 
m ulti ple - d ose P K of P F- 0 7 2 5 8 6 6 9. Tr o u g h P K sa m ples will als o be c ollecte d o n Da y s 4, 7, 
a n d 1 0 t o ai d i n t he deter mi nati o n of ti me t o stea d y- state. Uri ne sa m ples will be c ollecte d t o 
e val uate re nal cleara nce of P F - 0 7 2 5 8 6 6 9. Sa m pli n g ti mes a n d/ or d urati o n of sa m pli n g ma y  
be m o difie d a n d/ or e xte n de d if data ge nerate d i n pre vi o us c o h orts i n dicat e t hat t he t½ is 
l o n ger t ha n e x pecte d base d o n preli mi nar y  data ge nerate d i n C 4 5 4 1 0 0 1 .
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 0
 
 
A c o m pre he nsi ve li pi d pa nel, c o nsisti n g of t otal c h olester ol, tri gl yc eri des, H D L, a n d L D L, 
will be c ollecte d after at least 1 2 h o urs of fasti n g a n d m o nit or e d wit h cli nical safet y la b tests 
d ue t o t he o bser vati o n of i ncrease d tri gl yc eri des a n d c h olester ol n ote d i n t he 1 -m o nt h rat 
t o xicit y st u d y. Ele vate d plas ma tri glyc eri des ha ve als o bee n re p orte d i n 2 partici pa nts i n 
C 4 5 4 1 0 0 1 si n gle asce n di n g d ose cli nical st u d y.
Res pirat or y  rate a n d b o d y te m perat ure will als o be meas ure d a n d m o nit ore d d ue t o t he
o bser vati o n of tra nsie nt l o wer res pirat or y  rate a n d b o d y te m perat ure i n rats after
a d mi nistrati o n of P F -0 7 2 5 8 6 6 9 i n t o xic ol o g y  st u dies.
B o d y  wei g ht will be meas ure d i n t his st u d y beca use M C 4 R a nta g o nis m is e x pecte d t o 
i ncrease f o o d c o ns u m pti o n a n d b o d y wei g ht. 
 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 1
 Si milar o bser vati o ns ha ve bee n ma de i n a m o use m o del wit h 
M C 4 R
deficie nc y  b ut n ot i n a M C 4 R k n oc k o ut m o use m o del.2 1 ,2 2
I n vitr o data i n dicate t hat P F- 0 7 2 5 8 6 6 9 is pri maril y meta b olize d b y C Y P 3 A, as s uc h t he use 
of m o derate or str o n g C Y P 3 A i n hi bit ors or i n d ucers is n ot per mitte d d uri n g t he st u dy a n d 
wit hi n 2 8 da y s or 5 half li ves ( w hic he ver is l o n ger) pri or t o first d ose of st u d y i nter ve nti o n. 
Refer t o Secti o n 6. 8 f or a d diti o nal details. In a d diti o n, i n vitr o data i n dicate t hat 
P F -0 7 2 5 8 6 6 9 ma y  be a p ote ntial T DI of C Y P 3 A 4/ 5, as s uc h c o nc o mita nt me dicati o ns t hat 
are C Y P 3 A s u bstrates ma y be restricte d. Refer t o Secti o n 6. 8. 1 f or a d diti o nal details.
Base d o n n o ncli nical data, t he p ote ntial e xists t hat P F - 0 7 2 5 8 6 6 9 m a y  ca use wea k i n d ucti on 
of C Y P 3 A at hi g h d oses , re prese nti n g a re g ulat or y ris k. E val uati o n of t he uri nar y  
6 -h y dr o x y c ortis ol/c ortis ol rati o, plas ma 4 -h y dr o x y c h olester ol/c h olester ol rati o, a n d ser u m 
e xtracell ular vesicles will all o w f or e x pl orat or y  e val uati o n of i n d ucti o n p ote ntial. H o we ver, 
ser u m e xtracell ular vesicles ma y  n ot be a nalyz e d if uri nar y 6-h y dr o x y c ortis ol/c ortis ol, 
plas ma 4 -h y dr o x y c h olester ol/c h olester ol , a n d/ or mi daz ola m ( Part B) data s u g gest n o 
i n d ucti o n.
Plas ma sa m ples will be c ollecte d f or e x pl orat or y  q ualitati ve meta b olite pr ofili n g t o i de ntif y
p ote ntial maj or meta b olites.
Alt h o u g h t here is n o s us pici o n of h u ma n terat o ge nicit y  base d o n t he e x pecte d p har mac ol o g y
of P F -0 7 2 5 8 6 6 9, h u ma n re pr o d ucti ve safet y data are n ot a vaila ble f or P F -0 7 2 5 8 6 6 9.
T heref ore, t he use of a hi g hl y effecti ve met h o d of c o ntrace pti o n is re q uire d f or male st u d y
partici pa nts a n d is rec o m me n de d f or part ners of male st u d y  partici pa nts w h o are W O C B P
(see A p pe n di x 4 ).
4. 2. 2. R ati o n ale f or P art B
P F - 0 7 2 5 8 6 6 9 is a p ote ntial T DI of C Y P 3 A 4/ 5 at pr ojecte d t hera pe utic d oses a n d a p ote ntial 
i n d ucer of C Y P 3 A 4/ 5 at d oses greater t ha n t he pr ojecte d t hera pe utic d ose . E val uati n g t he 
p ote ntial P K i nteracti o ns bet wee n P F -0 7 2 5 8 6 6 9 a n d mi daz ola m ma y  pr o vi de i nsi g hts i nt o 
P K or safet y iss ues t hat ma y  arise i n f ut ure cli nical st u dies or i nf or m decisi o ns relate d t o t he 
i ncl usi o n of patie nts i n f ut ure st u dies w h o ma y  be ta ki n g c o nc o mita nt me dicati o ns t hat are 
C Y P 3 A s u bstrates . 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 2
 at
t he projecte d efficaci o us d ose.
At p r ojecte d t hera pe utic e x p os ures , P F -0 7 2 5 8 6 6 9 is n ot e x pecte d t o i n d uce C Y P 3 A . 
Alt h o u g h i n d ucti o n was n ot o bser ve d at t he e nz y me acti vit y le vel i n vitr o at t h ose e x p os ures ,
P F - 0 7 2 5 8 6 6 9 de m o nstrate d
m R N A i n d ucti o n of C Y P 3 A 4. H o we ver, at hi g her 
e x p os ures ass ociate d wit h t he hi g hest d oses pla n ne d t o be e val uate d i n t his s t u d y, 
P F -0 7 2 5 8 6 6 9 has t he p ote ntial t o i n d uce C Y P 3 A.
Gi ve n t he pre p o n dera nce of C Y P 3 A 4/ 5 s u bstrates i n t he i nte n de d patie nt p o p ulati o n of 
el derl y patie nts wit h a n ore xia , a cli nical D DI st u d y  assessi n g t he effect of P F- 0 7 2 5 8 6 6 9 o n 
t he P K of a se nsiti ve C Y P 3 A 4/ 5 s u bstrate nee ds t o be c o n d ucte d t o deter mi ne t he effect of 
P F - 0 7 2 5 8 6 6 9 o n C Y P 3 A 4/ 5. Mi daz ola m is a se nsiti ve C Y P 3 A 4/ 5 s u bstrate w hic h u n der g oes 
e xte nsi ve meta b olis m b y C Y P 3 A 4/5. T he P K a n d P D pr o perties of mi daz ola m ma ke it 
wi del y  acce pte d as a pr o be i n vitr o, a n d i n cli nical st u dies f or assessi n g C Y P 3 A acti vit y a n d 
is rec o m me n de d b y  t he F D A as a pr o be s u bstrate f or C Y P 3 A D DI st u dies . T he c urre nt st u d y 
is desi g ne d t o deter mi ne t h e effect of P F- 0 7 2 5 8 6 6 9 o n t he P K of mi daz ola m.
T he o nset of i n hi biti o n effect o n C Y P 3 A b y  p ote ntial i n hi bit ors is relati vel y ra pi d. Alt h o u g h 
T DI d oes n ot occ ur as q uic kl y  as c o m petiti ve i n hi biti o n, near ma xi mal T DI of C Y P 3 A wit h 
clarit hr o m yci n was s h o w n t o be ac hie ve d at a p pr o xi matel y  1 da y a n d 4 da ys i n t he g ut a n d 
li ver, res pecti vel y.2 3 Gi ve n t he s h ort ter mi nal t½ ( < 6. 3 h o urs) o bser ve d i n C 4 5 4 1 0 0 1, 
acc u m ulati o n of P F - 0 7 2 5 8 6 6 9 is e x pecte d t o be mi ni mal after m ulti ple d osi n g. T heref ore, 
mi daz ola m will als o be c o -a d mi nistere d wit h P F-0 7 2 5 8 6 6 9 o n Da y  2 of Peri o d 2 t o assess 
t he p ote ntial effect of C Y P 3 A i n hi biti o n b y P F-0 7 2 5 8 6 6 9 o n mi daz ola m P K , w hic h ma y
i nf or m dec o n v ol ut i o n of C Y P 3 A i n hi biti o n fr o m p ote ntial mi xe d i n d ucti o n /i n hi biti o n t hat 
ma y  be o bser ve d o n Da y 10.
B ot h i n d ucti o n a n d T DI ca n ta ke se veral da ys t o e xert t heir effects o n C Y P 3 A acti vit y. T h us, 
m ulti ple d oses of P F -0 7 2 5 8 6 6 9 will be a d mi nistere d f or 1 0 d a y s t o e ns ure t hat C Y P 3 A T DI 
a n d i n d ucti o n ca n be o bser ve d a n d e val uate d, if t here is p ote ntial f or P F-0 7 2 5 8 6 6 9 t o i n d uce 
C Y P 3 A . Mi daz ola m will be c o -a d mi nistere d wit h P F -0 7 2 5 8 6 6 9 o n Da y  1 0 of Peri o d 2 t o 
e val uate t he p ote ntial effect of mi xe d C Y P 3 A i n d ucti o n a n d i n hi biti o n b y  P F- 0 7 2 5 8 6 6 9 o n 
mi daz ola m P K.
Res pirat or y  de pressi o n, h y p ote nsi o n, a n d s o m n ole nce are a m o n g t he rec o g nized p ote ntial 
si de effects of hi g her d oses of mi daz ola m. Alt h o u g h s uc h a d verse e ve nts are n ot c o nsi dere d 
li kel y at mi daz ola m e x p os ures a ntici pate d i n Part B, all partici pa nts will be cl osel y m o nit ore d 
f or t hese si de effects o n da ys of mi daz ola m d osi n g. T his will i ncl u de c o nti n u o us p ulse 
o xi metr y  f or all partici pa nts fr o m 3 0 mi n utes bef ore t hr o u g h at least 6 h o urs after mi daz ola m 
d osi n g.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 3
T he plas ma 4 -h y dr o x yc h olester ol/c h olester ol rati o will als o be e val uate d i n Part B t o all o w 
f or e x pl orat or y e val uati o n of t hese C Y P 3 A i n d ucti o n bi o mar kers i n t he sa me partici pa nts i n 
w hic h t he p ote ntial mi daz ola m P K D DI was e val uate d. S er u m e xtracell ular vesicle sa m ples 
a n d t he uri ne sa m ples f or meas ure me nt of t he 6-h y dr o x yc ortis ol/c ortis ol rati o will be als o 
c ollecte d b ut m a y n ot be a nal yz e d if uri nar y 6-h y dr o x yc ortis ol/c ortis ol ( Part A) , plas ma 
4 -h y dr o x y c h olester ol/c h olester ol ( Parts A a n d B), a n d/ or mi daz ola m ( Part B) data s u g gest 
n o i n d ucti o n.
 
I nitially, a P F - 0 7 2 5 8 6 6 9 d ose/e x p os ure le vel si milar t o t he M T D deter mi ne d i n Part A is 
pla n ne d t o be use d t o ma xi mize t he p ossi bilit y  of detecti n g a P K i nteracti o n wit h mi daz ola m
i n Part B. H o we ver, a l o wer d ose le vel ma y  be e val uate d base d o n t he res ults of Part A. 
O pti o nal c o h orts ma y  be a d de d if it is necessar y t o e val uate t he effect of a d diti o nal d ose 
le vels of P F-0 7 2 5 8 6 6 9 o n mi daz ola m P K.
Preca uti o nar y  se nti nel d osi n g m a y be e m pl o y e d as descri be d i n Secti o n 4. 1. 2 . Part B 
partic i pa nts will be all ocate d t o sta n dar d diet o nl y.
4. 2. 3. C h oice of C o ntr ace pti o n/ B arrier Re q uire me nts
H u ma n re pr o d ucti ve safet y  data are n ot yet a vaila ble f or P F - 0 7 2 5 8 6 6 9, b ut t here is n o 
s us pici o n of h u ma n terat o ge nicit y base d o n t he i nte n de d p har mac ol o g y of t he c o m p o u n d.
T heref ore, t he use of a hi g hl y effecti ve met h o d of c o ntrace pti o n is re q uire d (see A p pe n di x 4 ).
4. 2. 4. C ollecti o n of Ret ai ne d Rese arc h S a m ples
Retai ne d Researc h Sa m ples will be c ollecte d a n d st ore d f or f urt her a nal ys es 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 nter ve nti o n.
4. 3. J ustific ati o n f or D ose
T he pr o p ose d d ose le vels of P F -0 7 2 5 8 6 6 9 i n t his st u d y were deri ve d base d o n c u m ulati ve 
cli nical a n d n o ncli nical data wit h P F -0 7 2 5 8 6 6 9, i ncl u di n g i n vitr o a n d i n vi v o p har mac ol o g y 
a n d P K data, n o ncli nical t o xicit y st u dies, a n d t he si n gle-d ose h u ma n safet y,  t olera bilit y, a n d 
P K res ults fr o m St u d y  C 4 5 4 1 0 0 1 (Secti o n 2. 2. 6 ). D ose le vels ha ve bee n selecte d t o brac ket 
t he e x pecte d cli nical d ose a n d e x p os ure ra n ge, w hile c o nsi deri n g u ncertai nt y  i n t he pr ojecte d 
cli nicall y efficaci o us d ose. T he d ose le vels a n d d osi n g re gi me ns b e y o n d t he C o h ort 1 starti n g 
d ose le vel/re gi me n m a y  be m o difie d base d o n e mer gi n g h u ma n safet y, t olera bilit y, a n d P K 
data i n t he c urre nt st u d y .
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 4
4. 3. 2. H u m a n E x p os ure St o p pi n g Li mits
T he h u ma n e x p os ure st o p pi n g li mits are base d o n e x p os ures o bser ve d i n d o gs i n n o ncli nical 
t o xic ol o g y st u dies a n d are c orrecte d f or s pecies-de pe n de nt plas ma pr otei n bi n di n g bet wee n 
d o g a n d h u ma n 
4. 3. 3. R ati o n ale f or D ose Selecti o n
4. 3. 3. 1. P art A P F -0 7 2 5 8 6 6 9 D ose Selecti o n
T he pla n ne d P F -0 7 2 5 8 6 6 9 d ose ra n ge t o be e val uate d i n Part A of t his st u d y  is s h o w n i n 
Ta ble 2 . 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 5
T a ble 2. 
Pre dicte d P F- 0 7 2 5 8 6 6 9 Ste a d y -St ate E x p os ures
C o h ort
1
2
3
4
5
T he starti n g d ose le vel of P F- 0 7 2 5 8 6 6 9 pr o p ose d f or Part A of t his st u d y  is 
 
 T his starti n g d ose le vel is pr ojecte d t o be safe gi ve n t hat P F-0 7 2 5 8 6 6 9 has 
bee n well t olerate d wit h a n acce pta ble safet y pr ofile at si n gle oral d oses u p t o 
 
 
 
Base d o n safet y a n d t olera bilit y  
o bser ve d i n C 4 5 4 1 0 0 1, n o cli nicall y  si g nifica nt a d verse effects o n E C Gs, vital si g ns, or 
cli nical safet y la b orat ories are e x pecte d at t his d ose.
 
 
 
 
 
T he d ose /e x p os ure ra n ge t o be st u die d was selecte d t o acc o u nt f or u ncertai nties i n t he 
pr ojecte d C eff a n d t he pr ojecte d t hera pe utic d ose, w hile als o brac keti n g t he e x pecte d 
cli nicall y effecti ve d ose ra n ge i n h u ma ns f or cli nicall y rele va nt p har mac ol o gical acti vit y of 
geriatric a n ore xia a n d pr o vi di n g safet y  c o vera ge f or a wi de ra n ge of P F-0 7 2 5 8 6 6 9 d oses.
 
I n a d diti o n t o M C 4 R a nta g o nis m bei n g a n o vel a p pr oac h t o treati n g geriatric a n ore xia, 
u ncertai nties i n C eff are als o d ue t o t he u n k n o w n q ua ntitati ve tra nslati o n of a ge d-rat f o o d 
i nta ke a n d b o dy wei g ht data t o h u ma ns. D oses hi g her t ha n t he pr ojecte d h u ma n t hera pe utic 
d ose ma y  be e val uate d i n f ut ure cli nical st u dies t o ma xi mize t he p ote ntial t o o bser ve 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 6
efficac y. Q 8 H d osi n g i n t his st u d y  all o ws f or e val uati o n of hi g her A U C s t ha n ha ve bee n 
e val uate d i n t he si n gle asce n di n g d ose st u d y ( C 4 5 4 1 0 0 1) t o date. I n a d diti o n, Q 1 2 H d osi n g 
ma y  als o be e x pl ore d t o e val uate hi g her A U Cs t ha n ha ve bee n e val uate d i n C 4 5 4 1 0 0 1 or if 
m ulti ple d ose P K is n ot as e x pecte d (e g, if t he o bser ve d t ½ is l o n ger t ha n e x pecte d d ue t o 
a ut o-i n hi biti o n of C Y P 3 A).
E x p os ures at t he pr o visi o nal d oses o utli ne d i n Ta ble 2 were pr ojecte d usi n g a preli mi nar y  
p o p ulati o n P K m o del t hat was de vel o pe d usi n g preli mi nar y  draft si n gle-d ose P K data 
ge nerate d i n C 4 5 4 1 0 0 1.
 
 
D ose escalati o n i ncre me nts are pla n ne d t o be u p t o a p pr o xi matel y  se mi-l o garit h mic i ncreases 
i n e x p os ure fr o m t he pre vi o us hi g hest d ose. If a ut o-i n hi biti o n is o bser ve d, res ulti n g i n greater 
t ha n d ose pr o p orti o nal e x p os ure i ncreases, t he d ose escalati o n sc he me i n Ta ble 2 will n ot be 
use d. D ose le vels will be a dj uste d s uc h t hat pre dicte d e x p os ures will n ot e xcee d 3. 3 -f ol d 
i ncre me nts bet wee n d ose le vels. A ct ual d oses, tar get e x p os ures, d ose re gi me ns, a n d d ose 
i ncre me nts ma y be re peate d or a dj uste d ( hi g her or l o wer) d uri n g t he st u d y  base d o n e mer gi n g 
h u ma n safet y, t olera bilit y, a n d P K data, b ut pr ojecte d e x p os ures will n ot e xcee d t he 
pre -defi ne d h u ma n e x p os ure li mits . Ot her d ose re gi me ns (e g, Q 6 H or Q 1 2 H) or titrati o n 
sc he mes ma y als o be a d mi nistere d. A n y  decisi o n t o alter t he pla n ne d d osi n g sc he mes will be 
ma de j oi ntl y  b y t he i n vesti gat or a n d t he s p o ns or after caref ul e val uati o n of all a vaila ble data.
T he P K data fr o m b ot h C 4 5 4 1 0 0 1 a n d t he prese nt st u d y will be use d t o pre dict e x p os ures f or 
s u bse q ue nt d ose le vels. T he s u bse q ue nt d ose le vels will be selecte d base d o n re vie w of 
o bser ve d safet y, t olera bilit y , a n d P K u p t o Da y 1 4 fr o m pre vi o us d ose le vels.
D oses a d mi ni stere d t o n o n -Ja pa nese partici pa nts all ocate d t o t he H F H C diet (if e nr olle d),
Ja pa nese partici pa nts (if e nr olle d) a n d/ or ol der a d ult partici pa nts (if e nr olle d) will be less 
t ha n or e q ual t o t he hi g hest safe a n d well-t olerate d d ose e val uate d i n healt h y a d ult 
n o n- Ja pa nese partici pa nts all ocate d t o sta n dar d diet i n Part A. If e nr olle d, t he first c o h ort 
all ocate d t o t he H F H C diet will li kel y  e val uate safet y, t olera bilit y, P K, a n d P D at t he 
ma xi m u m t olerate d d ose of P F - 0 7 2 5 8 6 6 9 i de ntifie d i n earlier d ose-escalati o n c o h orts 
all ocate d t o sta n dar d diet . A n o pti o nal sec o n d c o h ort all ocate d t o t he H F H C diet ma y  be 
e nr olle d t o e val uate safet y, t olera bilit y, P K, a n d P D at a l o wer d ose/e x p os ure t o f urt her 
c haracterize t he d ose/ e x p os ure -res p o nse relati o ns hi p a n d i nf or m d ose selecti o n f or later 
cli nical st u dies. Base d o n t he pr ojecte d cleara nce pat h wa y s of P F-0 7 2 5 8 6 6 9 ( Secti o n 2. 2. 3 ), 
si g nifica nt differe nces i n P F-0 7 2 5 8 6 6 9 e x p os ures bet wee n n o n -Ja pa nese, Ja pa nese, a n d ol der 
a d ults are n ot a ntici pate d. 
T he ma xi m u m d ose of P F -0 7 2 5 8 6 6 9 t o be a d mi nistere d i n Part A will n ot e xcee d a t otal 
dail y  d ose of 2 0 0 0 m g.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 7
4. 3. 3. 2. P art B D ose Selecti o n
4. 3. 3. 2. 1. P F -0 7 2 5 8 6 6 9 i n P art B
T he P F - 0 7 2 5 8 6 6 9 d ose le vel/re gi me n t o be use d i n Part B will be deter mi ne d base d o n t he 
res ults of Part A . Dose le vel(s)/re gi me n(s) pr ojecte d t o ac hie ve e x p os ure s less t ha n or e q ual 
t o t h ose ass ociate d wit h t he M T D deter mi ne d i n Part A will be use d t o e val uate p ote ntial P K 
i nteracti o ns bet wee n P F -0 7 2 5 8 6 6 9 a n d mi daz ola m i n Part B. T he res ults of Part B will be 
use d t o i nf or m P F - 0 7 2 5 8 6 6 9 d ose selecti o n a n d decisi o ns re late d t o t he i ncl usi o n of patie nts 
w h o ma y  be ta ki n g c o nc o mita nt me dicati o ns i n f ut ure cli nical st u dies.
T he M T D is pla n ne d t o be e val uate d t o ma xi mize t he i nteracti o ns bet wee n P F -0 7 2 5 8 6 6 9 a n d 
mi daz ola m. H o we ver, l o wer d oses of P F -0 7 2 5 8 6 6 9 ma y  be e val uate d f or reas o ns s uc h as, b ut 
n ot li mite d t o, u ne x pecte d e x p os ures, hi g her t ha n e x pecte d varia bilit y , or if u ne x pecte d 
safety or t olera bilit y si g nals are o bser ve d. If n o nli near P F -0 7 2 5 8 6 6 9 P K res ulti n g i n hi g her 
t ha n e x pecte d e x p os ures is o bser ve d i n Part A d ue t o p ote ntial a ut o -i n hi biti o n of C Y P 3 A, a 
P F - 0 7 2 5 8 6 6 9 d ose le vel less t ha n t he M T D ma y be e val uate d. A d diti o nal o pti o nal c o h orts 
ma y  be a d de d if it is necessar y t o e val uate t he effect of a d diti o nal d ose le vels of 
P F - 0 7 2 5 8 6 6 9 o n mi daz ola m P K .
Alt h o u g h T DI d oes n ot occ ur as q uic kl y  as c o m petiti ve i n hi biti o n, near ma xi mal T DI of 
C Y P 3 A wit h clarit hr o m yci n was s h o w n t o be ac hie ve d at a p pr o xi matel y  1 da y a n d 4 da ys i n 
t he g ut a n d li ver, res pecti vel y. B ot h i n d ucers a n d ti me-de pe n de nt i n hi bit ors ca n ta ke se ve ral 
da y s t o e xert t heir effects o n e nz yme acti vit y . T h us, m ulti ple d oses of P F - 0 7 2 5 8 6 6 9 will be 
a d mi nistere d f or 1 0 d a y s. If t here is a p ote ntial f or C Y P 3 A 4/ 5 T DI a n d/ or i n d ucti o n d ue t o 
P F - 0 7 2 5 8 6 6 9, d osi n g f or t his d urati o n will e ns ure t hat it ca n be o bser ve d a n d e val uate d.
T he ma xi m u m d ose of P F -0 7 2 5 8 6 6 9 t o be a d mi nistere d i n Part B will n ot e xcee d a t otal dail y  
d ose of 2 0 0 0 m g.
4. 3. 3. 2. 2. Mi d az ol a m i n P art B
T he rec o m me n de d d ose of mi daz ola m oral s ol uti o n f or pre me dicati o n pri or t o s ur ger y  a n d 
se dati o n f or brief dia g n ostic a n d t hera pe utic pr oce d ures a n d f or t he s h ort -ter m treat me nt of 
slee p dis or ders is 7. 5 t o 1 5 m g.2 8 Mi daz ola m has als o bee n a d mi nistere d at d oses of 2 t o 
1 5 m g t o assess C Y P 3 A D DIs 2 5 ,2 6 a n d has bee n ge nerall y well t olerate d. 
 
 
 
T heref ore, a 1 m g oral d ose of mi daz ola m is pla n ne d t o be a d mi n istere d. T his d ose is 
e x pecte d t o pr o vi de s ufficie nt e x p os ure t o c haracterize mi daz ola m cleara nce i n t he a bse nce 
of P F -0 7 2 5 8 6 6 9 w hile a v oi di n g sat urati o n of first- pass e xtracti o n a n d mi ni mizi n g A Es i n t he
prese nce of P F -0 7 2 5 8 6 6 9 .
H o we ver, base d o n t he res ults of Part A , t he pre dicte d P F- 0 7 2 5 8 6 6 9 e x p os ure at t he pla n ne d 
d ose, a n d w het her n o nli near P F -0 7 2 5 8 6 6 9 P K is o bser ve d d ue t o p ote ntial a ut o-i n d ucti o n or 
a ut o-i n hi biti o n of C Y P 3 A, t he mi daz ola m d ose ma y  be a dj uste d hi g her or l o wer, 
res pecti vely, s uc h t hat mi daz ola m c o nce ntrati o ns c a n be m ore a de q uatel y assesse d (ie, hi g her 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 8
c o nce ntrati o ns f urt her a b o ve t he LL O Q) a n d pre dicte d c o nce ntrati o ns re mai n wit hi n a ra n ge 
t hat will n ot ha ve u n d ue p har mac ol o gical effects. A mi daz ola m d ose > 1 m g will o nl y  be use d 
if net a ut o-i n d ucti o n is o bser ve d i n Part A. T he ma xi m u m d ose of mi daz ola m t o be 
a d mi nistere d i n Part B will n ot e xcee d 8 m g.
W hile t he pre dicte d e x p os ure of mi daz ola m w he n c o-a d mi nistere d wit h P F- 0 7 2 5 8 6 6 9 is n ot 
e x pecte d t o e xc ee d t hat of a n 8 m g mi daz ola m d ose , t he pr o p ose d e x p os ure li mit of 
mi daz ola m ( or ma x e x p os ure e x pecte d) will n ot e xcee d t hat of a 1 5 m g si n gle oral d ose of 
mi daz ola m w hic h is k n o w n t o be safe a n d ge nerall y  well -t olerate d. A cross 2 3 st u dies
(i de ntifie d usi n g t he U ni versit y of Was hi n gt o n dr u g i nteracti o n data base) usi n g 1 5 m g oral 
mi daz ola m, mea n C ma x a n d A U C were a p pr o xi matel y 78 ± 2 8 n g/ m L (ra n ge 4 3 -1 7 1) a n d 
2 4 9 ± 9 8 n g• h/ m L (ra n ge 1 3 8 -5 7 8), res pecti vel y. 2 9
4. 4. E n d of St u d y Defi niti o n
T he e n d of t he st u d y is defi ne d as t he date of t he last sc he d ule d pr oce d ure s h o w n i n t he S o A
f or t he last partici pa nt i n t he trial.
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y  if he/s he has c o m plete d all peri o ds of 
t he st u d y, i ncl u di n g t he last sc he d ule d pr oce d ure s h o w n i n t he S o A .
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 nt s 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 nt s 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 c o n diti o ns s h o ul d be 
ta ke n i nt o c o nsi derati o n w he n deci di n g w het her a partic ular 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.
Healt h y male partici pa nts a n d fe males of n o nc hil d beari n g p ote ntial m ust be 1 8 t o
6 0 ye ars of a ge, i ncl usi ve, at t he ti me of si g ni n g t he I C D .
F or o pti o n al c o h ort of ol der a d ult p artici p a nts o nl y: M ale partici pa nts a n d fe male 
partici pa nts of n o n -c hil d beari n g p ote ntial m ust be 6 5 t o 9 0 ye ars of a ge , i ncl usi ve, at 
t he ti me of si g ni n g t he I C D. Atte m pts will be ma de t o e ns ure t hat t he a ge c o m p ositi o n 
of t his c o h ort (e g, a p pr o xi matel y 7 0 % of partici pa nts ≥7 0 y ears of a ge) is c o m para ble 
t o t hat of t he a ntici pate d patie nt p o p ulati o n i n later cli nical st u dies.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 4 9

Refer t o A p pe n di x 4 f or re pr o d ucti ve criteria f or male (Secti o n 1 0. 4. 1 ) a n d fe male 
(Secti o n 1 0. 4. 2 ) partici pa nts. Fe male partici pa nts m ust meet criteria f or 
n o nc hil d beari n g p ote ntial s pecifie d i n Secti o n 1 0. 4. 3 .
T y pe of P artici p a nt a n d Dise ase C h ar acteristics:
2.
Fe male partici pa nts of n o nc hil d beari n g p ote ntial a n d male partici pa nts w h o are 
o vertl y  healt h y as deter mi ne d b y me dical e val uati o n i ncl u di n g me dical hist or y, 
p h y sical e xa mi nati o n, la b orat or y tests, a n d car diac m o nit ori n g.
F or o pti o n al c o h ort of ol der a d ult p artici p a nts o nl y: Partici pa nts m ust be i n a 
sta ble c o n diti o n at a d missi o n. T hese partici pa nts m ust be i n reas o na bl y g o o d healt h as 
deter mi ne d b y t he i n vesti gat or base d o n a detaile d me dical hist or y, f ull p h ysical 
e xa mi nati o n, vital si g ns assess me nts, 1 2- lea d E C G, a n d cli nical la b orat or y tests. 
Partici pa nts wit h mil d, c hr o nic, sta ble disease (e g, c o ntr olle d h y perte nsi o n, n o n -
i ns uli n de pe n de nt dia betes, oste oart hritis) ma y be e nr olle d if dee me d me dicall y 
pr u de nt b y t he i n vesti gat or.  
3.
J a p a nese p artici p a nts o nl y: Partici pa nts e nr olli n g as Ja pa nese m ust ha ve 4 
bi ol o gical Ja pa nese gra n d pare nts w h o were b or n i n Ja pa n.
4.
Partici pa nts w h o are willi n g t o a v oi d direct s u nli g ht e x p os ure or a n y hi g h i nte nsit y 
ultra vi olet li g ht e x p os ure fr o m a d missi o n t o t he f oll o w- u p c o ntact a n d t o a p pl y  
s u nscree n/l oti o n wit h a hi g h s u n pr otecti o n fact or a n d t o wear e ye pr otecti o n , as 
a p pr o priate.
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, lifest yle c o nsi derati o ns, a n d ot her st u d y pr oce d ures.
Wei g ht:
6.
B MI of 1 7. 5 t o 2 8. 5 k g/ m 2; a n d a t otal b o d y wei g ht > 5 0 k g ( 1 1 0 l b).
F or o pti o n al c o h ort of ol der a d ult p artici p a nts o nl y: B MI of 1 7. 5 t o 3 2 . 4 k g/ m 2; 
a n d a t otal b o d y wei g ht > 5 0 k g ( 1 1 0 l bs). Eff orts will be ma de t o e nr oll at least 
3 ol der a d ult partici pa nts wit h B MI < 2 5 k g/ m 2, if feasi ble.
I nf or me d C o nse nt:
7.
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 restricti o ns liste d i n t he IC D a n d i n 
t his pr ot oc ol.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 0
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 n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns:
1.
E vi de nce or hist or y  of cli nicall y si g nifica nt he mat ol o gical, re nal, e n d ocri ne
(i ncl u di n g, b ut n ot li mite d t o, t h yr oi d disease, dia betes i nsi pi d us) , p ul m o nar y, 
gastr oi ntesti nal, car di o vasc ular, he patic, ps y c hiatric (i ncl u di n g, b ut n ot li mite d t o, 
pri mar y  p ol ydi psia, o bsessi ve c o m p ulsi ve dis or der, a n xiet y  dis or der, sc hiz o p hre nia), 
ne ur ol o gic al (i ncl u di n g, b ut n ot li mite d t o, seiz ure dis or der, tra u matic brai n i nj ur y), 
i m m u n o deficie nc y (i ncl u di n g, b ut n ot li mite d t o, se vere i nfecti o n t hat re q uire d I C U 
a d missi o n, pr ol o n ge d h os pitalizati o n , or pr ol o n ge d treat me nt) or aller gic disease 
(i ncl u di n g dr u g aller gies, b ut e xcl u di n g u ntreate d, as ym pt o matic, seas o nal aller gies at 
t he ti me of d osi n g), as well as prese nce of cli nical la b orat or y a b n or malities defi ne d i n 
E xcl usi o n Criteri o n # 1 9 bel o w .
F or o pti o n al c o h ort of ol der a d ult p artici p a nts o nl y: Partici pa nts wit h c hr o nic 
c o n diti o ns ( e g, h yperte nsi o n) t hat are c o ntr olle d b y  eit her diet or sta ble d oses of 
me dicati o ns ma y  be i ncl u de d. See Secti o n 6. 8 f or f urt her i nf or mati o n o n c o nc o mita nt 
me dicati o ns . Rece nt e vi de nce (ie, wit hi n pre vi o us 6 m o nt hs) or hist or y  of u nsta ble 
disease or m o derate t o se vere c o n diti o ns w hic h w o ul d, i n t he i n vesti gat or’s o pi ni o n, 
i nterfere wit h t he st u d y e val uati o ns or ha ve a n i m pact o n t he safety of partici pa nts .
2.
Hist or y  of sy m pt o matic ort h ostatic h y p ote nsi o n.
3.
H ist or y of s ym pt o matic bra d y car dia.
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, bariatric s ur ger y , gastrect o m y , 
c h olec ystect o my).
5.
Hist or y  of p h ot ot o xicit y  or p h ot ose nsiti vit y.
6.
Hist or y  of HI V i nfecti o n, he patitis B, or he patitis C; p ositi ve testi n g f or HI V,
he patitis B s urface a nti ge n ( H Bs A g), he patitis B c ore a nti b o d y ( H Bc A b) or he patitis 
C a nti b o d y  ( H C V A b). He patitis B vacci nati o n is all o we d. As a n e xce pti o n a p ositi ve 
H Bs A b test d ue t o he patitis B vacci nati o n is per missi ble.
7.
Hist or y  of eati n g dis or ders (eg, a n ore xia ner v osa, b uli mia ner v osa , bi n ge-eati n g 
dis or der , a v oi da nt/restricti ve f o o d i nta ke dis or der).
8.
Part A o nl y : F or partici pa nts w h o a ns wer “ Yes” t he C- S S R S q uesti o ns 4 or 5, a ris k 
assess me nt s h o ul d be d o ne b y a q ualifie d M H P (ie, a ps yc hiatrist or lice nse d P h D 
le vel cli nical psyc h ol o gist) t o assess w het her it is safe f or t he partici pa nt t o partici pate 
i n t he st u d y. I n a d diti o n, partici pa nts dee me d b y  t he i n vesti gat or t o be at si g nifica nt 
ris k of s uici dal or vi ole nt be ha vi or s h o ul d be e xcl u de d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 1
9.
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, or ot her c o n diti o ns or 
sit uati o ns relate d t o t he C O VI D -1 9 pa n de mic (e g , c o ntact wit h p ositi ve case, 
resi de nce, or tra vel t o a n area wit h hi g h i nci de nce) t hat ma y i ncrease t he ris k of st u d y 
partici 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 0. Use of prescri pti o n or n o n prescri pti o n dr u gs a n d dietar y  an d her bal s u p ple me nts 
wit hi n 7 da y s or 5 half -li ves ( w hic he ver is l o n ger) pri or t o t he first d ose of st u d y 
i nter ve nti o n. Refer t o Secti o n 6. 8 f or a d diti o nal details.
F or o pti o n al c o h ort of ol der a d ult p artici p a nts o nl y : 

Partici pa nts ta ki n g dail y  prescri pti o n or n o n-prescri pti o n me dicati o ns (t hat are n ot 
m o derate or str o n g C Y P 3 A i n d ucers or i n hi bit ors) f or ma na ge me nt of acce pta ble 
c hr o nic me dical c o n diti o ns are t o be o n a sta ble d ose, as defi ne d b y n o c ha n ge i n 
d ose f or t he 2 8 da y s or 5 half-li ves ( w hic he ver is l o n ger) bef ore t he scree ni n g 
visit .

Use of sta ble c o nc o mita nt me diati o ns n ote d a b o ve t hat are C Y P 3 A s u bstrates
ma y  be restricte d. Refer t o Secti o n 6. 8. 1 f or restricti o ns re gar di n g use of 
C Y P 3 A s u bstrates .

All me dicati o ns m ust be re vie we d o n a case -b y -case basis b y t he i n vesti gat or a n d 
a p pr o ve d b y t he sp o ns or d uri n g t he scree ni n g peri o d f or eli gi bi lit y p ur p oses.
1 1. Use of m o derate or str o n g C Y P 3 A i n hi bit ors or i n d ucers wit hi n 2 8 da ys or 
5 half -li ves ( w hic he ver is l o n ger) pri or t o Scree ni n g . Refer t o Secti o n 6. 8 f or 
a d diti o nal details.
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce:
1 2. Pre vi o us a d mi nistrati o n wit h a n i n vesti gati o nal dr u g wit hi n 3 0 d a y s ( or as deter mi ne d 
b y  t he l ocal re q uire me nt) or 5 halfli v es 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).
Di a g n ostic Assess me nts:
1 3. A p ositi ve uri ne dr u g test at S cree ni n g ( Parts A a n d B), D a y  - 2 ( Part A), or Da y - 1 
( Part B).
1 4. Scree ni n g s u pi ne B P ≥1 4 0 m m H g (s ys t olic) or ≥9 0 m m H g ( diast olic), f oll o wi n g at 
least 5 mi n utes of s u pi ne rest. If B P is ≥1 4 0 m m H g (s ys t olic) or ≥9 0 m m H g 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 2
( diast olic), t he B P s h o ul d be re peate d 2 m ore ti mes a n d t he a vera ge of t he 3 B P 
val ues s h o ul d be use d t o deter mi ne t he partici pa nt’s eli gi bilit y .
1 5. Scree ni n g s u pi ne bl o o d press ure val ues < 9 0 m m H g (s yst olic) or < 5 0 m m H g 
(diast olic ) f oll o wi n g at least 5 mi n utes of rest . If B P is < 9 0 m m H g (sys t olic) or 
< 5 0 m m H g ( diast olic), t he B P s h o ul d be re peate d 2 m ore ti mes a n d t he a vera ge of t he 
3 B P val ues s h o ul d be use d t o deter mi ne t he partici pa nt’s eli gi bilit y .
1 6. E vi de nce of ort h ostatic h y p ote nsi o n at scree ni n g visit, defi ne d as a decrease of 
≥2 0 m m H g i n s y st olic bl o o d press ure a n d/ or ≥1 0 m m H g i n diast olic bl o o d press ure 
2 mi n utes after sta n di n g fr o m a s u pi ne p o siti o n.
1 7. A heart rate of < 4 5 b p m o n baseli ne sta n dar d 1 2 -lea d E C G perf or me d at scree ni n g 
visit .
1 8. Baseli ne sta n dar d 1 2- lea d E C G t hat de m o nstrates cli nicall y rele va nt a b n or malities t hat 
ma y
affect partici pa nt safet y or i nter pretati o n of st u d y res ults (e g, baseli ne Q Tc F
i nter val > 4 5 0 msec,
c o m plete L B B B, si g ns of a n ac ute or i n deter mi nate- a ge 
m y ocar dial i nfarcti o n, S T-T i nter val c ha n ges s u g gesti ve of m y ocar dial isc he mia, 
sec o n d- or t hir d -de gree A V bl oc k, or seri o us bra d y arr h yt h mias or tac h yarr h yt h mias). 
If the baseli ne u nc orrecte d Q T i nter val is > 4 5 0 msec, t his i nter val s h o ul d be 
rate-c orrecte d usi n g t he Fri dericia met h o d a n d t he res ulti n g Q Tc F s h o ul d be use d f or 
decisi o n ma ki n g a n d re p orti n g. If Q TcF e xcee ds 4 5 0 msec, or Q R S e xcee ds 
1 2 0 msec, t he E C G s h o ul d be re peate d 2 m ore ti mes a n d t he a vera ge of t he 3 Q Tc F or 
Q R S val ues s h o ul d be use d t o deter mi ne t he partici pa nt’s eli gi bilit y . 
C o m p uter -i nter prete d E C Gs s h o ul d be o verrea d by a p h ysicia n e x perie nce d i n 
rea di n g E C Gs bef ore e xcl u di n g a partici pa nt.
1 9. Partici pa nts wit h A N Y of t he f oll o wi n g a b n or malities i n cli nical la b orat or y  tests at 
scree ni n g, as assesse d by t he st u d ys pecific la b orat or y a n d c o nfir me d b y a si n gle 
re peat test, if dee me d necessar y: 

A S T or A L T le vel ≥1. 2 5 × U L N;

T otal bilir u bi n le vel ≥1. 5 × U L N; partici pa nts wit h a hist or y of Gil bert's s y n dr o me 
ma y  ha ve direct bilir u bi n meas ure d a n d w o ul d be eli gi ble f or t his st u d y pr o vi de d 
t he direct bilir u bi n le vel is ≤U L N;

e G F R < 8 1 m L / mi n/ 1.7 3 m 2 (< 6 0 m L / mi n/ 1. 7 3 m2 f or o pti o nal c o h ort of ol der a d ult 
part ici pa nts o nl y);

Fasti n g ser u m t ri glyceri des > 2 × U L N .
2 0. P ositi ve test res ult b y  P C R f or S A R S-C o V -2 i nfecti o n at t he ti me of Scree ni n g 
( Parts A a n d B), Da y  -2 ( Part A), or Da y  -1 ( Part B). 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 3
Ot her E xcl usi o ns:
2 1. Hist or y  of alc o h ol a b use or bi n ge dri n ki n g a n d/ or a n y ot her illicit dr u g use or 
de pe n de nce wit hi n 6 m o nt hs of Scree ni n g. Bi n ge dri n ki n g is defi ne d as a patter n of 
5 ( male) a n d 4 (fe male) or m ore alc o h olic dri n ks i n a b o ut 2 h o urs . As a ge neral r ule, 
alc o h ol i nta ke s h o ul d n ot e xcee d 1 4 u nits per wee k ( 1 u nit = 8 o u nces ( 2 4 0 m L ) beer, 
1 o u nce ( 3 0 m L ) of 4 0 % s pirit or 3 o u nces ( 9 0 m L) of wi ne).
2 2. Use of t o bacc o or nic oti ne c o ntai ni n g pr o d ucts i n e xcess of t he e q ui vale nt of 
5 ci garettes/ da y or 2 c he ws of t o bacc o/ da y.
2 3. Bl o o d d o nati o n (e xcl u di n g plas ma d o nati o ns) of a p pr o xi matel y 1 pi nt ( 5 0 0 m L ) or 
m ore wit hi n 6 0 da y s pri or t o d osi n g.
2 4. Hist or y  of se nsiti vit y t o he pari n or he pari n-i n d uce d t hr o m b oc yt o pe nia.
2 5. Part B o nl y: Partici pa nts w h o ha ve a hist or y  of se nsiti vit y reacti o ns t o mi daz ola m, or 
w h o acc or di n g t o t he pr o d uct la bel f or mi daz ola m w o ul d be at i ncrease d ris k if d ose d 
wit h mi daz ola m (ie, i ncl u di n g b ut n ot li mite d t o partici pa nts wit h a hist or y  of 
m y ast he nia gra vis or te n di nitis/te n d o n r u pt ure).
2 6. U n willi n g or u na ble t o c o m pl y  wit h t he criteria i n t he Li fest yle C o nsi derati o ns
secti o n of t his pr ot oc ol.
2 7. Acti vel y  f oll o wi n g a cal orie-restricte d diet f or p ur p oses of i nte nti o nal wei g ht l oss. 
2 8. 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. Lifest yle C o nsi der ati o ns
T he f oll o wi n g g ui deli nes are pr o vi de d:
5. 3. 1. 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 or st u d y  i nter ve nti o n 
a d mi nistrati o n ) at least 1 2 h o urs pri or t o a ny safet y la b orat or y  e val uati o ns.

Part A: O n Da y s 1 a n d 1 4 (serial P K sa m pli n g da ys), partici pa nts will a bstai n fr o m all 
f o o d a n d dri n k (e xce pt water or st u d y  i nter ve nti o n a d mi nistrati o n ) f or at least 
1 2 h o urs o ver ni g ht pri or t o m or ni n g d osi n g. Water is per mitte d u ntil 1
h o ur pri or t o 
m or ni n g st u d y i nter ve nti o n a d mi nistrati o n. Water ma y  be c o ns u me d wit h o ut 
restricti o n be gi n ni n g 1 h o ur after m or ni n g d osi n g. F o o d ma y  be c o ns u me d be gi n ni n g 
4 h o urs after m or ni n g d osi n g.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 4

T here are n o f o o d or dri n k restricti o ns ( ot her t ha n t h ose descri be d bel o w) f or 
after n o o n/e ve ni n g d osi n g or f or d osi n g o n ot her da y s i n Part A, wit h t he e xce pti o n 
of 1 2 h o ur fasti n g (e xce pt water or st u dy i nter ve nti o n a d mi nistrati o n) o n D a ys 2, 
4, 7, a n d 1 0 i n w hic h safet y la b orat or y e val uati o ns are c o n d ucte d.

Part B: 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 or st u d y  
i nter ve nti o n a d mi nistrati o n) f or at least 1 2 h o urs pri or t o m or ni n g d osi n g wit h 
mi daz ola m o n Da y  1 of Peri o d 1 a n d t he da ys i n w hic h mi daz ola m is c o-a d mi nistere d 
wit h P F -0 7 2 5 8 6 6 9 ( Da y  2 a n d Da y 1 0 of Peri o d 2). Water is per mitte d u ntil 1
h o ur 
pri or t o mi daz ola m a d mi nistrati o n. Water ma y  be c o ns u me d wit h o ut restricti o n 
be gi n ni n g 1 h o ur after mi daz ola m d osi n g. F o o d ma y  be c o ns u me d be gi n ni n g 4 h o urs 
after m or ni n g d osi n g o n Da y 1 of P eri o d 1 a n d t he m or ni n g d osi n g o n da ys i n w hic h 
mi daz ola m is c o -a d mi nistere d wit h P F-0 7 2 5 8 6 6 9 ( Da y 2 a n d Da y 1 0 of Peri o d 2). 
T here are n o f o o d or dri n k restricti o ns ( ot her t ha n t h ose descri be d bel o w) f or all d oses 
a n d ot her da y s of Part B, wit h t he e xce pti o n of 1 2 h o ur fasti n g (e xce pt water or st u d y 
i nter ve nti o n a d mi nistrati o n) o n Da y  2 of Peri o d 1 a n d Da y s 2, 4, 7, 1 0 , a n d 1 1 i n 
w hic h safet y la b orat or y  e val uati o ns are c o n d ucte d, pr o vi de d ot her restricti o ns are 
f oll o we d.

N o nca ffei nate d dri n ks (e xce pt gra pefr uit or gra pefr uit-relate d citr us fr uit j uices; see 
bel o w) ma y  be c o ns u me d wit h meals a n d s nac ks.

Partici pa nts will refrai n fr o m c o ns u mi n g re d wi ne, gra pefr uit, or gra pefr uit -relate d 
citr us fr uits (e g, Se ville ora n ges, p o mel o s, fr uit j uices) fr o m 7 d a y s pri or t o t he first 
d ose of st u d y  i nter ve nti o n u ntil c ollecti o n of t he fi nal P K bl o o d sa m ple. 

L u nc h will be pr o vi de d a p pr o xi matel y  4 h o urs after m or ni n g d osi n g.

Di n ner will be pr o vi de d a p pr o xi matel y  9 t o 1 0 h o urs after m o r ni n g d osi n g.

C o h orts will be all ocate d t o 1 of 3 diets as f oll o ws:
Diet
D ail y kc al L i mit
F at
Pr otei n
C ar b o h y dr ate
Sta n dar d
< 3 2 0 0
3 0 % 
1 5 %
5 5 %
H C H C
N o li mit
3 0 % 
1 5 %
5 5 %
H F H C
< 4 5 0 0
5 5 % 
1 5 %
3 0 %
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 5
Refer t o Secti o n 1. 2 f or dietar y all ocati o n t o pla n ne d c o h orts. 
A d diti o nal c o h orts ma y be a d de d t o a n y dietar y all ocati o n as nee de d.

All partici pa nts e nr olle d i n a gi ve n c o h ort will ha ve t he sa me dietar y all ocati o n. T he 
decisi o n re gar di n g dietar y all ocati o n will be c o m m u nicate d t o C R U pri or t o 
a d missi o n of t he c o h ort, a n d C R U staff will i nf or m partici pa nts of dietar y  all ocati o n. 

F or st a n d ar d diet , mai n meals w ill be c o nstr ucte d t o yiel d a t otal daily n utriti o nal 
c o m p ositi o n of a p pr o xi matel y 5 5 % car b o h y drate, 3 0 % fat, a n d 1 5 % pr otei n . T he 
dail y  cal oric i nta ke per partici pa nt s h o ul d n ot e xcee d a p pr o xi matel y 3 2 0 0 kcal, as per 
sta n dar d C R U pr oce d ure f or P hase 1 st u dies i n healt h y  partici pa nts. Sec o n d hel pi n gs 
at meal ti mes will n ot be offere d , a n d s nac ks will be li mite d i n kee pi n g wit h dail y  
cal orie li mit. T he n utriti o nal c o m p ositi o n of s nac ks will be fle xi ble t o cater t o 
partici pa nt prefere nces.

F or H C H C diet , mai n meals will be c o nstr ucte d t o y iel d a t otal dail y n utriti o nal 
c o m p ositi o n of a p pr o xi matel y 5 5 % car b o h y drate, 3 0 % fat, a n d 1 5 % pr otei n.
Partici pa nts will be pr o vi de d wit h a mi ni m u m of a p pr o xi matel y  3 2 0 0 kcal per da y , 
wit h o ut a n y ma xi m u m dail y  cal orie li mit. Partici pa nts will be offere d sec o n d hel pi n gs 
at meal ti mes a n d s u p ple me ntal s nac ks bet wee n meals a n d after di n ner. T he 
n utriti o nal c o m p ositi o n of s nac ks will be fle xi ble t o cater t o partici pa nt prefere nces.

F or H F H C diet , mai n meals will be c o nstr ucte d t o y iel d a t otal dail y n utriti o nal 
c o m p ositi o n of a p pr o xi matel y 3 0 % car b o h ydrate, 5 5 % fat, a n d 1 5 % pr otei n. D ail y 
cal orie i nta ke per partici pa nt s h o ul d n ot e xcee d a p pr o xi matel y 4 5 0 0 kcal. T his
macr o n utrie nt brea k d o w n a n d dail y  calorie li mit is i nf or me d b y  p u blis he d data fr o m 
healt h y  male partici pa nts resi de nt i n a C R U t hat de m o nstrate t olera bilit y wit h o ut 
preci pitati n g a b n or malities i n ke y  la b orat or y para meters (e g , L F Ts) .3 2 S ec o n d 
hel pi n gs at meal ti mes a n d s u p ple me ntal s nac ks bet wee n meals a n d after di n ner will 
be a vaila ble f or partici pa nts u p o n re q uest . T he n utriti o nal c o m p ositi o n of s nac ks 
a vaila ble t o partici pa nts f oll o wi n g H F H C diet will offer a hi g her fat t ha n 
car b o h y drate c o nte nt.

Partici pa nts are n ot re q uire d t o acce pt, c o ns u me, or c o m plete f o o d offeri n gs.

Me n u c h oices, p orti o n sizes, a n d access t o sec o n d hel pi n gs a n d s u p ple me nt s nac ks 
will be c o nsiste nt acr oss c o h orts all ocate d t o t he sa me diet as m uc h as feasi ble.

Partici pa nts will eat se paratel y fr o m partici pa nts of ot her si m ulta ne o us st u dies as 
m uc h as is feasi ble.
5. 3. 2. C affei ne, Alc o h ol, a n d T o b acc o

Partici pa nt s will a bstai n fr o m caffei ne-c o ntai ni n g pr o d ucts f or 2 4 h o urs pri or t o t he 
start of d osi n g u ntil c ollecti o n of t he fi nal P K sa m ple of eac h st u d y  peri o d. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 6

Partici pa nt s will a bstai n fr o m alc o h ol f or 2 4 h o urs pri or ( or as s pecifie d a b o ve f or re d 
wi ne) t o a d missi o n t o t he C R U a n d c o nti n ue a bstai ni n g fr o m alc o h ol u ntil c ollecti o n 
of t he fi nal P K sa m ple of eac h st u d y peri o d. Partici pa nt s ma y u n der g o a n alc o h ol 
breat h test or bl o o d alc o h ol test at t he discreti o n of t he i n vesti gat or.

Partici pa nt s will a bstai n fr o m t he use of t o bacc o- or nic oti ne -c o ntai ni n g pr o d ucts f or 
2 4 h o urs pri or t o d osi n g a n d d uri n g c o nfi ne me nt i n t he C R U.
5. 3. 3. Acti vit y

Partici pa nts will a bstai n fr o m stre n u o us e xercise (e g, hea v y lifti n g, wei g ht trai ni n g, 
calist he nics, aer o bics) f or at least 4 8 h o urs pri or t o eac h bl o o d c ollecti o n f or cli nical 
la b orat or y tests. Wal ki n g at a n or mal pace will be per mitte d.

I n or der t o sta n dar dize t he c o n diti o ns o n serial P K sa m pli n g da y s (Part A – D a ys 1 
a n d 1 4; Part B – Peri o d 1/ Da y  1 a n d Peri o d 2/ Da ys 2 a n d 1 0), partici pa nts will be 
re q uire d t o refrai n fr o m l yi n g d o w n (e xce pt w he n re q uire d f or B P, P R, R R, a n d E C G 
meas ure me nts) f or first 4 h o urs after m or ni n g d ose, a n d ma y  be re q uire d t o f oll o w 
meals a n d dietar y  restricti o ns.  

I n Part A o nl y, partici pa nts will be c o nfi ne d t o t he pr oce d ure r o o m f or t he first 
4 h o urs after d osi n g o n Da y s 1, 7, a n d 1 4 d uri n g c o nti n u o us car diac m o nit ori n g, 
e xce pt t o use t he bat hr o o m. After t his, if t he e q ui p me nt set u p all o ws, partici pa nts ma y  
be a m b ulat or y  d uri n g t he E C G m o nit ori n g peri o d, b ut s h o ul d n ot e n ga ge i n stre n u o us 
acti vities. 

Partici pa nts will be a d vise d t o a v oi d direct s u nli g ht e x p os ure or a n y  hi g h i nte nsit y 
ultra vi olet li g ht e x p os ure, fr o m a d missi o n t hr o u g h t he o nsite f oll o w-u p visit. I n 
a d diti o n, participa nts will be i nstr ucte d t o a p pl y s u n crea m/l oti o n wit h a hi g h s u n 
pr otecti o n fact or of ≥5 0 a n d t o use e ye pr otecti o n , as a p pr o priate.
5. 3. 4. D ail y Me dic ati o n (O pti o n al C o h ort of O l der P artici p a nts O nl y )
Ol der partici pa nts s h o ul d c o nti n ue t o ta ke t heir per mitte d dail y  prescri pti o n or n o n -
prescri pti o n me dicati o ns at a p pr o xi matel y  t he sa me ti me eac h da y d uri n g t he st u d y. T hese 
partici pa nts m ust be esta blis he d o n a sta ble d ose of all per mitte d me dicati o ns , as defi ne d by 
n o c ha n ge i n d ose or d ose re gi me n f or t he 2 8 da ys or 5 half-li ves ( w hic he ver is l o n ger) 
bef ore t he scree ni n g visit.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 7
5. 3. 5. 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 partici pa nt , 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 
partici pa nt a n d his or her part ner(s) fr o m t he per mitte d list of c o ntrace pti o n met h o ds (see 
Secti o n 1 0. 4. 4 ) an 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 sc he d ule of acti vities (S o A ), 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 nt s 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 sel ecte d met h o ds of c o ntrace pti o n) c o nsi deri n g t hat t heir ris k f or pre g na nc y  ma y 
ha ve c ha n ge d si nce t he last visit . In 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 ued 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. 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 nr olle d i n t he st u d y. Scree n 
fail ure data are c ollecte d a n d re mai n as s o urce a n d are n ot re p orte d o n t he C R F .
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y be 
rescree ne d if t he pri or reas o n(s) f or n ot meeti n g t he eli gibilit y  criteria ha ve bee n res ol ve d. 
6. S T U D Y I N T E R V E N TI O N S( S) A N D C O N C O MI T A N T T H E R A P Y
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 P F - 0 7 2 5 8 6 6 9, place b o f or 
P F - 0 7 2 5 8 6 6 9, or mi daz ola m.
6. 1. St u d y I nter ve nti o n(s) A d mi nistere d
P F -0 7 2 5 8 6 6 9 a n d matc hi n g place b o will be s u p plie d as ta blets t o t he C R U i n b ul k al o n g wit h 
i n di vi d ual d osi n g c o ntai ners f or u nit d osi n g. Ta blets will be pr o vi de d i n stre n gt hs of 1 m g , 
5 m g, 2 5 m g, a n d 1 0 0 m g. 
P F - 0 7 2 5 8 6 6 9 a n d matc hi n g place b o will be prese nte d t o t he partici pa nts i n i n di vi d ual d osi n g 
c o ntai ners.
F or P art B, c o m merciall y-a vaila ble m i daz ola m oral s ol uti o n ( 2 m g/ m L, 3 0 m L) will be 
pr o vi de d t o t he C R U .
6. 1. 1. A d mi nistr ati o n
A d mi nistrati o n of st u d y  i nter ve nti o n will occ ur u n der t he c o n diti o ns descri be d i n t he Meals 
a n d Dietar y Restricti o ns i n Secti o n 5. 3. 1 .
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 8
I n or der t o sta n dar dize t he c o n diti o ns o n serial P K sa m pli n g da y s ( Part A – Da y s 1 a n d 1 4; 
Part B – Peri o d 1/ Da y  1 a n d Peri o d 2/ Da ys 2 a n d 1 0), all partici pa nts will be re q uire d t o 
refrai n fr o m lyi n g d o w n (e xce pt w he n re q uire d f or B P, P R , R R, a n d E C G mea s ure me nts), 
eati n g, a n d dri n ki n g be vera ges ot her t ha n water d uri n g t he first 4 h o urs after t he m or ni n g 
d osi n g.

Part A : Partici pa nt s will recei ve st u d y i nter ve nti o n at a p pr o xi matel y 0 8: 0 0 h o urs 
( ± 2 h o urs ) fr o m Da y 1 t o t he m or ni n g of Da y 1 4. O n d a y s of serial P K sa m pli n g 
(ie, D a y s 1 a n d 1 4), partici pa nts will a bstai n fr o m all f o o d a n d dri n k (e xce pt water or 
st u d y i nter ve nti o n a d mi nistrati o n) f or at least 1 2 h o urs o ver ni g ht pri or t o m or ni n g 
d osi n g . I n vesti gat or site pers o n nel will a d mi nister st u d y i nter venti o n d uri n g eac h 
peri o d wit h a m bie nt te m perat ure water t o a t otal v ol u me of a p pr o xi matel y 2 4 0 m L . 
Partici pa nt s 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 d diti o nal water ( u p t o 1 0 0 m L ) 
ma y  be c o ns u me d b y t he partici pa nts (e g, e xtra ri nse) i n a n atte m pt t o e ns ure t hat t he 
f ull d ose is c o ns u me d.
F or o pti o n al c o h ort of ol der p artici p a nts o nl y: Healt h y ol der partici pa nts s h o ul d 
c o nti n ue t o ta ke t heir per mitte d dail y  prescri pti o n or n o n- prescri pti o n me dicati o ns at 
a p pr o xi matel y t he sa me ti me eac h da y d uri n g t he st u d y. O n da ys of de nse P K 
sa m pli n g ( m or ni n g d osi n g o n Da y 1 a n d Da y 1 4), a d mi nistrati o n of c o nc o mita nt 
me dicati o ns s h o ul d occ ur at least 1 - 2 h o urs pri or t o m or ni n g d osi n g of P F - 0 7 2 5 8 6 6 9 
or wit h hel d u ntil 4 h o urs after m or ni n g d osi n g of P F -0 7 2 5 8 6 6 9. T here are n o 
restricti o ns o n ot her da ys of t he st u d y.

Part B: I n Peri o d 1, f oll o wi n g a n o ver ni g ht fast of at least 1 2 h o urs, partici pa nts will 
recei ve mi daz ola m at a p pr o xi matel y 0 8: 0 0 h o urs ( ± 2 h o urs), f oll o we d b y i nta ke of 
5 0 m L  of a m bie nt te m perat ure water. A d diti o nal water ( u p t o 1 0 0 m L) ma y  be 
c o ns u me d b y t he partici pa nts (e g, e xtra ri nse) i n a n atte m pt t o e ns ure t hat t he f ull 
d ose is c o ns u me d.
T he d osi n g re gi me n f or P F- 0 7 2 5 8 6 6 9 t o be use d i n Peri o d 2 will be base d o n t he 
res ults of Part A of t his st u d y. I n Peri o d 2, t he first d ose of P F - 0 7 2 5 8 6 6 9 will be 
a d mi nistere d at 0 8: 0 0 h o urs (± 2 h o urs ) o n Da y  1. P F -0 7 2 5 8 6 6 9 d osi n g will c o nti n ue 
fr o m Da y 1 t hr o u g h D a y  1 0. In vesti gat or site pers o n nel will pr o vi de P F- 0 7 2 5 8 6 6 9 t o 
t he partici pa nt wit h a m bie nt te m perat ure water t o a t otal v ol u me of a p pr o xi matel y  
2 4 0 m L . Partici pa nts will s wall o w t he ta blets w h ole a n d will n ot ma ni p ulate or c he w 
t he ta blets pri or t o s wall o wi n g. A d diti o nal water ( u p t o 1 0 0 m L ) m a y  be c o ns u me d b y 
t he partici pa nts (e g, e xtra ri nse) i n a n atte m pt t o e ns ure t hat t he f ull d ose is c o ns u me d. 
O n t he da y s of c o -a d mi nistrati o n of mi daz ola m a n d P F - 0 7 2 5 8 6 6 9 i n Part B ( Da y 2 
a n d Da y 1 0): Foll o wi n g a n o ver ni g ht fast of at least 1 2 h o urs (e xce pt water or st u d y 
i nter ve nti o n a d mi nistrati o n), P F - 0 7 2 5 8 6 6 9 will be a d mi nistere d t o partici pa nts at 
a p pr o xi matel y 0 8: 0 0 h o urs ( ± 2 h o urs) wit h a m bie nt te m perat ure water t o a t otal 
v ol u me of a p pr o xi matel y 2 4 0 m L  a n d will be f oll o we d b y t he a d mi nistrati o n of 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 5 9
mi daz ola m wit hi n 5 mi n utes w hic h will be f oll o we d b y  i nta ke of 5 0 m L of a m bie nt 
te m perat ure water. A d diti o nal water ( u p t o 1 0 0 m L) ma y  be c o ns u me d b y t he 
partici pa nts (e g, e xtra ri nse) i n a n atte m pt t o e ns ure t hat t he f ull d oses of 
P F - 0 7 2 5 8 6 6 9 a n d mi daz ola m are c o ns u me d o n da y s of c o-a d mi nistrati o n .
6. 2. Pre p ar ati o n , H a n dli n g , St or a ge , a n d 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 d y  i nter ve nti o n. 
2.
O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y inter 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) area 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 y s m ust 
i n dicate t he mini 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 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 pro 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 I P ma n ual a n d C R U site pr oce d ures .
4.
A n y  st ora ge c o n diti ons 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.
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 nte r ve nti o n acc o u nta bility f or m/rec or d.
7.
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 C R U’s site pr oce d ures a n d I P ma n ual. All 
destr ucti o n m ust 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 y e d i n 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 0
c o m plia nce wit h a p plica ble e n vir o n me ntal re g ulati o ns, i nstit uti o nal p olic y , a n d a n y 
s pecial i nstr ucti 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
Wit hi n t his pr ot oc ol, pre parati o n refers t o t he i n vesti gat or site acti vities perf or me d t o ma ke 
t he st u d y i nter ve nti o n rea d y f or a d mi nistrati o n or dis pe nsi n g t o t he partici pa nt b y  q ualifie d 
staff. Dis pe nsi n g is defi ne d as t he pr o visi o n of st u d y i nter ve nti o n, c o nc o mita nt treat me nts, 
a n d acc o m pa n yi n g i nf or mati o n b y  q ualifie d staff me m ber(s) t o a healt hcare pr o vi der, 
partici pa nt i n acc or da nce wit h t his pr ot oc ol. Local healt h a ut h orit y  re g ulati o ns or i n vesti gat or 
site g ui deli nes ma y use alter nati ve ter ms f or t hese acti vities.
P F -0 7 2 5 8 6 6 9 a n d matc hi n g place b o t a blets will be pre pare d at t he C R U i n t he i n di vi d ual 
d osi n g c o ntai ners b y 2 o perat ors, 1 of w h o m is a n a p pr o priatel y q ualifie d a n d e x perie nce d 
me m ber of t he st u d y staff (e g, p h ys icia n, n urse, p h ysicia n’s assista nt, n urse practiti o ner, 
p har mac y  assista nt/tec h nicia n, or p har macist). T he ta blets will be pr o vi de d i n u nit d ose 
c o ntai ners a n d la bele d i n acc or da nce wit h Pfizer re g ulati o ns a n d t he cli nical site’s la beli n g 
re q uire me nts. See t he I P Ma n ual a n d/ or C R U's site pr oce d ure f or i nstr ucti o ns o n h o w t o 
pre pare t he st u d y i nter ve nti o n f or a d mi nistrati o n .
Mi daz ola m (2 m g/ m L  oral s ol uti o n) will be pre pare d a n d dis pe nse d at t he C R U i n t he 
i n di vi d ual oral s yri n ges b y 2 o perat ors, 1 of w h o m is a n a p pr o priately q ualifie d a n d 
e x perie nce d me m ber of t he st u d y  staff (e g, p h ysicia n, n urse, p h ysicia n’s assista nt, n urse 
practiti o ner, p har mac y assista nt/tec h nicia n, or p har macist) as all o we d b y  l ocal, state a n d 
i nstit uti o nal g ui da nce. T he oral s ol uti o n will be pr o vi de d i n u nit d ose oral s yri n ges a n d 
la bele d i n acc or da nce wit h Pfizer re g ulati o ns a n d t he cli nical site’s la beli n g re q uire me nts. 
C R U staff s h o ul d refer t o t he S m P C o n h o w t o pre pare mi daz ola m f or a d mi nistrati o n t o 
partici pa nts.
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
T he i n vesti gat or will assi g n partici pa nt n u m bers t o t he partici pa nt s as t he y are scree ne d f or 
t he st u d y. Pfizer will pr o vi de a ra n d o mizati o n sc he d ule t o t he i n vesti gat or a n d, i n acc or da nce 
wit h t he ra n d o mizati o n n u m bers, t he partici pa nt will recei ve t he st u d y treat me nt re gi me n 
assi g ne d t o t he c orres p o n di n g ra n d o mizati o n n u m ber.
Partici pa nts will be ra n d o ml y  assi g ne d t o recei ve st u d y i nter ve nti o n fr o m a ce ntral 
ra n d o mizati o n sc he me.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 1
In Part A of t his st u d y , in vesti gat ors a n d partici pa nts will re mai n bli n de d t o eac h 
partici pa nt’s assi g ne d st u d y i nter ve nti o n t hr o u g h o ut t he c o urse of t he st u dy. I n or der t o 
mai ntai n t his bli n d, a n ot her wise u ni n v ol ve d t hir d part y (f or e xa m ple, p har macist) will be 
res p o nsi ble f or t he pre parati o n a n d dis pe nsi n g of all st u d y i nter ve nti o n acc or di n g t o t he 
ra n d o mizati o n sc he d ule a n d assi g ne d treat me nt f or t he i n di vi d ual partici pa nt .
I n Part B of t his st u dy, t he i n vesti gat or’s k n o wle d ge of t he treat me nt s h o ul d n ot i nfl ue nce t he 
decisi o n t o e nr oll a partic ular partici pa nt or affect t he or der i n w hic h partici pa nts are 
e nr olle d.
6. 3. 2. Bre a ki n g t he Bli n d
T he met h o d f or brea ki n g t he bli n d i n t his st u d y  will be ma n ual. 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 c o 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. W he n t he bli n di n g c o de is br o ke n, t he reas o n m ust 
be f ull y  d oc u me nte d i n t he C R F.
Bl o o d s peci me ns will be o btai ne d fr o m all partici pa nts f or P K a nal ys is t o mai ntai n t he st u d y 
bli n d at t he i n vesti gat or site. O nl y  t he i n vesti gat or site staff a n d bli n de d st u d y m o nit or, if 
assi g ne d, will be bli n de d t o st u d y  treat me nt. A li mite d n u m ber of Pfizer st u d y tea m pers o n nel 
will be u n bli n de d t o partici pa nt treat me nts i n or der t o per mit real -ti me i nter pretati o n of t he 
safety a n d P K data a n d pr o vi de i nf or mati o n necessar y  t o p ote ntiall y alter t he d ose-escalati o n 
se q ue nce. T he bli n de d st u d y m o nit or, if assi g ne d, will re mai n bli n de d t o treat me nt u ntil all 
m o nit ori n g f or t he st u d y has bee n c o m plete d. S peci me ns fr o m partici pa nts ra n d o mize d t o 
place b o will n ot be r o uti nel y  a nalyz e d. T o mi ni mize t he p ote ntial f or bias, treat me nt 
ra n d o mizati o n i nf or mati o n will be ke pt c o nfi de ntial b y  Pfizer u n bli n de d pers o n nel a n d will 
n ot be release d t o t he bli n de d i n vesti gat or or bli n de d i n vesti gat or site pers o n nel u ntil t he 
st u d y data base has bee n l oc ke d or t he i n vesti gat or re q uests u n bli n di n g f or safety reas o ns.
6. 4. St u d y I nter ve nti o n C o m pli a nce
W he n t he i n di vi d ual d ose f or a partici pa nt is pre pare d fr o m a b ul k s u p pl y, t he pre parati o n of 
t he d ose will be c o nfir me d b y a sec o n d q ualifie d me m ber of t he st u d y site staff.
W he n partici pa nts are d ose d at t he site, t he y  will recei ve st ud y  i nter ve nti o n directl y fr o m t he 
i n vesti gat or or desi g nee, u n der me dical s u per visi o n. T he date a n d ti me of eac h d ose 
a d mi nistere d i n t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he C R F. 
T he d ose of st u d y i nter ve nti o n a n d st u d y part ici pa nt i de ntificati o n will be c o nfir me d at t he 
ti me of d osi n g by a me m ber of t he st u d y site staff ot her t ha n t he pers o n a d mi nisteri n g t he 
st u d y i nter ve nti o n. St u d y site pers o n nel will e xa mi ne eac h partici pa nt’s m o ut h t o e ns ure t hat 
t he st u d y i nter ve nti o n was i n geste d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 2
6. 5. D ose M o dific ati o n
T he decisi o n t o pr ocee d t o t he ne xt d ose le vel a n d/ or d ose re gi me n of P F -0 7 2 5 8 6 6 9 (e g, a n 
i ncrease, decrease , or re peat of a pre vi o us d ose le vel) will be ma de by t he st u d y tea m a n d t he 
i n vesti gat or base d o n safet y, t olera bilit y, a n d preli mi nar y P K data o btai ne d at t he pri or d ose 
le vel. Wit h t he e xce pti o n s of t he o pti o nal Ja pa nese a n d ol der a d ult c o h orts, at least 
8 partici pa nts (i ncl u di n g at least 1 place b o partici pa nt) m ust c o m plete t he pri or d ose le vel i n 
Part A . Safety, t olera bilit y, a n d P K data t hr o u g h at least 1 4 da y s will be re vie we d.
T he mi daz ola m d ose i n Part B ma y  als o be m o difie d as o utli ne d i n Secti o n 4. 3. 3. 2. 2 . 
T he d osi n g sc he d ule ma y als o be a dj uste d t o e x pa n d a d osi n g c o h ort t o f urt her e val uate 
safety, t olera bility, a n d/ or P K fi n di n gs at a gi ve n d ose le vel or t o a d d c o h orts t o e val uate 
ad diti o nal d ose le vels. T he st u d y  pr oce d ures f or t hese a d diti o nal partici pa nt(s)/c o h ort(s) will 
be t he sa me as t hat descri be d f or ot her st u d y partici pa nts/c o h orts.
6. 5. 1. D ose Esc al ati o n a n d St o p pi n g R ules
Preca uti o nar y  se nti nel d osi n g m a y be e m pl o ye d i n Part A a n d Par t B as descri be d i n 
Secti o n 4. 1. 1 a n d Secti o n 4. 1. 2 , res pecti vely.
D ose escalati o n st o p pi n g r ules will be use d t o deter mi ne w het her t he ma xi mal t olerate d d ose 
has bee n attai ne d. D ose escalati o n ma y  be st o p pe d if it is deter mi ne d t hat t he li mits of safet y 
a n d/ or t olera bilit y ha ve bee n reac he d. T his decisi o n will be ma de after a disc ussi o n ta kes 
place bet wee n t he s p o ns or st u d y  tea m a n d t he i n vesti gat or. T he s p o ns or st u d y tea m ma y n ot 
o verr ule t he i n vesti gat or’s decisi o n t o st o p d ose escalati o n. If d ose escalati o n is st o p pe d 
beca use of a n y of t hese criteria, a d diti o nal c o h orts ma y recei ve t he sa me or l o wer d oses of 
t he st u d y i nter ve nti o n.
T he d ose escalati o n will be ter mi nate d base d o n t he f oll o wi n g criteria:

If 5 0 % or m ore of t he partici pa nt s receivi n g acti ve dr u g at a gi ve n d ose le vel ( b ut n ot 
partici pa nt s recei vi n g place b o) de vel o p si milar cli nicall y si g nifica nt la b orat or y, E C G, 
or vital si g n a b n or malities, i n t he sa me or ga n class, i n dicati n g d ose -li miti n g 
i nt olera nce.

Se vere n o nseri o us A Es , c o nsidere d as, at least, p ossi bl y  relate d t o st u d y i nter ve nti o n
a d mi nistrati o n, i n 2 partici pa nts at a gi ve n d ose le vel ( b ut n ot partici pa nts recei vi n g 
place b o), i n de pe n de nt of wit hi n or n ot wit hi n t he sa me s yste m or ga n class, i n dicati n g 
d ose -li miti n g i nt olera nce.

D osi n g will be pa use d f or a n y S A E t hat occ urs i n a partici pa nt recei vi n g acti ve 
treat me nt u ntil ca usalit y is f ull y assesse d b y t he PI a n d s p o ns or. D osi n g ma y res u me 
if t he S A E is deter mi ne d t o be n ot dr u g-relate d by t he PI a n d s p o ns or. If t he S A E is 
deter mi ne d t o be eit her dr u g-relate d or u n k n o w n, eit her d osi n g will cease or t he S A E 
will be e val uate d b y t he s p o ns or’s pr ot oc ol re vie w c o m mittee ( or si milar re vie w 
gr o u p), w hic h is i n de pe n de nt of t he st u d y  tea m a n d i n vesti gat ors. If t he pr ot oc ol 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 3
revie w c o m mittee deter mi nes t hat d osi n g ma y  res u me, a pla n t hat miti gates ris ks t o 
partici pa nt s wit h t he res u m pti o n of d osi n g will be i m ple me nte d. S uc h a pla n c o ul d 
i ncl u de a re visi o n of i ncl usi o n/e xcl usi o n criteria, re peati n g or re d uci n g t he d ose, or 
a d di n g a p pr o priate safet y m o nit ori n g .

 
D osi n g ma y res u me if t he A E is deter mi ne d t o n ot be dr u g -relate d b y t he 
i n vesti gat or a n d s p o ns or. If t he A E is deter mi ne d t o be eit her dr u g relate d or 
u n k n o w n, eit her d osi n g will cease or t he A E will be e val uate d b y t he s p o ns or’s 
pr ot oc ol re vie w c o m mittee ( or si milar re vie w gr o u p), w hic h is i n de pe n de nt of t he 
st u d y tea m a n d i n vesti gat ors, t o pr o vi de f urt her directi o n.

It is deter mi ne d t hat t he li mit of safet y a n d/ or t olera bilit y has bee n reac he d. T his 
decisi o n will be ma de f oll o wi n g disc ussi o ns bet wee n t he st u d y  tea m a n d t he 
i n vesti gat or.

Ot her fi n di n gs t hat, at t he discreti o n of t he st u d y t ea m a n d i n vesti gat or, i n dicate t hat 
d ose escalati o n s h o ul d be halte d .


If, base d o n t he o bser ve d data, t he gr o u p mea n Cma x or A U C ( base d o n t otal plas ma 
c o nce ntrati o n) of t he ne xt pla n ne d d ose is pr ojecte d t o e xcee d t he escalati o n li mits, 
t hat d ose will n ot be e x pl ore d. M o difie d d oses ma y be e x pl ore d if t he y are n ot 
e x pecte d t o e xcee d P K st o p pi n g criteria.
Pr o gressi o n t o t he ne xt d ose will occ ur if t he last d ose was well t olerate d a n d after 
satisfact or y re vie w of t he a vaila ble safety a n d P K data.
6. 6. C o nti n ue d Access t o St u d y I nter ve nti o n A fter t he E n d of t he St u d y
N o i nter ve nti o n will be pr o v i de d t o st u d y partici pa nts at t he e n d of t heir st u d y partici pati o n.
6. 7. Tre at me nt of O ver d ose
6. 7. 1. O ver d ose of P F -0 7 2 5 8 6 6 9
F or t his st u d y , a n y d ose of P F - 0 7 2 5 8 6 6 9 greater t ha n 2 0 0 0 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.
T here is n o s pecific treat me nt f or a n o ver d ose.
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or or treati n g p hys icia n 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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 4
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 y s after t he o ver d ose of P F - 0 7 2 5 8 6 6 9 ( w hic he ver 
is l o n ger).
3.
D oc u me nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose i n 
t he C R F.
4.
O ver d ose is re p orta ble t o Pfizer Safet y  o nl y w he n ass oci ate d wit h a n S A E .
5.
O btai n a bl o o d sa m ple f or P K a nal ys is wit hi n 5 da ys fr o m t he date of t he last d ose of 
st u d y i nter ve nti o n if re q ueste d b y t he me dical m o nit or ( deter mi ne d o n a case-b y -case 
basis).
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. 
6. 7. 2. O ver d ose of Mi d az ol a m
F or t his st u d y , a n y d ose of mi daz ola m t hat e xcee ds 1 5 m g, or a n y cli nical si g ns/s ym pt o ms 
i n dicati ve of e xa g gerate d mi daz ola m p har mac ol o g y (i ncl u di n g b ut n ot li mite d t o e xcessi ve 
se dati o n, h yp ote nsi o n, or res pirat or y  de pressi o n) t hat re q uires me dical i nter ve nti o n will be 
c o nsi dere d a n o ver d ose.
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or or treati n g p hys icia n s h o ul d:
1.
I m me diatel y i nstit ute car di ores pirat or y s u p p ort i n kee pi n g wit h I LS g ui deli nes. T he 
c o m petiti ve be nz o diaze pi ne a nta g o nist, fl u maze nil, ma y  be use d at t he discreti o n of 
t he i n vesti gat or i n acc or da nce wit h l ocal pr ot oc ols. T he partici pa nt m a y  be tra nsferre d 
t o a n affiliate d h os pital facilit y if dee me d necessar y at t he discreti o n of t he 
i n vesti gat or. T he partici pa nt m ust be cl osel y  m o nit ore d t hr o u g h rec o ver y t o baseli ne.
2.
O btai n a bl o o d sa m ple f or b ot h mi daz ola m P K a n d P F -0 7 2 5 8 6 6 9 a nal ys is, if p ossi ble,
as s o o n as t he partici pa nt has bee n me dicall y sta bilize d or at t he earliest p ossi ble 
ti me. 
3.
C o ntact t he me dical m o nit or wit hi n 2 4 h o urs.
4.
D oc u me nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose i n 
t he C R F.
5.
O ver d ose is re p orta ble t o Pfizer Safet y  o nl y w he n ass oci ate d wit h a n S A E .
Decisi o ns re gar di n g c o nti n ue d partici pati o n i n Part B, 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. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 5
6. 8. C o nc o mit a nt T her a p y
Use of prescri pti o n or n o n prescri pti o n dr u gs a n d dietar y  a n d her bal s u p ple me nts are 
pr o hi bite d wit hi n 7 da y s or 5 half -li ves ( w hic he ver is l o n ger) pri or t o t he first d ose of st u d y 
i nter ve nti o n a n d f or t he d urati o n of t he st u d y. See Secti o n 6. 8. 1 f or e xce pti o ns f or t he 
o pti o nal c o h ort of ol der a d ult partici pa nts.
Treat me nts ta ke n wit hi n 2 8 da y s bef ore t he first d ose of st u d y i nter ve nti o n will be 
d oc u me nte d as a pri or treat me nt. Treat me nts ta ke n after t he first d ose of st u d y  i nter ve nti o n 
will be d oc u me nte d as c o nc o mita nt treat me nts.
F or all partici pa nts, a ll c o nc o mita nt treat me nts 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, dail y d ose, a n d start a n d st o p dates of a d mi nistrati o n. All partici pa nts will be 
q uesti o ne d a b o ut c o nc o mita nt treat me n t at eac h cli nic visit.
Fe males ta ki n g h or m o ne re place me nt t hera p y m a y be eli gi ble t o partici pate i n t his st u d y if 
t he y are willi n g t o disc o nti n ue t hera p y at least 2 8 da y s pri or t o t he first d ose of st u d y 
i nter ve nti o n a n d re mai n off h or m o nal t hera p y f or t h e d urati o n of t he st u d y.
As P F - 0 72 5 8 6 6 9 is pri maril y  meta b olize d b y C Y P 3 A, use of m o derate or str o n g C Y P 3 A 
i n hi bit ors or i n d ucers are pr o hi bite d f or all partici pa nts wit hi n 2 8 da y s or 5 half -li ves 
( w hic he ver is l o n ger) pri or t o Scree ni n g a n d f or t he d urati o n of t he st u d y. A n o n -e x ha usti ve 
list of e xcl u de d c o nc o mita nt me dicati o ns is i n A p pe n di x 1 3 . If a me dicati o n is n ot liste d, it 
s h o ul d n ot a ut o maticall y be ass u me d it is per mitte d t o c o-a d mi nister. T heref ore, all 
me dicati o ns m ust be re vie we d o n a case -b y -case basis b y  t he i n vesti gat or a n d a p pr o ve d b y 
t he s p o ns or d uri n g t he scree ni n g peri o d f or eligi bilit y  p ur p oses.
Li mite d use of n o n prescri pti o n me dicati o ns t hat are n ot belie ve d t o affect partici pa nt safet y  
or t he o verall res ults of t he st u d y  ma y be per mitte d o n a case-b y -case basis f oll o wi n g 
a p pr o val b y t he s p o ns or . Aceta mi n o p he n/ paraceta m ol ma y  be use d at d oses of ≤1 g / da y.
6. 8. 1. O pti o n al C o h ort of Ol der A d ult P artici p a nts O nl y
Partici pa nts i n t he o pti o nal c o h ort of ol der a d ult partici pa nts o nl y  m a y  ta ke certai n dail y 
prescri pti o n or n o n -prescri pti o n me dicati o ns f or ma na ge me nt of acce pta ble c hr o nic me di cal 
c o n diti o ns . T he y are t o be o n a sta ble d ose, as defi ne d b y  n o c ha n ge i n d ose f or t he 2 8 d a y s 
or 5 half -li ves ( w hic he ver is l o n ger) bef ore t he scree ni n g visit. H o we ver, c o nc o mita nt 
a d mi nistrati o n of m o derate or str o n g C Y P 3 A i n hi bit ors or i n d ucers are n o t all o we d. 
A d diti o nall y , as descri be d bel o w, de pe n di n g o n res ults of Part B of t he st u d y, c o nc o mita nt 
a d mi nistrati o n of certai n C Y P 3 A s u bstrates ma y  als o n ot be all o we d.
I n vitr o, P F -0 7 2 5 8 6 6 9 is a p ote ntial ti me - de pe n de nt i n hi bit or a n d/ or i n d ucer of C Y P 3 A. T he 
effect of P F - 0 7 2 5 8 6 6 9 o n a pr o be C Y P 3 A s u bstrate, mi daz ola m, will be assesse d i n Part B of 
t his st u d y. T he res ults of Part B of t his st u d y will i nf or m t he a bilit y t o c o-a d mi nster
P F - 0 7 2 5 8 6 6 9 wit h C Y P 3 A s u bstrates i n t his st u d y.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 6
Ba se d o n t he o verall i n ter pretati o n of t he res ults of Part B, a n d ta ki n g i nt o acc o u nt t he d ose 
le vel/re gi me n t o be e val uate d i n t he ol der a d ult c o h ort, t he f oll o wi n g restricti o ns will a p pl y 
re gar di n g use of C Y P 3 A s u bstrates i n ol der a d ult partici pa nts:

If n o i nteracti o n (ie, P F-0 7 2 5 8 6 6 9 res ults i n < 1. 2 5 -f ol d i ncrease i n mi daz ola m A U C )
– n o restricti o ns;

If a mil d i nteracti o n (ie, P F- 0 7 2 5 8 6 6 9 res ults i n ≥1. 2 5- t o < 2 -f ol d i ncrease i n 
mi daz ola m A U C ) – use of se nsiti ve C Y P 3 A s u bstrates wit h narr o w t hera pe utic i n de x 
will be restricte d;

If a m o derate i nteracti o n (ie, P F-0 7 2 5 8 6 6 9 res ults i n ≥2- t o < 5 -f ol d i ncrease i n 
mi daz ola m A U C ) or a str o n g i nteracti o n (ie, P F-0 7 2 5 8 6 6 9 res ults i n ≥5 -f ol d i ncrease 
i n mi daz ola m A U C ) – use of se nsiti ve C Y P 3 A s u bstrates a n d C Y P 3 A s u bstrates wit h
narr o w t hera pe utic i n de x will be restricte d .
A n o n -e x ha usti ve list of pr o hi bite d a n d preca uti o nar y  me dicati o ns is pr o vi de d i n 
A p pe n di x 1 3 . If a me dicati o n is n ot liste d, it s h o ul d n ot a ut o maticall y be ass u me d it is 
per mitte d t o c o-a d mi nister. T heref ore, all me dicati o ns m ust be re vie we d o n a case -b y -case 
basis b y  t he i n vesti gat or a n d a p pr o ve d b y t he s p o ns or d uri n g t he scree ni n g peri o d f or 
eli gi bilit y p ur p oses.
Healt h y ol der partici pa nts s h o ul d c o nti n ue t o ta ke t h eir per mitte d dail y prescri pti o n or n o n-
prescri pti o n me dicati o ns at a p pr o xi matel y  t he sa me ti me eac h da y d uri n g t he st u d y. O n da ys 
of de nse P K sa m pli n g ( m or ni n g d osi n g o n Da y  1 a n d Da y 1 4), a d mi nistrati o n of c o nc o mita nt 
me dicati o ns s h o ul d occ ur at least 1 - 2 h o urs pri or t o m or ni n g d osi n g of P F-0 7 2 5 8 6 6 9 or 
wit h hel d u ntil 4 h o urs after m or ni n g d osi n g of P F- 0 7 2 5 8 6 6 9. T here are n o restricti o ns o n 
ot her da y s of t he st u dy.
6. 8. 2. Resc ue Me dici ne
T here is n o resc ue t hera p y t o re verse t he A Es o bser ve d wit h P F - 0 7 2 5 8 6 6 9; stan 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. 
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
It ma y be necessar y f or a partici pa nt t o per ma ne ntl y disc o nti n ue st u d y i nter ve nti o n. Reas o ns 
f or per ma ne nt disc o nti n uati o n of st u d y  i nter ve nti o n i ncl u de t he f oll o wi n g: a d verse e ve nt or 
s o me ot her (a d mi nistrati ve) reas o n.
If st u d y i nter ve nti o n is per ma ne ntl y disc o nti n ue d, t he partici pa nt will n ot re mai n i n t he st u d y  
f or f urt her e val u ati o n. See t he S o A 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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 7
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 d y 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. 1. 1. E C G C h a n ges
A partici pa nt w h o meets eit her of t he f oll o wi n g b ullete d criteria base d o n t he a vera ge of 
tri plicate E C G rea di n gs will be wit h dra w n fr o m t he st u d y i nter ve nti o n. 

Q Tc F > 5 0 0 ms ec.

C ha n ge fr o m baseli ne: Q Tc F > 6 0 ms ec.
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o, c ha n ges fr o m 
baseli ne i n Q T c F after e nr oll me nt), t he i n vesti gat or or q ualifie d desi g nee will deter mi ne if 
t he partici pa nt ca n c o nti n ue i n t he st u d y a n d if a n y c ha n ge i n partici pa nt ma na ge me nt is 
nee de d. T his re vie w of t he E C G pri nte d at t he ti me of c ollec ti o n m ust be d oc u me nte d. A n y 
ne w cli nicall y rele va nt fi n di n g s h o ul d be re p orte d as a n A E.
7. 1. 2. P ote nti al C ases of Ac ute Ki d ne y I nj ur y
A b n or mal val ues i n S Cr c o nc urre nt wit h prese nce or a bse nce of i ncrease i n B U N t hat meet 
t he criteria bel o w, i n t he a bse nce of ot her ca uses of ki d ne y i nj ur y, are c o nsi dere d p ote ntial 
cases of ac ute ki d ne y i nj ur y a n d s h o ul d be c o nsi dere d i m p orta nt me dical e ve nts. 
A n i ncrease of ≥0. 3 m g / d L ( or ≥2 6. 5 µ m ol/ L ) i n S Cr le vel relati ve t o t he partici pa nt’s o w n 
baseli ne meas ure me nt s h o ul d t ri g ger a n ot her assess me nt of S Cr as s o o n as practically 
feasi ble, prefera bly wit hi n 4 8 h o urs fr o m a ware ness.
If t he sec o n d assess me nt (after t he first o bser vati o ns of ≥0. 3 m g/ d L [or ≥2 6. 5 µ m ol/ L ] i n S Cr
relati ve t o t he partici pa nt’s o w n baseli ne meas ure me nt) is ≥0. 4 m g/ d L ( or ≥3 5. 4 µ m ol/ L ), t he 
partici pa nt s h o ul d be disc o nti n ue d fr o m t he st u d y a n d a de q uate, i m me diate, s u p p orti ve 
meas ures ta ke n t o c orrect a p pare nt ac ute ki d ne y  i nj ur y.
Partici pa nts 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 sec o n d assess me nt c o nfir mi n g a b n or mal 
S Cr res ult. 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 o n t o re peati n g S Cr, la b orat or y tests s h o ul d i ncl u de ser u m B U N, ser u m 
creati ne ki nase, a n d ser u m electr ol yt es (i ncl u di n g at a mi ni m u m p otassi u m, s o di u m, 
p h os p hate/ p h os p h or us, a n d calci u m), i n a d diti o n t o uri nar y  di pstic k, uri ne micr osc o pic 
e xa mi nati o n, a n d uri nar y i n dices. All cases c o nfir me d o n re peat testi n g as meeti n g t he 
la b orat or y criteria f or ac ute ki d ne y i nj ur y, wit h n o ot her ca use(s) of la b orat or y a b n or malities 
i de ntifie d, s h o ul d be c o nsi dere d p ote ntial cases of dr u g-i n d uce d ki d ne y i nj ur y irres pecti ve of 
a vaila bilit y of all t he res ults of t he i n vesti gati o ns perf or me d t o deter mi ne eti ol o g y  of t he 
a b n or mal S Cr. If ≥2 healt h y  partici pa nts i n a gi ve n c o h ort are n ote d t o ha ve 2 c o nsec uti ve 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 8
S Cr res ults of ≥0. 3 m g/ d L ( or ≥2 6. 5 µ m ol/ L ), a n assess me nt of w het her t he fi n di n g ma y be 
c o nsi dere d a n ad verse dr u g reacti o n s h o ul d be u n derta ke n.
7. 2. P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al F r 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 uati 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 he r st u d y pr oce d ures;

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 safet y 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 pr ot oc ol re q uire d sc he d ule of st u d y 
visits or pr oc e d ures.
At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a n earl y disc o nti n uati o n visit s h o ul d 
be c o n d ucte d . See t he S o A 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. 
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.  
T he partici pa nt will be per ma ne ntl y disc o nti n ue d fr o m t he st u d y i nter ve nti o n a n d t he st u d y  at 
t hat ti me.
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 the i n vesti gat or m ust d oc u me nt a n y  s uc h re q uests in t he 
site st u d y rec or ds a n d n otif y t he s p o ns or acc or di n gl y.
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 (see 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 be 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.
7. 2. 1. Wit h dr a w al of C o nse nt 
Partici pa nt s 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 pecifically 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 on. Partici pa nt s 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 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 6 9
c o nse nt fr o m f ut ure f oll o w - u p, w he ne ver p ossi ble. T he 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 wi t 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 a n 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 measure 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 ol l o w u p 
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y  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 cli nic f or /atte n d a 
re q uire d st u dy 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. Co 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 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 parti ci pa nt is dee me d l ost t o f oll o w -u p, t he i n ves ti 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. 
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 a si g ne d a n d 
date d I C D bef ore perf or mi n g a n y st u d y- s pecific pr oce d ures.  
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A . Pr ot oc ol wai vers or 
e xe m pti o ns are n ot all o we d.
S afet 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 , is esse ntial 
a n d re q uire d f or st u d y c o n d uct.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 0
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.
Partici pa nts will be scree ne d wit hi n 2 8 da y s pri or t o a d mi nistrati o n of t he st u d y i nter ve nti o n 
t o c o nfir m t hat t he y meet t he st u d y p o p ulati o n criteria f or t he st u d y. If t he ti me bet wee n 
scree ni n g a n d d osi n g e xcee ds 2 8 d a y s as a res ult of u ne x pecte d dela ys (e g, dela ye d dr u g 
s hi p me nt), t he n partici pa nts d o n ot re q uire rescree ni n g if t he la b orat or y res ults o btai ne d pri or 
t o first d ose a d mi nistrati o n meet eli gibilit y  criteria.
A partici pa nt w h o q ualifie d f or t his pr ot oc ol b ut di d n ot e nr oll fr o m a n earlier c o h ort/ gr o u p 
ma y  be use d i n a s u bse q ue nt c o h ort/ gr o u p wit h o ut rescree ni n g, pr o vi de d la b orat or y res ults 
o btai ne d pri or t o t he first d ose a d mi nistrati o n meet eli gi bilit y  criteria f or t his st u d y. I n 
a d diti o n, ot her cli nical assess me nts or s peci me n c ollecti o ns, e g, ba n ke d bi os peci me ns, ma y  
be use d wit h o ut re peat c ollecti o n, as a p pr o priate.
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 g at 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 or me 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 i n a ti mel y ma n ner.
A n y  safet y, la b orat or y, or a nal yt 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 gati ve sites or ot her bli n de d pers o n nel u ntil t he st u d y  has bee n u n bli n de d.
If a n I V cat heter is utilize d f or bl o o d sa m ple c ollecti o ns, E C Gs a n d vital si g n assess me nts 
(p ulse rate a n d B P) s h o ul d be c ollecte d pri or t o t he i nserti o n of t he cat heter.
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 part ici pa nts i n t his st u d y is a p pr o xi matel y 
2 6 0 m L f or Part A a n d a p pr o xi matel y 2 5 0 m L  f or Part B. T he act ual c ollecti o n ti mes of 
bl o o d sa m pli n g ma y  c ha n ge. A d diti o nal bl o o d sa m ples ma y be ta ke n f or safety 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 
5 5 0 m L  d uri n g a ny peri o d of 5 6 c o nsec uti ve da ys.
T o pre pare f or st u d y partici pati o n, partici pa nt s will be i nstr ucte d o n t he i nf or mati o n i n t he 
Lifest y le C o nsi derati o ns a n d C o nc o mita nt T hera p y secti o ns of t he pr ot oc ol.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 1
8. 1. Effic ac y Assess me nts
N o efficac y  assess me nts are bei n g c o n d ucte d i n t his st u d y.
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 . 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 dy t o assess a n y 
percei ve d safet y  iss ues.
8. 2. 1. P h ysic al E x a mi n ati o ns
P h y sical e xa mi nati o ns are t o be perf or me d at t he n o mi nal ti me p oi nts s pecifie d i n t he So A. 
A d diti o nal p h ys ical e xa mi nati o ns will be per mitte d, as necessar y, t o e ns ure a p pr o priate 
c ollecti o n of safet y data. 
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, hea d, ears, e yes, n ose, m o ut h, 
s ki n, heart a n d l u n g e xa mi nati o ns, l ym p h n o des, a n d gastr oi ntesti nal, m usc ul os keletal, a n d 
ne ur ol o gical s ys te ms. 
A brief 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 ge neral a p peara nce, 
t he res pirat or y a nd car di o vasc ular s ys te ms, a n d partici pa nt -re p orte d sy m pt o ms.
P h y sical e xa mi nati o ns ma y be c o n d ucte d b y a p hysicia n, trai ne d p h ys icia n's assista nt, or 
n urse practiti o ner as acce pta ble acc or di n g t o l ocal re g ulati o n. 
Hei g ht a n d wei g ht will als o be meas ure d a n d rec or de d as per t he S o A . F or meas uri n g wei g ht, 
a scale wit h a p pr o priate ra n ge a n d res ol uti o n is use d a n d m ust be place d o n a sta ble, flat 
s urface. Partici pa nt s m ust re m o ve s h oes, b ul k y la yers of cl ot hi n g, a n d jac kets s o t hat o nl y
li g ht cl ot hi n g re mai ns. T he y m ust als o re m o ve t he c o nte nts of t heir p oc kets a n d re mai n still 
d uri n g meas ure me nt of wei g ht. Please refer t o Secti o n 8. 5. 1 f or a m ore c o m plete descri pti o n 
of b o d y  wei g ht assess me nt.
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 x a 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 or S A E ( A p pe n di x 3 ) must be re p orte d acc or di n g t o t he pr ocesses i n 
Secti o n s 8. 3. 1 t o 8. 3. 3 .
8. 2. 2. Ne ur ol o gic al E x a mi n ati o ns ( P art A o nl y)
Ne ur ol o gical e xa mi nati o ns ma y  be c o n d ucte d by a p h ysicia n, trai ne d p h ysicia n's assista nt, or 
n urse practiti o ner as acce pta ble acc or di n g t o l ocal re g ulati o n at t he n o mi nal ti me p oi nts 
s pecifie d i n t he S o A . T he ne ur ol o gical e xa m will c o nsist of assess me nt of hi g her c ortical 
f u ncti o n, t he cra nial ner ves, m ot or f u ncti o n, dee p te n d o n refle xes, se ns or y e xa m, a n d 
c o or di nati o n a n d gait. T he e xa m s h o ul d be d o ne t o t he e xte nt nee de d t o assess t he partici pa nt 
f or a ny p ote ntial c ha n ges i n ne ur ol o gical stat us, as deter mi ne d b y t he i n vesti gat or ( or 
desi g nee ).
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 2
8. 2. 3. Vit al Si g ns
B P a n d p ulse rate 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 .
A d diti o na l c ollecti o n ti mes, or c ha n ges t o c ollecti o n ti mes, of B P a n d p ulse rate will be 
per mitte d, as necessar y , t o e ns ure a p pr o priate c ollecti o n of safet y data. S u pi ne B P 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 after a p pr o x i matel y 5 mi n utes of rest. T he sa me ar m ( prefera bl y  t he 
d o mi na nt ar m) will be use d t hr o u g h o ut t he st u d y . Partici pa nt s s h o ul d be i nstr ucte d n ot t o 
s pea k d uri n g meas ure me nts.
T he sa me pr o perl y size d a n d cali brate d B P c uff will be use d t o meas ure B P eac h ti m e. T he 
use of a n a ut o mate d de vice f or meas uri n g B P a n d p ulse rate is acce pta ble; h o we ver, w he n 
d o ne ma n uall y, p ulse rate will be meas ure d i n t he brac hial/ra dial arter y  f or at least 
3 0 sec o n ds. W he n t he ti mi n g of t hese meas ure me nts c oi nci des wit h a bl o o d c ollecti o n, B P 
a n d p ulse rate s h o ul d be o btai ne d pri or t o t he n o mi nal ti me of t he bl o o d c ollecti o n. W he n 
tri plicate meas ure me nts of s u pi ne B P or p ulse rate are re q uire d per S o A , meas ure me nts 
s h o ul d be c ollecte d 2-4 mi n utes a part. 
T he pr oce d ure f or c ollecti n g p ost ural or ort h ostatic data will be:

Assess B P after t he partici pa nt is i n t he s u pi ne p ositi o n f or a mi ni m u m of 5 mi n utes;
w he n ti mi n g of ort h ostatic B P assess me nt c oi nci des wit h ti mi n g of tri plicate s u pi ne 
B P assess me nt, t he last of t he tri plicate s u pi ne rea di n gs will be use d as t he s u pi ne 
rea di n g f or t he ort h ostatic assess me nt.

Ha ve t he partici pa nt sta n d u p f or 2 mi n utes .

Assess B P after t he partici pa nt is i n t he sta n di n g p ositi o n f or a p pr o xi matel y  
2 mi n utes.
Ort h ostatic h y p ote nsi o n is defi ne d as a decrease of ≥2 0 m m H g f or s ys t olic B P or 
≥1 0 m m H g f or diast olic B P 2 mi n utes after sta n di n g fr o m a s u pi ne p ositi o n. Ort h ostatic 
h y p ote nsi o n ma y  be sy m pt o matic or as y m pt o matic. S y m pt o ms of ort h ostatic h y p ote nsi o n are 
t h ose t hat de vel o p u p o n ass u mi n g t he erect p ost ure fr o m a s u pi ne p ositi o n a n d ma y i ncl u de: 
li g ht hea de d ness, dizzi ness, bl urre d visi o n, wea kness, fati g ue, c o g niti ve i m pair me nt, na usea, 
pal pitati o ns, tre m ul o us ness, hea dac he, a n d/ or nec k ac he. R e peate d meas ure me nts of 
s u pi ne/sta n di n g B P s h o ul d be o btai ne d i n t he e ve nt of eit her asy m pt o matic or s y m pt o matic 
ort h ostatic h y p ote nsi o n at t he discreti o n of t he i n vesti gat or.
If a partici pa nt ma nifests a n i ncrease i n p ulse rate of ≥3 0 beats per mi n ute [ b p m] wit h a 
decrease of < 2 0 m m H g f or s y st olic B P or < 1 0 m m H g f or diast olic B P 2 mi n utes after 
sta n di n g fr o m a s u pi ne p ositi o n, re peate d meas ure me nts of s u pi ne/sta n di n g B P s h o ul d be 
o btai ne d. Si milarl y , if a partici pa nt has s y m pt o ms s u g gesti ve of ort h ostasis, b ut n ot 
d oc u me nte d ort h ostatic h y p ote nsi o n, re peate d meas ure me nts of s u pi ne/sta n di n g B P s h o ul d 
be o btai ne d. Lesser de grees of B P re d ucti o n ma y  still be c o nsi dere d cli nicall y  si g nifica nt if 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 3
t he partici pa nt bec o mes s y m pt o matic u p o n sta n di n g, es peciall y i n t he prese nce of a 
si g nifica nt i ncrease i n p ulse rate ( ≥3 0 b p m).
8. 2. 3. 1. Res pir at or y R ate
Res pirat or y  rate will be meas ure d at ti mes s pecifie d i n t he S o A . After a p pr o xi matel y 
5 mi n utes rest i n s u pi ne p ositi o n, res pirat or y  rate will be meas ure d b y o bser vi n g a n d
c o u nti n g t he res pirati o ns of t he partici pa nt f or 3 0 sec o n ds a n d m ulti plie d b y 2. W he n B P is t o 
be ta ke n at t he sa me ti me, res pirati o n meas ure me nt will be d o ne d uri n g t he 5 mi n utes of rest 
a n d bef ore B P meas ure me nt.
8. 2. 3. 2. Or al B o d y Te m per at ure
B o d y te m perat ure will be meas ure d orall y. 
8. 2. 4. Electr oc ar di o gr a ms
Sta n dar d 1 2-l ea d E C Gs utilizi n g li m b lea ds ( w it 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 secti o n of t his pr ot oc ol 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 n ati 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) 
s h o ul d n ot be use 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 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 at least 5 mi n utes i n a s u pi ne p ositi o n. 
O n Da y 1 at -1 H, -0. 5 H, a n d 0 H pri or t o t he m or ni n g d ose , tri plicate 1 2-lea d E C Gs will be 
o btai ne d a p pr o xi matel y  2 t o 4 mi n utes a part at eac h ti me p oi nt. T he a vera ge of t he tri plicate 
E C G me as ure me nts o ver t he 3 pre- d ose meas ure me nt ti mes (t otal of 9 E C G meas ure me nts) 
c ollecte d bef ore m or ni n g d ose a d mi nistrati o n o n Da y 1 will ser ve as eac h partici pa nt’s 
baseli ne Q Tc val ue.
T o e ns ure safet y of t he partici pa nts, a q ualifie d i n di vi d ual at t he i n vesti gat or site will ma ke 
c o m paris o ns t o baseli ne meas ure me nts. A d diti o nal E C G m o nit ori n g will occ ur if a) t he mea n 
val ue fr o m t he tri plicate meas ure me nts f or a n y p ost d ose Q Tc F i nter val is i ncrease d b y 
≥6 0 ms ec fr o m t he baseli ne a n d is > 4 5 0 ms ec; or b) a n a bs ol ute Q T val ue is ≥5 0 0 ms ec f or 
a n y sc he d ule d E C G. If eit her of t hese c o n diti o ns occ urs, t he n a si n gle E C G meas ure me nt 
m ust be re peate d at least h o url y  u ntil Q Tc val ues fr o m 2 s uccessi ve E C Gs fall bel o w t he 
t hres h ol d val ue t hat tri g gere d t he re peat measure me nt .
If a) a p ost d ose Q Tc F i nter val re mai ns ≥6 0 ms ec fr o m t he baseli ne a n d is > 4 5 0 ms ec; or 
b) a n a bs ol ute Q T val ue is ≥5 0 0 ms ec f or a ny s c he d ule d E C G f or greater t ha n 4 h o urs ( or 
s o o ner, at t he discreti o n of t he i n vesti gat or); or c) Q Tc F i nter vals get pr o gressi vel y l o n ger, 
t he partici pa nt s h o ul d u n der g o c o nti n u o us E C G m o nit ori n g. A car di ol o gist s h o ul d be 
c o ns ulte d if Q Tc F i nter vals d o n ot ret ur n t o less t ha n t he criteria liste d a b o ve after 8 h o urs of 
m o nit ori n g ( or s o o ner, at t he discreti o n of t he i n vesti gat or).
I n s o me cases, it ma y be a p pr o priate t o re peat a b n or mal 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. It is i m p orta nt t hat lea ds be place d i n t he 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 4
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. If a mac hi ne-rea d Q Tc 
val ue is pr ol o n ge d, as defi ne d a b o ve, re peat meas ure me nts ma y  n ot be necessar y if a 
q ualifie d me dical pr o vi der’s i nter pretati o n deter mi nes t hat t he Q Tc F val ues are i n t he 
acce pta ble ra n ge.
E C G val ues of p ote ntial cli nical c o ncer n are liste d i n A p pe n di x 8 .
8. 2. 4. 1. C o nti n u o us C ar di ac M o nit ori n g b y Tele metr y ( P art A o nl y)
All a b n or mal r h yt h ms will be rec or de d a n d re vie we d b y  t he st u d y p h ysicia n f or t he prese nce 
of r h yt h ms of p ote ntial cli nical c o ncer n. T he ti me, d urati o n, a n d descri pti o n of t he cli nicall y 
si g nifica nt e ve nt will be rec or de d i n t he C R F. I n a d diti o n, a pri nte d rec or d of t he traci n g(s) of 
t he cli nicall y si g nifica nt r h yt h m(s) will be ma de a n d retai ne d wit h ot her s o urce d oc u me nts.
Tele metr y  s h o ul d be c ollecte d usi n g a ce ntralize d s yste m t hat als o all o ws f or t he st ora ge a n d
a d va nce d a nal ys is of all rec or de d data i n or der t o preser ve i m p orta nt e ve nts f or f ut ure
e val uati o ns. H olter m o nit ori n g s h o ul d n ot be use d i n parallel wit h c o nti n u o us tele metr y,
u nless it is t he o nl y  mea ns of data st ora ge a vaila ble at t he i n vesti gat or site, or verifia ble
arr h yt h mia q ua ntificati o n is re q uire d. T o esta blis h a baseli ne, tele metr y  s h o ul d be rec or de d
f or at least 2 h o urs o n Da y  - 1. T his ma y  be d o ne i m me diatel y pri or t o d osi n g or at s o me 
2- h o ur c o nti n u o us i nter val i n t he 2 4 h o urs pri or t o d osi n g, as l o n g as t he rec or di n g is 
perf or me d w he n t he partici pa nt is a wa ke. Tele metr y m a y  be st o p pe d wit hi n a reas o na bly
s h ort peri o d of ti me pri or t o d osi n g, i n or der t o a v oi d i nterfere nce wit h st u d y o perati o ns
c o n d ucte d i m me diatel y bef ore d osi n g. H o we ver, it is e x pecte d t hat t he tele metr y lea ds will
be i n place a n d t he s ys te m c o n necte d pri or t o d osi n g.
8. 2. 5. C o nti n u o us P ulse O xi metr y ( P art B O nl y)
C o nti n u o us p ulse o xi metr y will be perf or me d o n mi daz ola m d osi n g da y s i n Part B as 
o utli ne d i n t he S o A . M o nit ori n g will be i nitiate d at least 3 0 mi n utes pri or t o mi daz ola m 
d osi n g a n d will c o nti n ue t hr o u g h at least 6 h o urs after mi daz o la m d osi n g. T he d urati o n of 
m o nit ori n g ma y  be e xte n de d at discreti o n of t he i n vesti gat or. All a b n or mal o x yge n sat urati o n 
alerts will be rec or de d a n d re vie we d b y t he st u d y  p h ysicia n f or p ote ntial cli nical c o ncer n. 
Cli nical c orrelati o n t hr o u g h re vie w of t he partici pa nt will be s o u g ht f or a n y  alerts c o nsi dere d 
of p ote ntial cli nical c o ncer n. G ui da nce wit h res pect t o o ver d ose of mi daz ola m o utli ne d i n 
Secti o n 6. 7. 2 s h o ul d be c o nsi dere d i n t he setti n g of a b n or mal o xy ge n sat urati o n alerts 
dee me d c o ncer ni n g. T he ti me, d urati o n, a n d descri pti o n of t he cli nicall y  si g nifica nt e ve nt 
will be rec or de d i n t he C R F. C o nti n u o us p ulse o xi metr y s h o ul d be c ollecte d usi n g a 
ce ntralize d s ys te m t hat als o all o ws f or t he st ora ge a n d a d va nce d a nalys is of all rec or de d data 
i n or der t o preser ve i m p orta nt e ve nts f or f ut ure e val uati o ns.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 5
8. 2. 8. 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 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 . 
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 ny 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 t his 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 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.
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 1 4 da y s 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.
Partici pa nt s ma y u n der g o ra n d o m uri ne dr u g testi n g at t he discreti o n of t he i n vesti gat or. 
Dr u g testi n g c o n d ucte d pri or t o d osi n g m ust be ne gati ve f or partici pa nt s t o recei ve st u d y 
i nter ve nti o n. 
8. 2. 9. C O VI D - 1 9 Rel ate d Me as ures
Partici pa nts will u n der g o C O VI D -1 9 relate d meas ures per C R U pr oce d ures.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 6
8. 2. 1 1. S uici d al I de ati o n a n d Be h a vi or Ris k M o nit ori n g
8. 2. 1 1. 1. C ol u m bi a S uici de Se verit y R ati n g Sc ale ( P art A O nl y)
T he C -S S R S is a n i nter vie w base d rati n g scale t o s yste maticall y assess s uici dal i deati o n a n d 
s uici dal be ha vi or. Versi o ns are a vaila ble f or Scree ni n g/ Baseli ne ( Lifeti me assess me nt) 
assess me nt s a n d s u bse q ue nt assess me nts ( Si nce Last Visit assess me nt) d uri n g t he st u d y.
Baseli ne/ Lifeti me assess me nt t o be perf or me d at S cree ni n g. All ot her assess me nts s h o ul d use 
t he Si nce Last Visit assess me nt. 
T he C -S S R S s h o ul d be a d mi nistere d b y  a n a p pr o priatel y trai ne d staff me m ber.
At eac h s uici dalit y assess me nt , partici pa nts felt t o ha ve si g nifica nt s uici dal i deati o n wit h 
act ual pla n a n d i nte nt or s uici dal be ha vi or, m ust be e val uate d b y a cli nicia n/ M H P
s kille d i n 
t he e val uati o n of s uici dal i deati o n a n d be ha vi or i n t he partici pa n ts b y virt ue of trai ni n g or 
e x perie nce (e g, ps yc hiatrist, lice nse d cli nical ps yc h ol o gist) w h o will deter mi ne if it is safe f or 
t he partici pa nt t o partici pate/c o nti n ue i n t he trial. S pecific criteria t hat i n dicate a nee d f or 
s uc h a n assess me nt are:

S uici de i deati o n ass ociate d wit h act ual i nte nt a n d/ or pla n i n t he past y ear; (“ Y E S”
a ns wer t o C - S S R S q uesti o ns 4 “s o me i nte nt t o act wit h o ut s pecific pla n” or
5 “s pecific pla n a n d i nte nt ”);

Pre vi o us hist or y  of s uici de be ha vi ors i n t he past 5 years (a “ Y E S” a ns wer t o a n y of
t he s uici dal be ha vi or ite ms of t he C-S S R S wit h t he be ha vi or occ urri n g i n t he past
5 ye ars);

I n t he i n vesti gat or’s j u d g me nt, a ris k assess me nt or e xcl usi o n is warra nte d.
Ot her p ossi ble s uici dal i deati o n a n d be ha vi or A Es or ot her cli nical o bser vati o ns ma y , base d
o n t he j u d g me nt of t he i n vesti gat or, als o tri g ger a ris k assess me nt a n d re q uire a narrati ve.
S uici dalit y  A Es or ot her cli nical o bser vati o ns ma y, base d o n t he j u d g me nt of t he i n vesti gat or
a n d cli nicia n/ M H P, als o tri g ger a ris k assess me nt a n d a narrati ve usi n g i nf or mati o n fr o m t he
C- S S R S, a n d a vaila ble i nf or mati o n, pri or t o scree ni n g a n d baseli ne i nf or mati o n, a n d t he
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 7
cli nicia n/ M H P assess me nt. W he n t here is a p ositi ve res p o nse t o a ny q uesti o n o n t he C- S S R S, 
t he i n vesti gat or s h o ul d deter mi ne w het her a n A E has occ urre d.
At t he Scree ni n g/ Baseli ne assess me nt , a ris k assess me nt will be d o ne b y q ualifie d staff t o 
deter mi ne w het her it is safe f or t he partici pa nt t o be e nr olle d or t o c o nti n ue t o partici pate i n 
t he trial.
Partici pa nt s w h o res p o n d “ Y E S” t o ite ms 4, 5 or t o a n y be ha vi oral q uesti o n of t he C-S S R S at
a n y ti me after t he baseli ne visit will be assesse d b y cli nicia n/ M H P t o deter mi ne w het her it is
safe f or t he partici pa nt t o c o nti n ue i n t he trial.
Partici pa nts w h o res p o n d “ Y E S” t o ite ms 4, 5 or t o a n y  be ha vi oral q uesti o n of t he C-S S R S 
o n m ore t ha n o ne occasi o n d uri n g a trial m ust ha ve t heir s uici dalit y  ma na ge d a p pr o priately 
b y t he i n vesti gat or t o gether wit h cli nicia n/ M H P ( or t he i n vesti gat or al o ne if t he i n vesti gat or
is a q ualifie d me ntal healt h pr ofessi o nal). De pe n di n g o n t he s pecifics of t he partici pa nt as 
assesse d b y t he i n vesti gat or a n d/ or cli nicia n/ M H P, t he partici pa nt m a y  be disc o nti n ue d fr o m 
the trial.
8. 2. 1 1. 2. R ater Q u alific ati o ns
F or s pecific rati n g assess me nts, o nl y  q ualifie d raters will be all o we d t o e val uate a n d/ or rate 
partici pa nts i n t his st u d y . T he mi ni m u m q ualificati o ns a rater m ust meet f or eac h st u dy rati n g 
assess me nt will be o utli ne d i n t he C- S S R S Res o urce G ui de pr o vi de d t o eac h partici pati n g 
site. T he le vel of e x perie nce wit h t he tar get p o p ulati o n ( or e q ui vale nt), s pecific scale 
e x perie nce ( or e q ui vale nt), a n d certificati o n re q uire d (if a p plica ble) will be liste d a n d use d t o 
deter mi ne w het he r a rater is a p pr o ve d f or a gi ve n assess me nt. T he rater m ust bec o me 
certifie d t o perf or m selecte d st u d y  assess me nts bef ore he or s he ca n partici pate i n t he c o n d uct 
of t he st u d y . F or s pecificall y defi ne d assess me nts, rater trai ni n g a n d sta n dar dizati o n e xerc ises 
ma y  be c o n d ucte d, a n d writte n d oc u me ntati o n will be pr o vi de d b y t he site f or eac h rater’s 
certificati o n. In ret ur n, eac h site will be pr o vi de d writte n d oc u me ntati o n o utli ni n g eac h 
rater’s certificati o n f or s pecific st u dy assess me nts. Recertificati o n m a y be re q uire d at 
peri o dic i nter vals d uri n g t he st u d y . T he raters w h o a d mi nister s pecific st u d y assess me nts will 
be d oc u me nte d i n a ce ntralize d l ocati o n a n d all site staff w h o a d mi nister rati n gs will be 
verifie d i n t he site st u d y d oc u me ntati o n d uri n g t he c o n d uct of t he st u d y.
8. 3. A d verse E ve nts , Seri o us A d verse E ve nts , a n d Ot her S afet y Re p orti n g
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 ma y  arise fr o m sy m pt o ms or ot her c o m plai nts re p orte d t o t he i n vesti gat or b y t he 
partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or t he partici pa nt's le gall y 
a ut h orize d re prese ntati ve), or t he y  ma y arise fr o m cli nical fi n di n gs of t he I n vesti gat or or 
ot her healt hcare pr o vi ders (cli nical si g ns, test res u lts, etc.).
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 m e a n d t o assess w het her t he 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 8
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 (see Secti o n 7. 1 ). 
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 , 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 ollec ti 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 cale n dar da ys , e xce pt as i n dicate d bel o w, after t he last a d mi nistrati o n of t he 
st u d y i nter ve nti o n.
F ol l 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 ble t o t he 
i n vesti gat or.
F or partici pa nts w h o are scree n fail ures, t he acti ve c ollecti o n p eri 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 per ma ne ntl 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 i nf or mati o n o n A E s or S A E s 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 n y S A E, 
i ncl u di n g a deat h, at a ny 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 i m 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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 7 9
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, 
w hic h be gi ns after o btai ni n g i nf or me d c o nse nt as descri be d i n Secti o n 8. 3. 1 , will be 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.
Re p orti n g of A Es a n d S A Es f or partici pa nts w h o fail scree ni n g are s u bject t o t he C R F 
re q uire me nts as descri be d i n Secti o n 5. 4 .
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 E s 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 - Up of A Es a n d S A Es
After t he i nitial A E or 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 ossi 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 urt 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 an S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hi cal res p o nsi bilities t o war d 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 R B s/ E Cs, a n d i n vesti gat ors.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 0
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.
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 n vir o n me nt al E x p os ure, 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 n vir o n me ntal e x p os ure, occ urs w he n a pers o n n ot e nr olle d i n t he st u d y  as a partici pa nt 
recei ves u n pla n ne d direct c o ntact wit h or e x p os ure t o t he st u d y i nter ve nti o n. S uc h e x p os ure 
ma y  or ma y n ot lea d t o t he occ urre nce of a n A E or S A E. Pers o ns at ris k f or e n vir o n me ntal 
e x p os ure i ncl u de healt hcare pr o vi ders, fa mil y me m bers, a n d ot hers w h o ma y be e x p ose d. A n 
e n vir o n me ntal e x p os ure ma y  i ncl u de e x p os ure d uri n g pre g na nc y, e x p os ure d uri n g 
breastfe e di n g, a n d occ u pati o nal e x p os ure.
A n y  s uc h ex p os ure t o t he st u d y i nter ve nti o n u n der st u d y  are re p orta ble t o Pfizer Safety 
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 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.

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 D P : 

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 gesti o n, 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 gesti o n, i n halati o n, or s ki n c o ntact t he n 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). 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 1

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 least 
1 4 da y s 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 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.
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 
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 
de mise, ne o natal deat h, or c o n ge nital a n o mal y i n a li ve -b or n ba b y, a ter mi 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 d i 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 utc o mes will be ha n dle d o n a case-b y -case basis (e g, f oll o w- u p o n 
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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 2
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 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 mber 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 gesti o n, 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 uri 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 vir 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 
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 ure d uri n g breastfee di n g re p ort is n ot create d w he n a P fizer dr u g s pecifically 
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 breas tfee di n g.
8. 3. 5. 3. Occ u p ati o n al E x p os ure
T he i n vesti gat or m ust re p ort a n y i nsta nce of occ u pati o nal e x p os ure t o Pfizer Safety wit hi n 
2 4 h o urs of t he i n vesti gat or’s a ware ness usi n g t he C T S A E Re p ort F or m re gar dless of 
w het her t here is a n ass ociate d S A E. Si nce t he i nf or mati o n a b o ut t he occ u pati o nal e x p os ure 
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 m ust be mai ntai ne d i n t he 
i n vesti gat or site file.
8. 3. 6. C ar di o v asc ul ar a n d De at h E ve nts
N ot a p plica ble.
8. 3. 7. Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes N ot Q u alif yi n g as A Es 
or S A Es
N ot a p plica ble.
8. 3. 8. A d verse E ve nts of S peci al I nterest
 
 
 
 
 
 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 3
 
8. 3. 8. 1. L ac k of Effic ac y
T his secti o n is n ot a p plica ble beca use efficac y is n ot e x pecte d i n t he st u d y p o p ulati o n.
8. 3. 9. Me dic al De vice Deficie ncies
N ot a p plica ble.
8. 3. 1 0. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult fr o m t he a d mi nistrati o n or c o ns u m pti o n of t he 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 m a y occ ur i n cli nical trial setti n gs, s uc h as 
me dicati o n err ors.
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E Re p ort 
F or m t o 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 e rr 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 h e 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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 4
8. 4. P h ar m ac o ki netics 
8. 4. 1. Pl as m a f or A n al ysis of P F -0 7 2 5 8 6 6 9 C o nce ntr ati o ns ( P art A O nl y)
Bl o o d sa m ples of a p pr o xi matel y  3 m L , t o pr o vi de a mi ni m u m of a p pr o xi matel y 1 m L of 
plas ma, will be c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of P F - 0 7 2 5 8 6 6 9 as 
s pecifie d i n t he S o A . I nstr ucti o ns f or t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will 
be pr o vi de d i n t he la b orat or y ma n ual or b y  t he s p o ns or. T he act ual ti mes ma y c ha n ge; the 
act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h sa m ple will be rec or de d.
All eff orts will be ma de t o o btai n t he sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. 
C o llecti o n of sa m ples u p t o a n d i ncl u di n g 1 0 h o urs after d ose a d mi nistrati o n t hat are
o btai ne d wit hi n 1 0 % of t he n o mi nal ti me relati ve t o d osi n g (e g, wit hi n 6 mi n utes of a 
6 0 - mi n ute sa m ple) will n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he e xact ti me of 
t he c ollecti o n is n ote d o n t he s o urce d oc u me nt a n d t he C R F . C ollecti o n of sa m ples m ore t ha n 
1 0 h o urs after d ose a d mi nistrati o n t hat are o btai ne d ≤1 h o ur fr o m t he n o mi nal ti me relative t o
d osi n g will n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he e xact ti me of t he c ollecti o n 
is n ote d o n t he s o urce d oc u me nt a n d t he C R F . T his pr ot oc ol de viati o n wi n d o w d oes n ot 
a p pl y t o sa m ples t o be c ollecte d m ore t ha n 1 0 h o urs after d ose a d mi n istrati o n at 
o ut patie nt/f oll o w -u p visits wit h visit wi n d o ws.
Sa m ples will be use d t o e val uate t he P K of P F -0 7 2 5 8 6 6 9 . Sa m ples c ollecte d f or a nal ys es of 
P F - 0 7 2 5 8 6 6 9 plas ma c o nce ntrati o ns m a y  als o be use d t o e val uate safety or efficac y as pects 
relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y, f or meta b olite i de ntificati o n a n d/ or 
e val uati o n of t he bi oa nal ytical met h o d, or f or ot her i nter nal e x pl orat or y  p ur p oses.
Ge netic a nal ys es will not be perf or me d o n t hese plas ma sa m ples u nless c o nse nt f or t his was 
i ncl u de d i n t he i nf or me d c o nse nt. Partici pa nt c o nfi de ntialit y will be mai ntai ne d.
Sa m ples c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of P F -0 7 2 5 8 6 6 9 will be 
a nal yz e d usi n g a vali dat e d a nal yt ical met h o d i n c o m plia nce wit h a p plica ble S O Ps.
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 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 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 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 ha s bee n c o m pr o mise d.
Dr u g c o nce ntrati o n i nf or mati o n t hat ma y  u n bli n d t he st u d y will n ot be re p orte d t o 
i n vesti gator sites or bli n de d pers o n nel u ntil t he st u d y has bee n u n bli n de d.
A n y  c ha n ges i n t he ti mi n g or a d diti o n of ti me p oi nts f or a n y pla n ne d st u dy ass ess me nts m ust 
be d oc u me nte d a n d a p pr o ve d b y t he rele va nt st u d y tea m me m ber a n d t he n arc hi ve d i n t he 
s p o ns or a n d site st u d y files, b ut will n ot c o nstit ute a pr ot oc ol a me n d me nt. T he IR B/ E C will 
be i nf or me d of a n y safet y iss ues t hat re q uire alterati o n of t he safety m o nit ori n g sc he me or 
a me n d me nt of t he I C D.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 5
8. 4. 2. Uri ne f or A n al ysis of P F -0 7 2 5 8 6 6 9 C o nce ntr ati o ns ( P art A O nl y)
Uri ne will be c ollecte d as o utli ne d i n t he S o A . 
A s p ot u ri ne collecti o n will be c o m plete d pri or t o t he m or ni n g d os e o n Da y  1. Eac h 
partici pa nt will c o m plete a f orce d v oi d. A 1 0 m L  ali q u ot fr o m t his uri ne (“ uri ne bla n k”) will 
be c ollecte d a n d st ore d fr oze n f or meas ure me nt of P F- 0 7 2 5 8 6 6 9 c o nce ntrati o ns.
Eac h partici pa nt will e m pt y  his/ her bla d der j ust pri or t o d osi n g o n D a y  1 4, a n d uri ne 
c ollecti o n will occ ur o ver 0 -, acc or di n g t o t he d osi n g fre q ue nc y  (ie, 0- 8 h o urs f or Q 8 H
d osi n g ; 0- 1 2 h o urs f or Q 1 2 H d osi n g ). Uri ne will be st ore d at a p pr o xi matel y  4° C d uri n g t he 
c ollecti o n peri o d. At t he e n d of t he c ollecti o n peri o d, t he uri ne will be mi xe d t h or o u g hl y , a n d
t he t otal v ol u me will be meas ure d a n d rec or de d. A 1 0 m L  ali q u ot will be retai ne d f or 
meas ure me nt of P F -0 7 2 5 8 6 6 9 c o nce ntrati o ns a n d will be st ore d fr oze n at 
a p pr o xi matel y -2 0° C wit hi n 1 h o ur of t he e n d of t he c ollecti o n i nter val.
T he preferre d t u bes f or c ollecti o n a n d st ora ge will be i de ntifie d a n d t his i nf or mati o n will be
pr o vi de d t o t he site pri or t o start of t he st u d y. Sa m ples will be a nal yz e d usi n g a vali date d
a nal yt ical met h o d i n c o m plia nce wit h Pfizer sta n dar d o perati n g pr oce d ures.
As part of u n dersta n di n g t he P K of P F - 0 7 2 5 8 6 6 9, sa m ples ma y be use d f or meta b olite 
i de ntificati o n a n d/ or e val uati o n of t he bi oa nalyt ical met h o d. 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 re p ort. Sa m ples 
c ollecte d f or t his p ur p ose will be retai ne d i n acc or da nce t o l ocal re g ulati o ns a n d if n ot use d 
wit hi n t his ti mefra me, will be destr o y e d.
8. 4. 3. Pl as m a f or Q u alit ati ve Met a b olite Pr ofili n g ( P art A o nl y)
Bl o o d sa m ples ( 2 m L eac h) t o pr o vi de s ufficie nt plas ma will be c ollecte d f or meta b olite 
pr ofili n g i nt o a p pr o priatel y  la bele d t u bes c o ntai ni n g a ntic oa g ula nt at ti mes s pecifie d i n t he 
S o A . T hese sa m ples ma y be use d f or meta b olite i de ntificati o n a n d/ or e val uati o n of t he 
bi oa nal y tical met h o d. Sa m ples t o be use d f or t his p ur p ose will be s hi p pe d t o eit her a 
Pfizer -a p pr o ve d B B S facilit y or ot her desi g nate d la b orat or y a n d retai ne d f or u p t o 1 ye ar 
f oll o wi n g t he c o m pleti o n of t he st u d y. T hese data ma y be use d f or i nter nal e x pl orat or y 
p ur p oses a n d wil l n ot be i ncl u de d i n t he C S R f or t his st u d y.
8. 4. 4. Pl as m a f or A n al ysis of Mi d az ol a m C o nce ntr ati o ns ( P art B o nl y)
Bl o o d sa m ples of a p pr o xi matel y  3 m L , t o pr o vi de a mi ni m u m of a p pr o xi matel y 1 m L of 
plas ma, 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 K2E D T A f or 
meas ure me nt of plas ma c o nce ntrati o ns of mi daz ola m as s pecifie d i n t he S o A . I nstr ucti o ns f or 
t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d i n t he la b orat or y ma n ual 
or b y  t he s p o ns or. T he act ual ti me s ma y c ha n ge; the act ual date a n d ti me ( 2 4- h o ur cl oc k 
ti me) of eac h sa m ple will be rec or de d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 6
All eff orts will be ma de t o o btai n t he sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. 
C ollecti o n of sa m ples u p t o a n d i ncl u di n g 1 0 h o urs after d ose a d mi nistrati o n t hat are
o btai ne d wit hi n 1 0 % of t he n o mi nal ti me relati ve t o d osi n g (e g, wit hi n 6 mi n utes of a 
6 0 - mi n ute sa m ple) will n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he e xact ti me of 
t he c ollecti o n is n ote d o n t he s o urce d oc u me nt a n d t he C R F . C ollecti o n of sa m ples m ore t ha n 
1 0 h o urs after d ose a d mi nistrati o n t hat are o btai ne d ≤1 h o ur fr o m t he n o mi nal ti me relati ve t o 
d osi n g will n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he e xact ti me of t he c ollecti o n 
is n ote d o n t he s o urce doc u me nt a n d t he C R F . T his pr ot oc ol de viati o n wi n d o w d oes n ot 
a p pl y t o sa m ples t o be c ollecte d m ore t ha n 1 0 h o urs after d ose a d mi nistrati o n at 
o ut patie nt/f oll o w -u p visits wit h visit wi n d o ws.
Plas ma sa m ples will be a nal y ze d usi n g a vali date d a nal yt ical met h od i n c o m plia nce wit h 
Pfizer S O Ps. Sa m ples c ollecte d f or a nal ys es of mi daz ola m plas ma c o nce ntrati o n ma y  als o be 
use d t o e val uate safet y or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or after t he 
st u d y, f or meta b olite i de ntificati o n a n d/ or e val uati on of t he bi oa nal yt ical met h o d, or f or ot her 
i nter nal e x pl orat or y p ur p oses.
Ge netic a nal ys es will n ot be perf or me d o n t hese plas ma sa m ples u nless c o nse nt f or t his was 
i ncl u de d i n t he i nf or me d c o nse nt. Partici pa nt c o nfi de ntialit y will be mai ntai ne d.
Sa m ples c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of mi daz ola m will be a nal yz e d 
usi n g a vali date d a nal yt ical met h o d i n c o m plia nce wit h a p plica ble S O Ps. 
Detail pr oce d ure re gar di n g t he c ollecti o n, pr ocessi n g, st ora ge a n d s hi p pi n g of t he plas ma
sa m ples will be pr o vi de d i n t he la b orat or y ma n ual. 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 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 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 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 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 res ulti n g i n c o m pr o mise d sa m ple i nte grity will be 
c o nsi dere d a pr ot oc ol de viati o n.
As part of u n dersta n di n g t he P K of t he st u d y i nter ve nti o n, sa m ples ma y be use d t o e val uate 
safety as pects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y, f or meta b olite 
i de ntificati o n a n d/ or e val uati o n of t he bi oa nalyt ical met h o d, as well as f or ot her i nter nal 
e x pl orat or y p ur p oses.  T hese data will n ot be i ncl u de d i n t he C S R. 
8. 5. P h ar m ac o d y n a mics
8. 5. 1. B o d y W ei g ht
All b o d y  wei g ht assess me nts (e xce pt t he assess me nt at t he scree ni n g visit) s h o ul d be 
perf or me d usi n g t he cali brate d di gital b o d y  wei g ht s mart scale i nc or p orate d i nt o t he F D A 
a p pr o ve d m ulti-fre q ue nc y se g me ntal b o d y c o m p ositi o n a nal yzer descri be d i n Secti o n 8. 5. 2 . 
T he sa me scale s h o ul d be use d f or t he d urati o n of t he st u d y  (e xce pt at scree ni n g). B o d y
w ei g ht will be rec or de d i n eit her p o u n ds (l b) or kil o gra ms ( k g), a n d acc urac y t o t he nearest 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 7
0. 2 l b ( or 0. 1 k g); (ie, t he scale m ust be a ble t o disti n g uis h a differe nce bet wee n 1 5 0. 4 l b 
( 6 8. 4 k g) vers us 1 5 0. 2 l b ( 6 8. 3 k g). B o d y wei g ht m ust be rec or de d t o o ne deci mal place. T he 
scale m ust be place d o n a sta ble, flat s urface. Partici pa nts will be bli n de d t o b o d y  wei g ht 
meas ure me nt (e xce pt at scree ni n g). 
B o d y w ei g ht meas ure me nt s s h o ul d be ta ke n u n der t he f oll o wi n g c o n diti o ns:

After a n o ver ni g ht fast ;

After v oi d of uri ne;

After re m o val of s h oes, b ul k y  la yers of cl ot hi n g, a n d jac kets s o t hat o nl y li g ht 
cl ot hi n g re mai ns;

W hile re mai ni n g still d uri n g t he meas ure me nt.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 8
8. 6. Ge netics
8. 6. 1. S pecifie d Ge netics
Ge netics (s pecifie d a nal yses) are n ot e val uate d i n t his st u d y .
8. 6. 2. Ret ai ne d Rese arc h S a m ples f or Ge netics
A 2- m L  bl o o d sa m ple o pti mize d f or D N A is olati o n Pre p D 1. 5 will be c ollecte d acc or di n g t o 
t he S o A , as l ocal re g ulati o ns a n d IR Bs/ E Cs all o w.
Retai ne d Researc h Sa m ples 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). 
Ge nes a n d ot her a nal y tes (e g, pr otei ns, R N A, n o n dr u g meta b olites) ma y  be st u die d usi n g t he 
ba n ke d sa m ples. 
See A p pe n di x 5 f or inf or mati o n re gar di n g ge netic researc h. Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt of t hes e sa m ples ca n be f o u n d i n t he la b ma n ual a n d ot her 
s u p p orti n g d oc u me ntati o n.
8. 7. Bi o m ar kers
C ollecti o n of sa m ples f or bi o mar ker researc h is als o part of t his st u d y . 
8. 7. 2. Pl as m a f or Deter mi n ati o n of 4 - Hy dr o x yc h olester ol/ C h olester ol R ati o
Bl o o d sa m ples (a p pr o xi matel y  3 m L) t o pr o vi de a mi ni m u m of a p pr o xi matel y 1 m L  of 
plas ma f or t he a nal ys is of 4-h y dr o x yc h olester ol a n d c h olester ol will be c oll ecte d i nt o 
a p pr o priatel y la bele d t u bes c o ntai ni n g lit hi u m he pari n. Sa m ples will be c ollecte d acc or di n g 
t o t he ti mes o utli ne d i n t he S o A . Refer t o t he la b ma n ual f or s pecific i nstr ucti o ns.
8. 7. 3. Uri ne f or Deter mi n ati o n of 6 -H y dr o x yc ortis ol/ C ortis ol R ati o
A pre -d ose 2 4- h o ur uri ne c ollecti o n will be u n derta ke n o n Da y  -1 pri or t o d osi n g. I n 
a d diti o n, 2 4- h o ur uri ne c ollecti o n will als o be u n derta ke n o n D a y  7 f or Part B a n d D a y 1 4 f or 
Part A. T he Da y  1 4 c ollecti o n will c o nti n ue fr o m t he 0- sa m ple t hat was c ollecte d acc or di n g 
t o t he d osi n g fre q ue nc y as o utli ne d i n Secti o n 8. 4. 2 . At t he e n d of eac h of t he uri ne c ollecti o n 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 8 9
peri o d s ( 0 t o 2 4 h o urs), t he t otal uri ne v ol u me will be meas ure d a n d rec or de d, a n d a 5 m L  
ali q u ot will be tra nsferre d t o a n a p pr o priatel y la bele d scre w -ca p pe d p ol y pr o p yle ne t u be f or 
a nal ys is of cortis ol. A n ot her 5 m L  ali q u ot will be tra nsferre d t o a n a p pr o priatel y la bele d 
scre w-ca p pe d p ol y pr o p yl e ne t u be f or 6- hy dr o x yc ortis ol a nal y sis.
8. 7. 4. E xtr acell ul ar Vesicle A n al ysis of C Y P 3 A I n d ucti o n
Bl o o d sa m ples (f or ser u m) of a p pr o xi matel y  4 m L will be c ollecte d as o utli ne d i n S o A .
T hese ser u m sa m ples ma y be a nal yz e d t o assess na n o vesicle (e x os o me) -deri ve d bi o mar kers
f or dr u g meta b olis m pat h wa ys;2 7 of i nterest bei n g assess me nt of C Y P 3 A ac ti vit y at baseli ne
a n d f oll o wi n g re peate d d osi n g wit h P F- 0 7 2 5 8 6 6 9 . A n y re mai ni n g ser u m ma y be teste d i n
ot her platf or ms (tra nscri pt o mics, meta b ol o mics, pr ote o mics, etc) t o assess f or p ote ntial
C Y P 3 A i n d ucti o n , or i n relati o n t o t he st u d y i nter ve nti o n or ge riatric a n ore xia. T hese data, if
ge nerate d, 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 C S R.
8. 7. 5. Bi o m ar kers S a m ple H a n dli n g
I nstr ucti o ns f or t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d i n t he 
la b orat or y ma n ual or b y  t he s p o ns or. Sa m ples will be a nalyz e d usi n g vali date d a nal yt ical 
met h o ds i n c o m plia nce wit h a p plica ble S O Ps. 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 C S R.
T he act ual ti mes ma y  c ha n ge, b ut t he n u m ber of sa m ples will re mai n t he sa me. All eff orts 
will be ma de t o o btai n t he sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. C ollecti o n of 
sa m ples u p t o a n d i ncl u di n g 1 0 h o urs after d ose a d mi nistrati o n t hat are o btai ne d wit hi n 
1 0 % of t he n o mi nal ti m e relati ve t o d osi n g (e g, wit hi n 6 mi n utes of a 6 0- mi n ute sa m ple) will 
n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he e xact ti me of t he c ollecti o n is n ote d o n 
t he s o urce d oc u me nt a n d t he C R F. C ollecti o n of sa m ples m ore t ha n 1 0 h o urs after d ose 
a d mi nistrati o n t hat are o btai ne d ≤1 h o ur a wa y  fr o m t he n o mi nal ti me relati ve t o d osi n g will
n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he e xact ti me of t he c ollecti o n is n ote d o n 
t he s o urce d oc u me nt a n d t he C R F. T his pr ot oc ol de viati o n wi n d o w d oes n ot a p pl y t o sa m ples 
t o be c ollecte d m ore t ha n 1 0 h o urs after d ose a d mi nistrati o n at o ut patie nt/f oll o w-u p visits 
wit h visit wi n d o ws.
As part of u n dersta n di n g t he P D of t he 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 t he bi oa nal ytical met h o d, as well as f or ot her i nter nal e x pl orat or y p ur p oses. 
T he e x pl orat or y  bi o mar ker 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 
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 grity. A n y de viati o ns 
fr o m t he e x pl orat or y bi o mar kers sa m ple ha n dli n g pr oce d ures (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 grit y has bee n c o m pr o mise d.
8. 7. 6. S pecifie d Ge ne E x pressi o n ( R N A) Rese arc h
S pecifie d ge ne e x pressi o n ( R N A) researc h is n ot i ncl u de d i n t his st u d y .
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 0
8. 7. 7. S pecifie d Pr otei n Rese arc h
S pecifie d pr otei n researc h is n ot i ncl u de d i n t his st u d y .
8. 7. 8. S pecifie d Met a b ol o mic Rese arc h 
S pecifie d meta b ol o mic researc h is n ot i ncl u de d i n t his st u d y .
8. 7. 9. Ret ai ne d Rese arc h S a m ples f or Bi o m ar kers
T hese Retai ne d Researc h Sa m ples will be c ollecte d i n t his st u d y :

1 0 m L  bl o o d P re p B 1 o pti mize d f or plas ma ;

1 0 m L  bl o o d Pr e p B 2 o pti mize d f or ser u m .
Retai ne d Researc h Sa m ples will be c ollecte d as l ocal re g ulati o ns a n d I RB/ E Cs all o w
acc or di n g t o t he S o A . 
Retai ne d Researc h Sa m ples 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). 
Ge nes a n d ot her a nal y tes (e g, pr otei ns, R N A, n o n dr u g meta b olites) ma y  be st u die d usi n g t he 
retai ne d sa m ples. 
See A p pe n di x 5 f or inf or mati o n re gar di n g ge netic 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 t he la b ma n ual a n d ot her 
s u p p orti n g d oc u me ntati o n. 
8. 8. I m m u n o ge nicit y Assess me nts
I m m u n o ge nicity assess me nts are n ot i ncl u de d i n t his st u d y .
8. 9. He alt h Ec o n o mics
Healt h ec o n o mics/m e dical res o urce u tilizati o n a n d h ealt 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 nalys 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 dify 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 d p oi nt defi niti o ns or t heir a nalys es will als o be reflecte d i n a 
pr ot oc ol a me n d me nt.
9. 1. St atistic al H y p ot heses
N o f or mal statistical h y p ot hesis testi n g wil l be perf or me d i n t his st u d y.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 1
9. 2. 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 nal ys is sets are defi ne d:
P artici p a nt A n al ysis Set
Descri pti o n
E nr olle d/ Ra n d o ml y  
assi g ne d t o st u d y 
i nter ve nti o n 
" E nr olle d" mea ns a partici pa nt's a gree me nt t o partici pate i n a 
cli nical st u d y f oll o wi n g c o m pleti o n of t he i nf or me d c o nse nt 
pr ocess a n d scree ni n g. P ote ntial partici pa nts w h o are 
scree ne d f or t he p ur p ose of deter mi ni n g eli gi bilit y f or t he 
st u d y, b ut d o n ot partici pate i n t he st u d y, are n ot c o nsi dere d 
e nr olle d, u nl ess ot her wise s pecifie d b y t he pr ot oc ol. A 
partici pa nt will be c o nsi dere d e nr olle d if t he i nf or me d 
c o nse nt is n ot wit h dra w n pri or t o partici pati n g i n a n y  st u d y 
acti vit y after scree ni n g.
F ull A nal ys is Set ( F A S)
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n a n d 
w h o ta ke at least 1 d ose of st u d y  i nter ve nti o n, f or t he gi ve n 
part of t he st u d y ( Part A or B) .
Safet y  A nalys is Set
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n a n d 
w h o ta ke at least 1 d ose of st u d y  i nter ve nti o n, f or t he gi ve n 
part of t he st u d y ( Part A or B) . Partici pa nts will be a nalyz e d 
acc or di n g t o t he pr o d uct t he y act uall y recei ve d.
P K C o nce ntrati o n Set
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n a n d 
w h o ta ke at least 1 d ose of mi daz ola m a n d/ or st u d y 
i nter ve nti o n a n d i n w h o m at least 1 plas ma or uri ne 
c o nce ntrati o n val ue is re p orte d , f or t he gi ve n part of t he st u d y 
( Part A or B).
P K Para meter Set
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nter ve nti o n a n d 
w h o ta ke at least 1 d ose of mi daz ola m a n d/ or st u d y 
i nter ve nti o n a n d ha ve at least 1 of t he P K para meters of 
i nterest calc ulate d, f or t he gi ve n part of t he st u d y ( Part A 
or B) .
9. 3. 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 nalys es are p erf 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.
9. 3. 1. Ge ner al C o nsi der ati o ns
Part A a n d Part B of t he st u d y  will be prese nte d se paratel y.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 2
9. 3. 2. S afet y E n d p oi nts
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 , f or t he gi ve n part of t he st u dy 
( Part A or Part B) .
A Es, E C Gs, B P, p ulse rate , c o nti n u o us car diac m o nit ori n g (f or Part A o nl y), a n d safet y 
la b orat or y data will be re vie we d a n d s u m marize d o n a n o n g oi n g basis d uri n g t he st u d y t o 
e val uate t he safet y of partici pa nts. A n y cli nical la b orat or y , E C G, B P, a n d p ulse rate 
a b n or malities of p ote ntial cli nical c o ncer n will be descri be d. Safet y data 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, w here a p pr o priate.
Me dical hist or y , p h y sical e xa mi nati o n, a n d ne ur ol o gical e xa mi nati o n i nf or mati o n, as 
a p plica ble, c ollecte d d uri n g t he c o urse of t he st u d y will be c o nsi dere d s o urce data a n d wil l 
n ot be re q uire d t o be re p orte d, u nless ot her wise n ote d. H o we ver, a n y u nt o war d fi n di n gs 
i de ntifie d o n p h ysical a n d/ or ne ur ol o gical e xa mi nati o ns c o n d ucte d d uri n g t he acti ve 
c ollecti o n peri o d will be ca pt ure d as A Es, if t h ose fi n di n gs meet t he defi niti o n of a n A E. 
Data c ollecte d at scree ni n g t hat are use d f or i ncl usi o n/e xcl usi o n criteria, s uc h as la b orat or y  
data, E C Gs, a n d vital si g ns, 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. De m o gra p hic data c ollecte d at scree ni n g will be re p orte d.
9. 3. 2. 1. 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 (ie, Q T i nter val, heart rate, Q Tc F i nter val, P R 
i nter val, a n d Q R S c o m ple x) 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 p ost d ose Q Tc F val ues a n d ma xi m u m 
i ncreases fr o m baseli ne i n t he f oll o wi n g cate g ories will be ta b ulate d b y  treat me nt: 
S afet y Q Tc F Assess me nt
De gree of Pr ol o n g ati o n
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
I ncrease fr o m baseli ne
3 0 -6 0
> 6 0
I n a d diti o n , t he n u m ber of partici pa nts wit h u nc orrecte d Q T val ues > 5 0 0 msec will be
s u m marize d.
If m ore t ha n 1 E C G is c ollecte d at a n o mi nal ti me after d ose a d mi nistrati o n (f or e xa m ple, 
tri plicate E C Gs), t he mea n of t he re plicate meas ure me nts will be use d t o re prese nt a si n gle 
o bser vati o n at t hat ti me p oi nt . If a n y of t he 3 i n di vi d ual E C G traci n gs has a Q TcF val ue 
> 5 0 0 msec, b ut t he mea n of t he tri plicates is n ot > 5 0 0 msec, t he data fr o m t he partici pa nt’s 
i n di vi d ual traci n g will be descri be d i n a safet y secti o n of t he C S R i n or der t o place t he 
> 5 0 0 -msec val ue i n a p pr o priate cli nical c o nte xt. H o we ver, val ues fr o m i n di vi d ual traci n gs 
wit hi n tri plicate meas ure me nts t hat are > 5 0 0 msec will n ot be i ncl u de d i n t he cate g orical 
anal ys is u nless t he a vera ge fr o m t he tri plicate meas ure me nts is als o > 5 0 0 msec. C ha n ges 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 3
fr o m baseli ne will be defi ne d as t he c ha n ge bet wee n t he p ost d ose Q TcF val ue a n d t he 
a vera ge of t he pre d ose tri plicate val ues o n Da y 1. 
I n a d diti o n, a n atte m pt will be ma de t o e x pl ore a n d c haracterize t he relati o ns hi p bet wee n 
plas ma c o nce ntrati o n a n d Q T i nter val le n gt h usi n g a P K/ P D m o deli n g a p pr oac h. If a P K/ P D 
relati o ns hi p is f o u n d, t he i m pact of partici pa nt fact ors (c o variates) o n t he relati o ns hi p will be 
e xa mi ne d. T he res ults of s uc h a nal ys es m a y n ot be i ncl u de d i n t he C S R.
9. 3. 3. P K E n d p oi nts
T he P K c o nce ntrati o n a n d para meter p o p ulati o ns f or t he gi ve n parts of t he st u d y  ( Part A or 
Part B) are defi ne d as i n Secti o n 9. 2 .
9. 3. 3. 1. Deri v ati o n of P F -0 7 2 5 8 6 6 9 P K P ar a meters ( P art A O nl y)
T he P K para meters f or P F- 0 7 2 5 8 6 6 9, f oll o wi n g oral d ose a d mi nistrati o n, will be deri ve d 
fr o m t he plas ma a n d uri ne c o nce ntrati o n-ti me pr ofiles as detaile d i n Ta ble 3 , as data per mit. 
I n all cases, act ual P K sa m pli n g ti mes will be use d i n t he deri vati o n of P K para meters.
T a ble 3 .
Deri v ati o n of P F - 0 7 2 5 8 6 6 9 P K P ar a meters
P a r a m eter
D a y(s)
Defi niti o n
M e t h o d of Deter mi n ati o n
A U C ta u
1, 1 4
Area u n der t he plas ma 
c o nce ntrati o n-ti me pr ofile fr o m 
ti me zer o t o ti me ta u (), t he 
d osi n g i nter val, w here
= 8 h o urs f or Q 8 H d osi n g, 
a n d 1 2 h o urs f or Q 1 2 H d osi n g.
Li near/ L o g tra pez oi dal 
met h o d
C ma x
1, 1 4
Ma xi m u m plas ma 
c o nce ntrati o n d uri n g t he d osi n g 
i nter val
O bser ve d directl y fr o m data
T ma x
1, 1 4
Ti m e f or C ma x 
O bser ve d directl y fr o m data 
as ti me of first occ urre nce
A U C ta u ( d n)
1, 1 4
D ose n or malize d A U C ta u
A U C ta u/ D ose
C ma x (d n)
1, 1 4
D ose n or malize d C ma x
C ma x / D ose
C L/ F
1 4
A p pare nt cleara nce f or oral 
d osi n g
D ose/ A U C t a u
C mi n
1 4
Mi ni m u m plas ma c o nce ntrati o n
d uri n g t he d osi n g i nter val
O bser ve d directl y fr o m data
C a v
1 4
A vera ge plas ma c o nce ntrati o n
d uri n g t he d osi n g i nter val
A U C ta u/ta u
R ac
1 4
O bser ve d acc u m ulati o n rati o
Da y  1 4 A U C ta u / 
Da y 1 A U C ta u
R ac, C ma x
1 4
O bser ve d acc u m ulati o n rati o 
f or Cma x
Da y  1 4 C ma x / Da y 1 C ma x
P T R
1 4
Pea k -t o-tr o u g h rati o
C ma x / Cmi n
t½ a
1 4
Ter m i nal half-life
L o g e( 2)/ kel, w here kel is t he 
ter mi nal p hase eli mi nati o n
rate c o nsta nt calc ulate d b y 
a li near re gressi o n of t he 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 4
T a ble 3 .
Deri v ati o n of P F - 0 7 2 5 8 6 6 9 P K P ar a meters
P a r a m eter
D a y(s)
Defi niti o n
M e t h o d of Deter mi n ati o n
l o g-li near 
c o nce ntrati o n-ti me c ur ve.  
V z/ Fa
1 4
A p pare nt v ol u me of 
distri b uti o n f or oral d osi n g
D ose/( A U C ta u * k el)
Ae ta u
1 4
A m o u nt of u nc ha n ge d dr u g 
rec o vere d i n uri ne d uri n g t he 
d osi n g i nter val
S u m of [ uri ne c o nce ntrati o n 
* sa m ple v ol u me] f or eac h 
c ollecti o n o ver t he d osi n g 
i nter val 
Ae ta u %
1 4
Perce nt of d ose rec o vere d i n 
uri ne as u nc ha n ge d dr u g
1 0 0 * Ae ta u/ D ose
C L r
1 4
Re nal cleara nce
Ae ta u/ A U Cta u
a.
If data per mit.
9. 3. 3. 2. Deri v ati o n of Mi d az ol a m P K P a r a meters ( P art B O nl y)
T he P K para meters f or mi daz ola m will be deri ve d fr o m t he plas ma c o nce ntrati o n -ti me 
pr ofiles as detaile d i n Ta ble 4 , as data per mit. In all case s, act ual P K sa m pli n g ti mes will be 
use d i n t he deri vati o n of P K para meters.
T a ble 4 .
Deri v ati o n of Mi d az ol a m P K P ar a meters
P a r a m eter
Defi niti o n
M e t h o d of Deter mi n ati o n
A U C last
Area u n der t he plas ma 
c o nce ntrati o n-ti me pr ofile fr o m 
ti me zer o t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n ( C last)
Li near/ L o g tra pez oi dal met h o d
A U C i nfa
Area u n der t he plas ma 
c o nce ntrati o n-ti me pr ofile fr o m 
ti me zer o e xtra p olate d t o i nfi nite 
ti me
A U C last + ( C last*/ k el),
w here C last* is t he pre dicte d plas ma c o nce ntrati o n at 
t he last q ua ntifia ble ti me p oi nt esti mate d fr o m t he 
l o g-li near re gressi o n a nal ysis.
C ma x
Ma xi m u m plas ma c o nce ntrati o n
O bser ve d directl y fr o m data
T ma x
Ti m e f or C ma x
O bser ve d directl y fr o m data as ti me of first occ urre nce
t½ a
T er m i nal half-life
L o g e( 2)/ kel,
w here k el is t he ter mi nal p hase rate c o nsta nt calc ulate d 
b y a li near re gressi o n of t he l o g -li near 
c o nce ntrati o n-ti me c ur ve. O nl y t h ose data p oi nts 
j u d ge d t o descri be t he ter mi nal l o g -li near decli ne will 
be use d i n t he re gressi o n.
C L/ F a
A p pare nt cleara nce f or oral d osi n g 
D ose/ A U C i nf
V z/ Fa
A p pare nt v ol u me of distri b uti o n f or 
oral d osi n g
A p pare nt v ol u me of distri b uti o n esti mate d fr o m 
ter mi nal p hase 
V z/ F = D ose /( A U Ci nf* k el)
a.
If data per mit.
9. 3. 3. 3. St atistic al Met h o ds f or P F -0 7 2 5 8 6 6 9 P K D at a ( P art A o nl y)
N o f or mal i nfere ntial statistics will be a p plie d t o t he P F - 0 7 2 5 8 6 6 9 P K data.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 5
Plas ma c o nce ntrati o ns of P F - 07 2 5 8 6 6 9 will be liste d a n d s u m marize d descri pti vel y b y  d ose,
p o p ulati o n , dietar y  all ocati o n, da y , a n d n o mi nal P K sa m pli n g ti me. I n di vi d ual partici pa nt, 
mea n a n d me dia n pr ofiles of t he plas ma c o nce ntrati o n -ti me data will be pl otte d b y d ose , 
p o p ulati o n , dietar y all ocati o n, a n d da y usi n g act ual (f or i n di vi d ual) a n d n o mi nal (f or mea n 
a n d me dia n) ti mes res pecti vel y . Mea n a n d me dia n pr ofiles will be prese nte d o n b ot h li near 
a n d l o g scales.
T he plas ma a n d uri ne P F - 0 7 2 5 8 6 6 9 P K para meters will be liste d a n d s u m marize d 
descri pti vel y b y d ose , p o p ulati o n, dietar y all ocati o n, a n d da y, as a p plica ble. D ose -n or malize d 
A U C ta u, a n d Cma x ma y  be pl otte d a gai nst d ose ( usi n g a l o garit h mic scale) f or eac h da y a n d 
will i ncl u de i n di vi d ual partici pa nt val ues a n d t he ge o metric mea ns f or eac h d ose. T he data 
fr o m t he Ja pa nese partici pa nts (if e nr olle d) a n d ol der a d ult partici pa nts (if e nr olle d) will be 
i de ntifie d b y differe nt s y m b ols/c ol ors.  
Attai n me nt of stea d y- state will be assesse d b y a pl ot of pre d ose c o nce ntrati o ns o ver ti me. 
T hese pl ots will be use d t o u n dersta n d t he relati o ns hi p bet wee n t he P K para meters a n d d ose.
A d diti o nal P K a nal y ses ma y be perfor me d if dee me d a p pr o priate a n d ma y n ot be i ncl u de d i n 
t he C S R.
9. 3. 3. 4. St atistic al Met h o ds f or Mi d az ol a m P K D at a ( P art B o nl y)
Plas ma c o nce ntrati o ns of mi daz ola m will be liste d a n d s u m marize d descri pti vel y  b y n o mi nal 
P K sa m pli n g ti me a n d treat me nt (mi daz ola m al o ne o n Peri o d 1 / Da y 1, c o-a d mi nistrati o n o n 
Peri o d 2/ D a y  2, a n d c o -a d mi nistrati o n o n Peri o d 2/ Da y  1 0). I n di vi d ual partici pa nt , mea n a n d 
me dia n pr ofiles of t he c o nce ntrati o n-ti me data will be pl otte d b y  treat me nt usi n g act ual (f or 
i n di vi d ual) a n d n o mi nal (f or mea n a n d me dia n ) ti mes res pecti vely. Mea n a n d me dia n pr ofiles 
will be prese nte d o n b ot h li near a n d l o g scales.
T he mi daz ola m P K para meters will be liste d a n d s u m marize d descri pti vel y by treat me nt. 
A U C i nf, A U Clast, a n d C ma x w ill be pl otte d b y treat me nt, a n d will i ncl u de i n di vi d ual partici pa nt 
val ues a n d t he ge o metric mea ns f or eac h treat me nt .
Nat ural l o g tra nsf or me d A U C i nf, A U Clast, a n d C ma x of mi daz ola m will be a nal y ze d usi n g a 
mi xe d effect m o del wit h treat me nt as a fi xe d effect a n d partici pa nt as a ra n d o m effect. 
Esti mates of t he a dj uste d mea n differe nces ( Test -Refere nce) a n d c orres p o n di n g 
9 0 % c o nfi de nce i nter vals will be o btai ne d fr o m t he m o del. T he a dj uste d mea n differe nces 
a n d 9 0 % c o nfi de nce i nter vals f or t he differe nces will be e x p o ne ntiate d t o p r o vi de esti mates 
of t he rati o of a dj uste d ge o metric mea ns ( Test/ Refere nce) a n d 9 0 % c o nfi de nce i nter vals f or 
t he rati os. Mi daz ola m al o ne ( Peri o d 1) will be t he Refere nce treat me nt, w hile t he mi daz ola m 
c o-a d mi nistere d wit h P F - 0 7 2 5 8 6 6 9 ( o n Da y 2 or 1 0 i n Perio d 2 ) will be t he Test treat me nt s.
A d diti o nal P K a nal y ses ma y be perf or me d if dee me d a p pr o priate a n d ma y n ot be i ncl u de d i n 
t he C S R.
If a d diti o nal c o h orts are i ncl u de d i n t he st u d y, all s u m maries a n d a nal yses will als o i ncl u de 
c o h ort/ d ose.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 6
9. 3. 4. Terti ar y/ E x pl or a t or y E n d p oi nt(s)
C ha n ge fr o m baseli ne i n b o d y  wei g ht i n t he o pti o nal a d diti o nal c o h orts all ocate d t o t he 
H F H C diet (if c o n d ucte d) will be a nal yz e d usi n g a n M M R M m o del wit h treat me nt, ti me (as a 
fact or), treat me nt-b y -ti me i nteracti o n, baseli ne (as a c o variate) a n d baseli ne -b y -ti me
i nteracti o n as fi xe d effects. Partici pa nt will be fitte d as a ra n d o m effect i n t he m o del wit h 
ti me as a re peate d effect wit hi n eac h partici pa nt . F urt her details will be gi ve n i n t he S A P . 
T he a nal ys is of ot her e x pl orat or y  e n d p oi nts will be detaile d i n t he S A P.
9. 3. 5. Ot her A n al yse (s)
P har mac o ge n o mic or bi o mar ker data fr o m Retai ne d Researc h Sa m ples ma y  be c ollecte d 
d uri n g or after t he trial a n d retai ne d f or f ut ure a nal yses; t he res ults of s uc h a nal ys es are n ot 
pla n ne d t o be i ncl u de d i n t he C S R.
9. 4. I nteri m A n al yses
N o f or mal i nteri m a nal ys is will be c o n d ucte d f or t his st u d y. As t his is a s p o ns or-o pe n st u d y ,
t he s p o ns or ma y c o n d uct u n bli n de d re vie ws of t he data d uri n g t he c o urse of t he st u d y f or t he 
p ur p ose of safet y assess me nt, facilitati n g d ose -escalati o n decisi o ns, facili tati n g P K/ P D 
m o deli n g, a n d/ or s u p p orti n g cli nical de vel o p me nt. A li mite d n u m ber of t he s p o ns or’s tea m 
me m bers (e xcl u di n g site staff) m a y  c o n d uct t he u n bli n de d re vie ws.
9. 5. S a m ple Size Deter mi n ati o n
Partici pa nts i n eit her Part A or Part B, w h o disc o nti n ue pri or t o c o m pleti o n of t he st u d y  f or 
reas o ns u nrelate d t o safet y , m a y  be re place d at t he discreti o n of t he i n vesti gat or a n d s p o ns or. 
9. 5. 1. P art A S a m ple Size
A sa m ple size of u p t o a p pr o xi matel y  1 0 healt h y  a d ult n o n-Ja pa nese partici pa nts per c o h ort 
( 8 acti ve, 2 place b o) has bee n selecte d t o mi ni mize e x p os ure t o h u ma ns t o a ne w c he mical 
e ntit y w hile all o wi n g f or a de q uate c haracterizati o n of safet y, t olera bilit y, a n d P K at eac h 
d ose le vel. T h is d ose escalati o n p orti o n c o nsists of u p t o 8 pla n ne d c o h orts . A d diti o nal 
o pti o nal c o h ort s ma y be e nr olle d t o re peat a d ose or t o e x pa n d t he d ose/e x p os ure ra n ge or 
better c haracterize a partic ular safet y or t olera bilit y si g nal or cli nical bi o mar ker of i nterest
(e g, b o d y  wei g ht).
A n o pti o nal c o h ort of a p pr o xi matel y 8 healt h y  Ja pa nese partici pa nts ( 6 acti ve, 2 pla ce b o) 
ma y  als o be i ncl u de d. T his sa m ple size has bee n j u d ge d s ufficie nt t o o btai n a preli mi nar y  
e val uati o n of safet y, t olera bilit y , a n d P K data i n t his p o p ulati o n.
I n a d diti o n, a n o pti o nal c o h ort of a p pr o xi matel y 8- 1 0 ol der a d ult partici pa nts ( a p pr o xi matel y 
6 - 8 acti ve, 2 place b o) ma y  be i ncl u de d. T his sa m ple size has bee n j u d ge d s ufficie nt t o o btai n 
a preli mi nar y e val uati o n of safety, t olera bilit y , a n d P K data i n t his p o p ulati o n.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 7
If c o n d ucte d, ap pr o xi matel y  2 4 partici pa nts will be ra n d o mize d i n a 1: 1 rati o t o eit her
P F - 0 7 2 5 8 6 6 9 or place b o i n t he first o pti o nal c o h ort of n o n -Ja pa nese partici pa nts all ocate d t o 
t he H F H C diet. T his sa m ple size was selecte d t o pr o vi de safety a n d t olera bilit y data u n der 
t he H F H C diet restricti o ns a n d pr o vi de acce pta bl e o perati n g c haracteristics t o assess c ha n ge
fr o m baseli ne i n b o d y wei g ht. T his y iel ds 8 0 % p o wer t o detect a place b o- a dj uste d i ncrease i n 
b o d y  wei g ht of 1. 7 8 k g (c o m pari n g P F- 0 7 2 5 8 6 6 9 t o place b o) at Da y 1 4, usi n g a 1 -si de d 
t-test at a 5 % le vel a n d ass u mi n g a c o nser vati ve S D of 1. 7 f or b o dy wei g ht c ha n ge fr o m 
baseli ne at D a y  1 4. Data fr o m 1 4 pre vi o us e xter nal st u dies were utilize d t o deri ve t his
c o nser vati ve esti mate of varia bilit y . 
A sec o n d o pti o nal c o h ort of n o n -Ja pa nese partici pa nts all ocate d t o t he H F H C diet ma y  als o
be e nr olle d t o f urt her c haracterize t he d ose/ e x p os ure -res p o nse relati o ns hi p wit h res pect t o 
c ha n ge fr o m baseli ne i n b o d y  wei g ht. In t h is c o h ort (if c o n d ucte d), a p pr o xi matel y 
1 6 partici pa nts will be ra n d o mize d i n a 3: 1 r ati o t o eit her P F -0 7 2 5 8 6 6 9 (a p pr o xi matel y  
1 2 partici pa nts) or place b o (a p pr o xi matel y  4 participa nts) . T his sa m ple size was selecte d t o 
gi ve si milar o perati n g c haracteristics as f or t he first c o h ort all ocate d t o t he H F H C diet, s uc h 
t hat partici pa nts o n plac e b o w o ul d be p o ole d acr oss c o h orts all ocate d t o t he H F H C diet . 
A p pr o xi matel y  4 partici pa nts recei vi n g place b o was selecte d t o mai ntai n t he bli n d i n t his 
sec o n d o pti o nal c o h ort all ocate d t o H F H C diet. 
9. 5. 2. P art B S a m ple Size
A sa m ple size of a p pr o xi matel y  12 partici pa nts per c o h ort will be e nr olle d s uc h t hat 
a p pr o xi matel y 1 0 e val ua ble partici pa nts per c o h ort c o m plete t he st u d y. T his n u m ber of 
e val ua ble partici pa nts s h o ul d pr o vi de s ufficie nt precisi o n t o assess t he differe nce i n A U C i nf
a n d C ma x f or t he c o-a d ministrati o n of mi daz ola m a n d P F - 0 7 2 5 8 6 6 9 vers us mi daz ola m al o n e. 
T he e x pecte d wi dt hs of t he 9 0 % c o nfi de nce i nter vals , wit h 8 0 % c o vera ge pr o ba bilit y , f or
t hese c o m paris o ns, are s h o w n i n Ta ble 5 , f or a ra n ge of p ossi ble effects base d o n a sa m ple
size of 10 partici pa nts.
T a ble 5.
E x pecte d Wi dt hs of t he 9 0 % CIs ( wit h 8 0 % C o ver a ge Pr o b a bilit y) f or 
Differe nt P ossi ble Esti m ate d Effects f or A U C i nf a n d C m a x
P a r a m eter
S a m ple Size
Esti m ate d Effect
( Test/ Refere nce)
Pr o b a ble
9 0 % CI
Pr o b a ble
CI Wi dt h
A U C i nf
N = 1 0
7 5 %
5 7 % t o 9 8 %
4 1 %
1 0 0 %
7 6 % t o 1 3 1 %
5 5 %
1 5 0 %
1 1 4 % t o 1 9 7 %
8 2 %
2 0 0 %
1 5 2 % t o 2 6 2 %
1 1 0 %
3 0 0 %
2 2 9 % t o 3 9 4 %
1 6 5 %
C ma x
N = 1 0
7 5 %
4 9 % t o 1 1 4 %
6 5 %
1 0 0 %
6 6 % t o 1 5 2 %
8 6 %
1 5 0 %
9 9 % t o 2 2 8 %
1 2 9 %
2 0 0 %
1 3 2 % t o 3 0 4 %
1 7 2 %
3 0 0 %
1 9 7 % t o 4 5 6 %
2 5 9 %
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 8
T hese esti mates are base d o n a n ass u me d c o nser vati ve sta n dar d de viati o n of 0. 2 8 4 
(e q ui vale nt t o a ge o metric c oefficie nt of variati o n of 2 9 %) i n l o geA U C i nf f or mi daz ola m; a n d 
0. 4 3 8 (e q ui vale nt t o a ge o metric c oefficie nt of variati o n of 4 6 %) i n l o g eC ma x . T h ese esti mates
of varia bilit y  are base d o n data fr o m pre vi o us i nter nal D DI st u dies wit h mi daz ola m.
A si n gle c o h ort is c urre ntl y  pla n ne d, b ut a d diti o nal o ptio nal c o h orts ma y  be a d de d if it is 
necessar y  t o e val uate t he effect of a d diti o nal d ose le vels of P F-0 7 2 5 8 6 6 9 o n mi daz ola m P K.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 9 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
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 ments 
(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, s u b mitte d t o a n IR B/ E C 
b y  t he i n vesti gat or, a n d re vie we d a n d a p pr o ve d b y  t he I R B/ 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.
Pr ot oc ols a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc ol will re q uire healt h a ut h orit y  
a p pr o val pri or t o i nitiati o 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 C P g ui deli nes, t he I R B/ E C, E ur o pea n re g ulati o n 
5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), E ur o pea n Me dical De vice Re g ulati o n 
2 0 1 7/ 7 4 5 f or cli nical de vice researc h (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.  
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 0
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 otec t t he st u d y partici pa nt s a gai nst a ny i m me diate hazar d, a n d 
of a n y seri o us breac hes of t his pr ot oc ol or of t he I C H G C P g ui deli nes t hat t he i n vesti gat or 
bec o mes a ware of.
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 state 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 , i ncl u di n g t he 
ris ks a n d be nefits, 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, pri vac y  a n d data pr otecti o n re q uire me nts, w here 
a p plica ble, 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 be rs, a n d by i ns pect 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 data.
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 o n w hic h t he writte n c o nse nt was 
o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C D.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 1
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.
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 he st u d y  site i n e ncr ypte d electr o nic a n d/ or pa per 
f or m a n d will be pass w or d -pr 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 
dis aster. 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 otificati o ns as re q uire d b y  la w.
T o pr otect t he ri g hts a n d free d o m s 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 nsferre 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 ntial list of partici pa nt s 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 D. 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 nt s’ pers o nal data 
c o nsiste nt wit h t he cli nical st u d y agree me nt a n d a p plica ble pri vac y  la ws.
1 0. 1. 5. C o m mittees Str uct ure
1 0. 1. 5. 1. D at a M o nit ori n g C o m mittee 
T his st u d y  will n ot use a D M C.
1 0. 1. 6. 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 the 
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 ducte d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 2
w w w.cli nicaltrials. g o v
Pfizer p osts cli 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 in w hic h t he st u d y  is c o n d ucte d. T hese r es 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 data, u n der P hase 1 of t his p olic y , i ncl u des cli nical 
o ver vie ws, cli nical su m maries, C S Rs, a n d a p pe n dices c o ntai ni n g t he p r ot oc ol a n d p r ot oc ol 
a me n d me nts, sa m ple C R F s, 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 hi n 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 ntrali ze 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 01 J ul y  2 0 1 5.
Data shari 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 data fr o m t hese trials a vaila ble 
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 nally i de ntifia ble i nf or mati o n 
re dacte d.
Data re q uests 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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 3
1 0. 1. 7. 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 
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.
G ui da nce o n c o m pleti o n of C R Fs will be pr o vi de d i n t he C R F Co m pleti o n Re q uire me nts 
d oc u me nt.
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 a n d/ or pa per f or m a n d are pass w or d - pr otecte d or sec ure d i n a l oc ke d r o o m t o 
pre ve nt access b y u na ut h orize d t hir d parti es.
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, 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 , i ncl u di n g defi niti o n of st u d y critical data items a n d 
pr ocesses (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 m a na ge me nt a n d 
m iti gati o n strate gies a n d anal 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, virt ual , or o n-site m o nit ori n g), are pr o vi de d i n t he data ma na ge me nt pla n a n d 
m o nit ori n g pla n mai ntai ne d a n d utilize d b y  t he s p o ns or or desi g nee.
T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y , i ncl u di n g 
q ualit y  c hec ki n g of t he data.
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C D s, 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 o n 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 part y 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 rec or 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 vest i 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 s p 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 will pr o m ptl y 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 4
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 m e nt o n res p o nses t o a n y s uc h fi n di n gs.
1 0. 1. 8. 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 a n d its ori gi n ca n be f o u n d i n t he s o urce d oc u me nt 
l ocat or, w hic h is mai ntai ne d b y t he s p o ns or.
Descri pti o n of t he use of t he c o m p uterize d s yste m is d oc u me nte d i n t he s o urce d oc u me nt 
l ocat or, w hic h is mai ntai ne d b y t he s p o ns or.
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.
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, IC H G C P g ui deli nes, a n d all a p plica ble re g ulat or y  re q uire me nts.
1 0. 1. 9. 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 f irst 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 s p 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  partici pa nts.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 5
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he s p o ns or 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 t he I C H 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 
in 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 
re q uire me nts. T he in 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 hera 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. 1 0. P u blic ati o n P olic y
T he 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 gator after p u blicati o n of t he o verall st u d y  res ults or 1 ye ar 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 mit s 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 ny 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 h e 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. I n t his case, a c o or di nati n g i n vesti gat 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 mi ttee of Me dical J o ur nal E dit ors a ut h ors hi p 
re q uire me nts. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 6
If p u blicati o n is a d dresse 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 1. 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 n s 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 cli nical trial ma na ge me nt s ys te m. 
T o facilitate access t o a p pr o priatel y q ualifie d me dical pers o n nel f or 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 n E C C at t he ti me of i nf or me d 
c o nse nt. T he E C C c o ntai ns, at a mi ni m u m, (a) pr ot oc ol a n d st u d y  i nter ve nti o n i de ntifiers, 
( b) partici pa nt’s st u d y  i de ntificati o n n u m ber, (c) site e mer ge nc y p h o ne n u m ber acti ve 
2 4 h o ur s/ da y, 7 da ys per wee k, a n d ( d) Pfizer C all C e nter n u m ber.
T he E C C is i nte n de d t o a u g me nt, n ot re place, t he esta blis he d c o m m u nicati o n pat h wa y s 
bet wee n t he i n vesti gat or, site staff, a n d st u d y  tea m. T he E C C is t o be use d b y healt hcare 
pr ofessi o nals n ot i n v ol ve d i n t he researc h st u d y o nl y , as a mea ns of reac hi n g t he i n vesti gat or 
or site staff relate d t o t he care of a partici pa nt. T he Pfizer Call Ce nter n u m ber s h o ul d o nl y  be 
use d w he n t he i n vesti gat or a n d site staff ca n n ot be reac he d. T he Pfizer Call Ce nter n u m ber is 
n ot i nte n de d f or use b y t he partici pa nt directl y ; if a partici pa nt calls t hat n u m ber directly, 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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 7
1 0. 2. A p pe n di x 2: Cli nic al L a b or at or y Tests
T he f oll o wi n g safet y la b orat or y  tests will be perf or me d at ti mes defi ne d i n t he S o A . 
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 cli nical la b orat or y, 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 a n y 
percei ve d safet y  iss ues.
T a ble 6.
Pr ot oc ol Re q uire d S afet y L a b or at or y Assess me nts
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 ocrit
R B C c o u nt
M C V
M C H
M C H C
Platelet c o u nt
W B C c o u nt
T otal ne utr o p hils ( A bs)
E osi n o p hils ( A bs)
M o n oc ytes ( A bs)
Bas o p hils ( A bs)
L y m p h oc ytes ( A bs)
B U N a n d creati ni ne
C ystati n C
e G F R ( C K D -E PI)
Gl uc ose (fasti n g)
Calci u m
S o di u m
P otassi u m
C hl ori de
T otal C O 2 ( bicar b o nate)
A S T, A L T
T otal bilir u bi n
Al kali ne p h os p hatase
Uric aci d
Al b u mi n
T otal pr otei n
Li pi d pa nel:
T otal c h olester ol
Tri gl yceri des
H D L
L D L (calc ulate d)
L ocal Di pstic k:
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
La b orat or y:
Micr osc o p y
a
Uri ne dr u g scree ni n g b
C O VI D -1 9 testi n g ( per C R U 
pr oce d ures)
At scree ni n g o nl y:
F S H c
He patitis B s urface 
a nti ge n
He patitis B s urface
anti b o d y
He patitis B c ore a nti b o d y
He patitis C a nti b o d y
H u ma n i m m u n o deficie nc y 
vir us
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.
T he mi ni m u m re q uire me nt f or dr u g scree ni n g i ncl u des c ocai ne, T H C, o piates/ o pi oi ds, be nz o diaze pi nes, 
a n d a m p heta mi nes ( ot hers are site a n d st u d y s pecific).
c.
F or c o nfir mati o n of p ost me n o pa u sal stat us o nl y. (Fe males w h o ha ve bee n a me n orr heic f or at least 
1 2 m o nt hs ).
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 t his 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.
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 other bli n de d pers o n nel u ntil t he st u d y  has bee n u n bli n de d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 8
A n y  re mai ni n g ser u m/ plas ma fr o m sa m ples c ollecte d f or cli nical safety la b orat or y 
meas ure me nts at baseli ne a n d at all ti mes after d ose a d mi nistrati o n ma y  be retai ne d a n d 
st ore d f or t he d urati o n of t he st u d y. U p o n c o m pleti o n of t he st u d y, t hese retai ne d safet y 
sa m ples ma y be use d f or t he assess me nt of e x pl orat or y safety bi o mar kers or u ne x pecte d 
safety fi n di n gs. T hese data will n ot be i ncl u de d i n t he C S R. Sa m ples t o be use d f or t his 
p ur p ose will be s hi p pe d t o eit her a Pfizer -a p pr o ve d B B S facilit y or ot her desi g nate d 
la b orat or y a n d retai ne d f or u p t o 1 ye ar f oll o wi n g t he c o m pleti o n of t he st u d y .
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 0 9
1 0. 3. A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w - Up, 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 ote : A n A E ca n t heref ore be a ny 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 disease ( 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 or 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 n 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 p ecte 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 or S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p o ssi 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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 0
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 t hat 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 udie 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 oci al 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 a n S A E
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 , meets o ne 
or m ore of t he criteri a liste d bel o w:
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. It d oes n ot refer t o a n e ve nt t hat
h y p ot heticall y  mi g ht ha ve ca use d deat h if it were m ore se vere.
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 o s 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 a d mitte 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 plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es. 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 w as necessar y, t he 
A E s h o ul d be c o nsi dere d seri o us.
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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 1
d.
Res ults i n persiste nt or si g nific a 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), t hat m a 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.
Is a s us pecte d tr a ns missi o n vi a a Pfizer pr o d uct of a n i nfecti o us a ge nt, p at h o ge nic 
or n o n- p at 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 sy m 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 P fizer 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 yn 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 p har 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.
g.
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 b y  t he i n vesti gat or 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 si g nifica nt 
me dical e ve nts t hat 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 hat 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.
1 0. 3. 3. Rec or di n g / Re p orti n g a n d F oll o w - Up of A E s a n d/ or S A E s D uri n g t he Acti ve 
C olle cti o n Peri o d
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 Es o n t he C R F a n d f or 
re p orti n g S A Es o n t he C T S A E Re p ort F or m t o Pfizer Safet y t hr o u g h o ut t he acti ve 
c ollecti o n peri o d. 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 Es; a n d ( 3) 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. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 2
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 Es s h o ul d be rec or de d usi n g c o ncise me dical 
ter mi n ol o g y a n d t he sa me A E ter m s h o ul d be use d o n b ot h t he C R F a n d t he C T SA 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
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
N ote: I nsta nces of E D P or 
E D B n ot ass ociate d wit h a n 
A E or S A E are n ot ca pt ure d 
i n t he C R F.
All i nsta nces of E D P are 
re p orte d ( w het her or n ot 
t here is a n ass ociate d 
S A E) *
All i nsta nces of E D B are 
re p orte d ( w het her or n ot 
t here is a n ass ociate d 
S A E). * *
E n vir o n me ntal or 
occ u pati o nal e x p os ure t o 
t he pr o d uct u n der st u dy 
t o a n o n-partici pa nt ( n ot 
i n v ol vi n g E D P or E D B).
N o ne.  E x p os ure t o a st u d y 
n o n - partici pa nt is n ot 
c ollecte d o n t he C R F.
T he e x p os ure ( w het her or 
n ot t here is a n ass ociate d 
A E or S A E) m ust be 
re p orte d. * * *
*
E D P ( wit h or wit h o ut a n ass ociate d A E or S A E): a n y pre g na nc y i nf or mati o n is re p orte d t o Pfizer 
Safet y usi n g 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; if t he E D P is ass ociate d w it h a n 
S A E, t he n t he S A E is re p orte d t o Pfizer Safet y usi n g t he C T S A E Re p ort F or m. 
* * E D B is re p orte d t o Pfizer Safet y usi n g t he C T S A E Re p ort F or m w hic h w o ul d als o i ncl u de details 
of a n y S A E t hat mi g ht be ass ociate d w it h t he E D B. 
* * * E n vir o n me nt al or Occ u p ati o n al e x p os ure: A E s or S A Es ass ociate d wit h occ u pati o nal e x p os ure are 
re p orte d t o Pfizer Safet y usi n g t he C T S A E Re p ort F or m. 

W he n a n A E
or 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 or S A E i nf or mati o n i n t he C R F.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 3

It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt’s 
me dical rec or ds t o 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 or 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 Pfizer Safet y . I n t his case, all partici pa nt i de ntifiers, wit h t he 
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 or 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: As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y ; 
i nter ve nti o n n ot i n dicate d.

M o derate: Mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -
a p pr o priate i nstr u me ntal A D L. I nstr u me ntal A D L refers t o pre pari n g meals, 
s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tele p h o ne, ma na gi n g m o ne y, etc.

Se vere: Se vere or me dicall y  si g nifica nt b ut n ot i m me diatel y life-t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g, li miti n g self 
care A D L. Self care A D L refers t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, 
usi n g t he t oilet, ta ki n g me dicati o ns, a n d n ot be dri d de n.
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 or S A E. T he i n vesti gat or will use cli nical 
j u d g me nt t o deter mi ne t he relati o ns hi p.

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.

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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 4

T he i n vesti gat or will als o c o ns ult t he I B a n d/ or p r o d uct inf or mati o n, f or mar kete d 
pr o d ucts, i n his/ her assess me nt.

F or eac h A E or 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 or 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 an 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 ord 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 - Up of A Es 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 ma 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 Safet y 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  s u b mitte d 
d oc u me nts .

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 pt of t he i nf or mati o n.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 5
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 a n Electr o nic D at a C ollecti o n T o ol

T he pri mar y  mec ha nis m f or re p orti n g a n S A E t o Pfizer Safet y will be t he 
electr o nic data c ollecti o n t o ol.

If t he electr o nic sys te m is u na vaila ble, t he n t he site will use t he pa per S A E data 
c ollecti o n t o ol (see ne xt secti o n) t o re p ort t he e ve nt wit hi n 2 4 h o urs.

T he site will e nter t he S A E data i nt o t he electr o nic s y ste m as s o o n as t he data
bec o me a vaila ble.

After t he st u d y is c o m plete d at a gi ve n site, t he electr o nic data c ollecti o n t o ol will 
be ta ke n off -li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o e xisti n g data.

If a site recei ves a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei ves u p date d 
data o n a pre vi o usl y  re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n 
ta ke n off-li ne, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m (see 
ne xt secti o n) or t o Pfizer Safet y  b y tele p h o ne.
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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 6
1 0. 4. A p pe n di x 4: C o ntr ace pti ve a n d B arrier 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
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 d a y s 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(s): 

Refrai n fr o m d o nati 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 nt ial as 
t heir preferre d a n d us ual lifest yle (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 c o ntrace pti o n/ barrier as detaile d bel o w :

A gree t o use a male c o n d o m w he n ha vi n g se x ual i nterc o urse wit h a w o ma n of 
c hil d beari n g p ote ntial w h o is n ot c urre ntl y  pre g na nt.

I n a d diti o n t o male c o n d o m use, a hi g hl y effecti ve met h o d of c o ntrace pti o n ma y  be 
c o nsi dere d i n W O C B P part ners of male partici pa nts (refer t o t he list of hi g hl y 
effecti ve met h o ds bel o w i n Secti o n 1 0. 4. 4 ).
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 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 ).
T he i n vesti gat or is res p o nsi 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 the ris k f or i ncl usi o n of a w o ma n wit h a n earl y 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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 7
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 BP:
1.
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 ote: 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 he site 
pers o n nel’s re vie w of t he partici pa nt’s me dical rec or ds, me dical e xa mi nati 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.
2.
P ost me n o pa usal fe male .

A p ost me n o pa usal state 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 ol d a n d n ot usi n g h or m o nal 
c o ntrace pti o n or H R T. 

A f e 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 uir e d t o 
use o ne of t he n o nestr 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.
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.
Hi g hl y Effecti ve Met h o ds T h at H a ve L o w User De pe n de n c y (f or W O C B P p art ners of 
m ale p artici p a nts)
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.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 8
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 (e g, bilateral t u bal li gati o n).
5.
Vasect o mize d pa rt ner.

A v asect o mize d part ner is a hi g hl y effecti ve c o ntrace 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 C B P
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 hly 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 d a y s.
Hi g hl y Effecti ve Met h o ds T h at Are User De pe n de nt (f or W O C B P
p art ners of m ale 
p artici p a nts)
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 ula ti 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.
O ne of t he f oll o wi n g effecti ve barrier met h o ds m ust be use d i n a d diti o n t o t he hi g hl y 
effecti ve met h o ds liste d a b o ve t hat are user de pe n de nt:

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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 1 9
1 0. 5. A p pe n di x 5: Ge netics
Use/ A n al ysis of D N A

Ge netic variati o n ma y  i m pact a partici pa nt’s res p o nse t o st u d y i nter ve nti o n, 
s usce pti bilit y t o, a n d se verit y a n d pr o gressi o n of disease. T heref ore, w here l ocal 
re g ulati o ns a n d I R Bs/ E Cs all o w, a bl o o d sa m ple will be c ollecte d f or D N A a nal ys is.

T he sc o pe of t he g e netic researc h ma y b e narr o w (e g, 1 or m ore ca n di date ge nes ) or
br oa d (e g, t he e ntire ge n o me), as a p pr o priate t o t he scie ntific q uesti o n u n der 
i n vesti gati o n.

T he sa m ples ma y  be a nal yze d as part of a m ultist u d y assess me nt of ge netic fact ors 
i n v ol ve d i n t he res p o nse t o P F -0 7 2 5 8 6 6 9/ place b o or st u d y  i nter ve nti o ns of t his class 
t o u n dersta n d treat me nts f or t he disease(s) u n der st u d y or t he disease(s) t he msel ves.

T he res ults of ge netic a nal y ses ma y be re p orte d i n t he C S R or i n a se parate st u d y 
s u m mar y, or ma y be use d f or i nter nal decisi o n ma ki n g wit h o ut bei n g i ncl u de d i n a 
st u d y re p ort.

T he s p o ns or will st ore t he D N A sa m ples i n a sec ure st ora ge s pace wit h a de q uate 
meas ures t o pr otect c o nfi de ntialit y . 

T he sa m ples will be retai ne d as i n dicate d:

Retai ne d sa m ples will be st ore d i n defi nitel y  or f or a not her peri o d as per l ocal 
re q uire me nts.  

Partici pa nt s ma y wit h dra w t heir c o nse nt f or t he st ora ge a n d/ or use of t heir Retai ne d 
Researc h Sa m ples at a n y ti me b y ma ki n g a re q uest t o t he i n vesti gat or; i n t his case, 
a n y re mai ni n g material will be destr o ye d. Data alrea d y ge nerate d fr o m t he sa m ples 
will be retai ne d t o pr otect t he i nte grity of e xisti n g a nal ys es.  

Sa m ples f or ge netic researc h will be la bele d wit h a c o de. T he ke y  bet wee n t he c o de 
a n d t he partici pa nt ’s pers o nall y i de ntif yi n g i nf or mati o n (e g, na me, a d dress) will be 
hel d sec urel y at t he st u d y site.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 0
1 0. 6. A p pe n di x 6: Li ver S afet y: S u g geste d Acti o ns a n d F oll o w- 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 nt s, 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 nt s 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 ury,  c o m m o nly referre d t o as DI LI. 
Partici pa nt s 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 da pt ors” 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  se veral da ys or wee ks. T he i ncrease i n T Bili t ypicall y  occ urs w hile 
A S T/ A L T is/are still ele vate d a b o ve 3 × U L N (ie, A S T/ A L T a n d T Bili val ues will be 
ele vate d wit hi n t he sa me la b 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 diti o ns. Partici pa nt s 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 nt s wit h A S T/ A L T a n d T Bili baseli ne val ues wit hi n t he n or mal ra n ge w h o 
s u bse q ue ntl y prese nt wit h A S T O R A 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 nt s wit h baseli ne A S T O R A L T O R T Bili val ues a b o ve t he U L N, t he 
f oll o wi n g t hres h ol d val ues are use d i n t he defi niti o n me nti o ne d a b o ve, as nee de d, 
de pe n di n g o n w hic h val ues are a b o ve t he U L N at 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).
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 1
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.
T he partici 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 o n 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 H y ’s la w 
cases , 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 nal yses 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 releva 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, or 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 , 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 B ili 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 ul ts 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 ults of 
reas o na ble i n vesti gati o ns ha ve bee n recei ve d a n d ha ve e xcl u de d a n alter nati ve eti ol o g y.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 2
1 0. 7. A p pe n di x 7: Ki d ne y S afet y: M o nit ori n g G ui deli nes
1 0. 7. 1. L a b or at or y Assess me nt of C h a n ge i n Ki d ne y F u ncti o n a n d Detecti o n of Ki d ne y 
I nj ur y
Sta n dar d ki d ne y  safet y m o nit ori n g re q uires assess me nt of baseli ne a n d p ost baseli ne ser u m 
creati ni ne ( SC r meas ure me nt t o estimate gl o mer ular filtrati o n rate [ S Cr- base d e G F R] or 
creati ni ne cleara nce [e Cr Cl]). Baseli ne a n d p ost baseli ne ser u m Sc y s ma kes it feasi ble t o 
disti n g uis h A KI fr o m ot her ca uses of Scr i ncrease. If S C r i ncrease is c o nfir me d after 
baseli ne, t he n refle x meas ure me nt of Sc y s is i n dicate d t o esti mate t he c o m bi ne d SCr- Sc y s 
e G F R calc ulati o n (f or a d ults o nl y ).
Re gar dless of w het her ki d ne y  f u ncti o n m o nit ori n g tests are re q uire d as a r o uti ne safety 
m o nit ori n g pr oce d ure i n t he st u d y , if t he i n vesti gat or or s p o ns or dee ms it necessar y t o f urt her 
assess ki d ne y safet y a n d q ua ntif y ki d ne y f u ncti o n, t he n t hese test res ults s h o ul d be ma na ge d 
a n d f oll o we d per sta n dar d of care.
1 0. 7. 2. A ge -S pecific Ki d ne y F u ncti o n C alc ul ati o n Rec o m me n d ati o ns
1 0. 7. 2. 1. A d ults ( 1 8 Ye ars a n d A b o ve) — 2 0 2 1 C K D- E P I E q u atio ns 3 3
2 0 2 1 C K D -
E PI 
S C r O nl y
Scr
( m g/ d L)
Sc ys
( m g/ L)
Rec o m me n de d e G F R E q u ati o n
Fe male
if ≤0. 7
N/ A
e G F R = 1 4 3 × ( Scr/ 0. 7) -0. 2 4 1 × ( 0. 9 9 3 8) A ge
Fe male
if > 0. 7
N/ A
e G F R = 1 4 3 × ( Scr/ 0. 7) -1. 2 0 0 × ( 0. 9 9 3 8) A ge
Male
if ≤0. 9
N/ A
e G F R = 1 4 2 × ( Scr/ 0. 9) -0. 3 0 2 × ( 0. 9 9 3 8) A ge
Male
if > 0. 9
N/ A
e G F R = 1 4 2 × ( Scr/ 0. 9) -1. 2 0 0 × ( 0. 9 9 3 8) A ge
2 0 2 1 C K D -
E PI 
S Cr- Sc ys 
C o m bi ne d
Scr
( m g/ d L)
Sc ys
( m g/ L)
Rec o m me n de d e G F R E q u ati o n
Fe male
if ≤0. 7
if ≤0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7)-0. 2 1 9 × ( Sc ys/ 0. 8) -0. 3 2 3 × ( 0. 9 9 6 1) A ge
Fe male
if ≤0. 7
if > 0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7) -0. 2 1 9 × ( Sc ys/ 0. 8) -0. 7 7 8 × ( 0. 9 9 6 1) A ge
Fe male
if > 0. 7
if ≤0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7) -0. 5 4 4 × ( Sc ys/ 0. 8) -0. 3 2 3 × ( 0. 9 9 6 1) A ge
Fe male
if > 0. 7 
if > 0. 8
e G F R = 1 3 0 × ( Scr/ 0. 7) -0. 5 4 4 × ( Sc ys/ 0. 8) -0. 7 7 8 × ( 0. 9 9 6 1) A ge
Male
if ≤0. 9
if ≤0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9) -0. 1 4 4 × ( Sc ys/ 0. 8) -0. 3 2 3 × ( 0. 9 9 6 1) A ge
Male
if ≤0. 9
if > 0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9) -0. 1 4 4 ×( Sc ys/ 0. 8) -0. 7 7 8 × ( 0. 9 9 6 1) A ge
Male
if > 0. 9
if ≤0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9)-0. 5 4 4 × ( Sc ys/ 0. 8) -0. 3 2 3 × ( 0. 9 9 6 1) A ge
Male
if > 0. 9 
if > 0. 8
e G F R = 1 3 5 × ( Scr/ 0. 9) -0. 5 4 4 × ( Sc ys/ 0. 8) -0. 7 7 8 × ( 0. 9 9 6 1) A ge
1 0. 7. 3. A d verse E ve nt Gr a di n g f or Ki d ne y S afet y L a b or at or y A b n or m alities
A E gra di n g f or decli ne i n ki d ne y f u ncti o n (ie, e G F R or e Cr Cl) will be acc or di n g t o K DI G O
criteria. 3 4
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 3
1 0. 8. A p pe n di x 8 : 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 Es

Mar ke d si n us b ra d ycar 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 ms ec.

Ne w pr ol o n gati o n of Q Tc F t o > 4 8 0 ms ec (a bs ol ute) or b y ≥6 0 ms ec fr o m baseli ne.

Ne w - onset 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 - onset ty p e I sec o n d- de gree ( We nc ke bac h) A V b l 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 S A Es

Q Tc F pr ol o n gati o n > 5 0 0 ms ec.

Ne w S T -T c ha n ges s u g gesti ve of m y ocar dial isc he mia .

Ne w - onset left b u n dle b ra nc h b l oc k ( Q R S > 1 2 0 ms ec).

Ne w - onset ri g ht b u n dle b ra nc h b l oc k ( Q R S > 1 2 0 ms ec).

S y m pt o matic b ra dyc ar dia.

As y st ole:

I n a wa ke, sy m pt o m -free partici pa nt s i n si n us r h yt h m, wit h d oc u me nte d peri o ds 
of as ys t ole ≥3. 0 sec o n ds or a ny esca pe rate < 4 0 b p m, or wit h a n esca pe r h y t 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 partici pa nt s wit h atrial fi brillati o n a n d bra d yc 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 su 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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 4

Ve ntric ular r h y t 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 (heart 
rate < 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
torsa des de p oi ntes) ).

T yp e II sec o n d- de gree ( M o bitz II) A V b l oc k.

C o m plete (t hir d- de gree) h eart b l oc k.
E C G Fi n di n gs T h at Q u alif y as S A Es

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 v e ntric ular ta c h yarr 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 nd 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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 5
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 6
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 7
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 8
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 2 9
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 0
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 1
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 2
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 3
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 4
1 0. 1 3. A p pe n di x 1 3 : Pr o hi bite d C o nc o mit a nt Me dic ati o ns T h at M a y Res ult i n D DI 
T he pr o hi bite d c o nc o mita nt me dicati o ns liste d bel o w s h o ul d n ot be ta ke n wit h P F - 0 7 2 5 8 6 6 9
d uri n g t he st u d y. T his is n ot a n all -i ncl usi ve list. All me dicati o ns m ust be re vie we d o n a 
case-b y - case basis by t he i nvesti gat or a n d a p pr o ve d b y t he sp o ns or d uri n g t he scree ni n g 
peri o d f or eli gi bilit y  p ur p oses.
T he Pfizer st u d y tea m is t o be n otifie d of a n y  pr o hi bite d me dicati o ns ta ke n d uri n g t he st u d y.
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
C Y P 3 A I n hi bit ors a ,b
C Y P 3 A I n d ucers a ,b
M o der ate
Str o n g
M o der ate
Str o n g
A pre pita nt
B oce pre vir
B ose nta n
A pal uta mi de
Ci pr ofl o xaci n
C o bicistat
Efa vire nz
Car ba maze pi ne
C o ni va pta n
Da n o pre vir
Etra viri ne
E nzal uta mi de
Criz oti ni b
Dasa b u vir
P he n o bar bital
Mit ota ne
C ycl os p ori ne
El vite gra vir
Pri mi d o ne
P he n yt oi n
Diltiaze m
I n di na vir
Rifa m pi n
Dr o ne dar o ne
Itrac o naz ole
St. J o h n’s w ort
Er yt hr o m yci n
Ket oc o naz ole
Fl uc o naz ole
L o pi na vir
Fl u v o xa mi ne
Parita pre vir
I mati ni b
O m bitas vir
T ofis o pa m
P osac o naz ole
Vera pa mil
Rit o na vir
Sa q ui na vir
Tela pre vir
Ti pra na vir
Telit hr o m yci n
Tr olea n d o m yci n
V oric o naz ole
Se nsiti ve C Y P 3 A S u bstr ates a, c
C Y P 3 A S u bstr ates 
wit h N arr o w T her a pe utic I n de x a, d
Alfe nta nil
L o vastati n
Alfe nta nil
At or vastati n
L u rasi d o ne
Aste miz ole
A va nafil
Mara vir oc
Cisa pri de
B u des o ni de
Mi daz ola m
C ycl os p ori ne
B us pir o ne
Nal o xe g ol
Di h y dr oer g ota mi ne
Darife naci n
Nis ol di pi ne
Er g ota mi ne
Dar u na vir
Q uetia pi ne
Fe nta n yl
Dasati ni b
Sil de nafil
Pi m ozi de
Dr o ne dar o ne
Si m vastati n
Q ui ni di ne
E basti ne
Sir oli m us
Sir oli m us
Eletri pta n
Tacr oli m us
Tacr oli m us
E plere n o ne
Tica grel or
Terfe na di ne
E ver oli m us
T ol va pta n
I br uti ni b 
Ti pra na vir
I n di na vir
Triaz ola m
Fel o di pi ne
Var de nafil
L o mita pi de
a.
N ot a n all -i ncl usi ve list. S o urce f or C Y P 3 A i n hi bit ors, i n d ucers, a n d se nsiti ve s u bstrates3 0: U S F D A, 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 n hi bit ors a n d I n d ucers (htt ps:// w w w.f da. g o v/ dr u gs/ dr u g -i nteracti o ns-la beli n g/ dr u g-
de vel o p me nt -a n d -dr u g -i nteracti o ns-ta ble-s u bstrates-i n hi bit ors-a n d -i n d ucers #ta ble 5- 1) accesse d 1 3-Ja n uar y-2 0 2 2; S o ur ce f or 
C Y P 3 A s u bstrates wit h narr o w t hera pe utic i n de x 3 1: G ui da nce f or In d ustr y – Dr u g I nteracti o n St u dies: St u d y Desi g n, Data 
A nal ysis, I m plicati o ns f or D osi n g, a n d La beli n g Rec o m me n dati o ns. U S De part me nt of Healt h a n d H u ma n Ser vice s, F o o d a n d 
Dr u g A d mi nistrati o n, Ce nter f or Dr u g E val uati o n a n d Researc h, Fe b 2 0 1 2.
b.
All pr o hi bite d dr u gs t hat are m o derate or str o n g C Y P 3 A i n hi bit ors or i n d ucers re q uire at least a 2 8 da y or 5 half -li ves ( w hic he ver 
is l o n ger) was h o ut pri or 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 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 5
c.
Will be pr o hi bite d if t he mi daz ola m A U C rati o is ≥2 i n Part B of t his st u d y.
d.
Will be pr o hi bite d if t he mi daz ola m A U C rati o is ≥1. 2 5 i n Part B of t his st u d y.
I n a sit u ati o n w here a p pr o pri ate me dic al c are of a p artici p a nt re q uires t he use of a pr o hi bite d C Y P 3 A i n hi bit or, i n d ucer, or 
s u bstr ate: T hese me dicati o ns are n ot per mitte d i n t he st u d y e xce pt i n e mer ge nc y sit uati o ns re q uiri n g n o m ore t ha n o ne da y of 
a d mi nistrati o n. T o pical a p plicati o n of a nti micr o bial a n d a ntif u n gal me dicati o ns is per mitte d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 6
1 0. 1 4. A p pe n di x 1 4: Pr ot oc ol A me n d me nt Hist or y 
T he Pr ot oc ol A me n d me nt S u m mar y  of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y  bef ore t he ta ble of c o nte nts.  T he pr ot oc ol a me n d me nt s u m mar y of c ha n ges ta bles 
f or past a me n d me nts ca n be f o u n d bel o w:
A m e n d me nt 3 ( 0 9 M arc h 2 0 2 2)
O ver all R ati o n ale f or t he A me n d me nt: 
 
 
 
 
 
 
 
 
 
 T he f oll o wi n g c ha n ges t o C 4 5 4 1 0 0 3 pr ot oc ol are n o w pr o p ose d: 
S ecti o n # a n d N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
1. 1 ( S y n o psis) a n d 
3 ( O bjecti ves a n d 
E n d p oi nts)
1. 1 ( S y n o psis) , 1. 3. 3 
( Part B – O verall S o A),
3 ( O bjecti ves a n d 
E n d p oi nts) , 
4. 2. 2 ( Rati o nale f or 
Part B), 8. 7. 3 (Uri ne f or 
Deter mi nati o n of 
6 -H y dr o x y c ortis ol/
C ortis ol Rati o )
A d de d meas ure me nt of 
uri nar y  
6 -h y dr o x y c ortis ol/ 
c ortis ol t o Part B.
Uri ne is n o w bei n g c ollecte d i n Part B 
 
 uri ne c ollecti o n ca n be 
use d f or meas ure me nt of 
6 -h y dr o x y c ortis ol/c ortis ol, w hic h is a 
mar ker of p ote ntial C Y P 3 A i n d ucti o n.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 7
S ecti o n # a n d N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
2. 2. 6 ( Cli nical 
O ver vie w)
Te xt u p date d t o reflect 
C 4 5 4 1 0 0 1 is fi nal; 
ad de d preli mi nar y  
C 4 5 4 1 0 0 3 safet y, 
t olera bilit y, a n d P K 
data .
Pr o vi des t he m ost u p t o date s u m mar y  
of cli nical safet y , t olera bilit y, a n d P K 
data f or P F - 0 7 2 5 8 6 6 9.
2. 3 ( Be nefit/ Ris k 
Assess me nt)
A d de d refere nce t o 
cli nical data.
Cli nical data f or C 4 5 4 1 0 0 1 a n d
C 4 5 4 1 0 0 3 preli mi nar y  data are n o w 
a vaila ble.
5. 2 ( E xcl usi o n Criteria)
E xcl usi o n Criteria # 1
a n d # 7: I ncl u de d 
a d diti o nal e xa m ples of 
e xcl u de d c o n diti o ns.
T hese a d diti o ns f urt her clarifie d, a n d 
pr o vi de d a d diti o nal e xa m ples of, 
me dical c o n diti o ns of partici pa nts n ot 
per mitte d i n t his st u d y . 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 8
S ecti o n # a n d N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
1 0 ( S u p p orti n g 
D oc u me ntati o n a n d 
O perati o nal 
C o nsi derati o ns) a n d te xt 
t hr o u g h o ut pr ot oc ol
A dj uste d n u m beri n g of 
a p pe n dices.
A d diti o n of
 
 re q uire d re-n u m beri n g 
of ot her a p pe n dices.
1 0. 8 
 
 
)
A d de d q uesti o n naire.
Pr o vi des e xa m ple q uesti o n naire wit h 
e xact q uesti o ns partici pa nts are t o 
a ns wer.
1 0. 1 3 ( A p pe n di x 1 3: 
Pr ot oc ol A me n d me nt 
Hist or y )
M o ve d S u m mar y  of 
C ha n ges ta ble f or 
A me n d me nt 2 fr o m 
be gi n ni n g of pr ot oc ol 
t o t he a p pe n di x.
M o ve d t o hi g hli g ht c ha n ges f or 
A me n d me nt 3 at t he be gi n ni n g of t he 
pr ot oc ol.
1 0. 1 4 ( A p pe n di x 1 4: 
A b bre viati o ns)
A d de d ne w 
a b bre viati o ns.
Ne w a b bre viati o ns were a d de d t o 
pr ot oc ol te xt.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 3 9
A m e n d me nt 2 ( 1 3 J a n u ar y 2 0 2 2)
O ver all R ati o n ale f or t he A me n d me nt: 

Safet y , t olera bilit y, a n d P K ma y be e val uate d i n a n o pti o nal c o h ort of ol der a d ults (a ge d 
6 5 t o 9 0 y ears ol d) t o i nf or m f ut ure cli nical de vel o p me nt of P F -0 7 2 5 8 6 6 9. C o nc o mita nt 
me dicati o ns ma y  be all o we d, wit h s o me restricti o ns, i n ol der a d ult partici pa nts. 
Eli gi bil it y criteria pertai ni n g t o heart rate, L D L c h olester ol, t otal c h olester ol, a n d 
tri glyceri des ha ve bee n u p date d f oll o wi n g re vie w of preli mi nar y safet y data fr o m C 4 5 4 1 0 0 1.
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Title, 1. 1 ( S y n o psis), 1. 2 
( Sc he ma), 2. 1 ( St u d y 
Rati o nale), 2. 3. 1 ( Ris k 
Assess me nt), 3 
( O bjecti ves a n d 
E n d p oi nts), 4. 1 ( O verall 
Desi g n), 4. 1. 1 ( O verall 
Desi g n of Part A), 4. 2. 1 
( Rati o nale f or Part A), 
4. 3. 3. 1 ( Part A 
P F -0 7 2 5 8 6 6 9 D ose 
Selecti o n), 6. 5 ( D ose 
M o dificati o n), 6. 8 
( C o nc o mita nt T hera py), 
9. 3. 3. 3. ( Statistical 
Met h o ds f or 
P F -0 7 2 5 8 6 6 9 P K Data 
[ Part A o nl y ]), 9. 5. 1 
( Part A Sa m ple Size)
A d de d a n o pti o nal 
c o h ort of ol der a d ult 
partici pa nts t o t he 
st u d y, u p date d t he t otal 
n u m ber of pla n ne d 
partici pa nts, a n d 
clarifie d t hat t he 
Ja panese c o h ort a n d 
ol der a d ult c o h ort are 
o pti o nal.
Safet y , t olera bilit y, a n d P K ma y be 
e val uate d i n ol der a d ults (a ge d 6 5 t o 
9 0 y ears ol d) t o i nf or m f ut ure 
cli nical de vel o p me nt of 
P F - 0 7 2 5 8 6 6 9. 
T he Ja pa nese a n d ol der a d ult 
c o h orts will o nl y be c o n d ucte d if 
res ults i n earlier c o h orts of t his 
st u d y s u p p ort a d diti o nal e val uati o n. 
T he ol der a d ult c o h ort will o nl y  be 
c o n d ucte d after res ults of Part B are 
a vaila ble.
1. 1 ( S y n o psis), 2. 2. 6 
( Cli nical O ver vie w), 2. 3 
( Be nefit/ Ris k 
Assess me nt), 2. 3. 1 ( Ris k 
Assess me nt), 4. 1. 1 ( Part 
A), 4. 2. 1 ( Rati o nale f or 
Part A), 4. 3. 3. 1 ( Part A 
P F -0 7 2 5 8 6 6 9 D ose 
Selecti o n, 8. 3. 8 ( A d verse 
E ve nts of S pecial 
I nterest)
U p date d i nf or mati o n 
a b o ut St u d y C 4 5 4 1 0 0 1.
All partici pa nts ha ve c o m plete d 
St u d y  C 4 5 4 1 0 0 1. T he preli mi nar y 
safety, t olera bility, a n d P K data 
prese nte d i n t his secti o n were 
u p date d acc or di n gl y.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 0
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 1 (I ncl usi o n Criteria)
I ncl usi o n Criteria # 1, 
# 6, a n d # 1 9: Defi ne d 
a ge ra n ge, B MI, a n d 
e G F R f or t he o pti o nal 
c o h ort of ol der a d ult 
partici pa nts.
A ge ra n ge, B M I, a n d e G F R 
pr o p o se d t o be m ore re prese ntati ve 
of ol der p o p ulati o n. 
5. 1 (I ncl usi o n Criteria), 
5. 2 ( E xcl usi o n Criteria)
I ncl usi o n Criteri o n # 2 
a n d E xcl usi o n Criteri o n 
# 1: Defi ne d 
c haracteristics of ol der 
a d ult partici pa nts.
Ol der a d ult partici pa nts i n 
reas o na bly g o o d heal t h wit h mil d, 
c hr o nic, sta ble disease ma y be 
e nr olle d.
5. 2 ( E xcl usi o n Criteria)
E xcl usi o n Criteria # 1, 
# 1 0, a n d # 1 1: 
Pri or/ C o nc o mita nt 
T hera p y.
All o ws ol der a d ult partici pa nts t o 
ta ke daily prescri pti o n or 
n o n -prescri pti o n me dicati o ns wit h 
s o me restricti ons.
5. 2 ( E xcl usi o n Criteria)
E xcl usi o n Criteri o n 
# 1 7: Re d uce d H R 
e xcl usi o n t o < 4 5 b p m.
Re vie w of t he safet y data fr o m 
C 4 5 4 1 0 0 1 d oes n ot re veal a n y  A Es 
of bra d yc ar dia or safet y c o ncer ns 
wit h res pect t o H R. T h us, t he l o wer 
li mit f or H R has bee n a dj uste d wit h 
t hese data i n mi n d. 
5. 2 ( E xcl usi o n Criteria)
E xcl usi o n Criteria # 1 
a n d # 1 9: Re m o ve d 
e xcl usi o n criteria f or 
t otal c h olester ol a n d 
L D L a n d i ncrease d 
tri glyceri de e xcl usi o n t o 
> 2 × U L N .
Re vie w of la b orat or y  data fr o m 
C 4 5 4 1 0 0 1 d oes n ot i de ntif y  a ny 
cli nicall y-si g nifica nt, d ose-relate d 
a d verse tre n ds i n t otal c h olester ol, 
L D L, or tri gl y ceri des i n relati o n t o 
d osi n g wit h P F -0 7 2 5 8 6 6 9. 
2. 3. 1 ( Ris k Assess me nt), 
4. 2. 1 ( Rati o nale f or 
Part A), 5. 2 ( E xcl usi o n 
Criteria), 5. 3. 4 ( Dail y  
Me dicati o n), 6. 1. 1 
( A d ministrati o n), 6. 8 
( C o nc o mita nt T hera py), 
6. 8. 1 ( O pti o nal C o h ort of 
Ol der A d ult Partici pa nts 
O nl y ), 1 0. 1 1 
A d de d t hat s o me 
bac k gr o u n d 
me dicati o ns are 
per mitte d f or ol der 
a d ult partici pa n ts; 
pr o vi de d a list of 
pr o hi bite d me dicati o ns 
a n d criteria f or w he n 
t hese me dicati o ns are 
restricte d.
T o e na ble recr uit me nt of 
partici pa nts f or t his st u d y, ol der 
partici pa nts are per mitte d t o ta ke 
prescri pti o n or n o n -prescri pti o n 
me dicati o ns f or ma na ge me nt of 
acce pta ble c hr o nic me dical 
c o n diti o ns, as l o n g as t h ose 
me dicati o ns are n ot s pecificall y  
e xcl u de d i n Secti o n 5. 2, Secti o n 6. 8, 
Secti o n 6. 8. 1, or Secti o n 1 0. 1 1.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 1
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
( A p pe n di x 1 1: Pr o hi bite d 
C o nc o mita nt 
Me dicati o ns T hat Ma y  
Res ult i n D DI )
1. 3. 1 ( Part A O verall 
S o A), 1. 3. 2 ( Part A S o A 
f or Da ys 1 a n d 1 4), 4. 2. 1 
( Rati o nale f or Part A), 
 
1 0. 2 ( A p pe n di x 2: 
Cli nical L a b orat or y 
Tests)
1. 3. 1 ( Part A O verall 
S o A), 1. 3. 2 ( Part A S o A 
f or Da ys 1 a n d 1 4), 1. 3. 3 
( Part B O verall S o A), 
8 ( St u d y Assess me nts 
a n d Pr oce d ures), 8. 7. 9 
( Retai ne d Researc h 
Sa m ples f or Bi o mar kers
Pre p B 1 a d de d t o Pre p 
B 2 as retai ne d researc h 
sa m ples, a n d u p date d 
bl o o d v ol u me i n 
Secti o n 8 acc or di n gl y.
T o facilitate f ut ure e x pl orat or y  
bi o mar ker a nal ys is.
4. 1. 1 ( Part A O verall 
Desi g n)
Clarifie d d urati o n of 
partici pa nt sta y  i n C R U
N o n -se nti nel partici pa nts ma y be gi n 
t heir sta y at t he C R U o n t he sa me 
da y  as t he se nti nel partici pa nts i n 
or der t o sta n dar dize c o n diti o ns f or 
all partici pa nts of a gi ve n c o h ort.
4. 1. 2 ( Part B O verall 
Desi g n), 4. 3 
(J ustificati o n f or D ose), 
4. 3. 3. 2. 1 ( P F- 0 7 2 5 8 6 6 9 
i n Part B), 6. 5 ( D ose 
M o dificati o n)
Clarifie d t hat Part B
d ose a n d d ose re gi me n 
will be deter mi ne d b y 
res ults of Part A
Pre vi o usl y  o nly state d t hat d ose 
re gi me n w o ul d be i nf or me d b y 
res ults of Part A.
4. 2. 2 ( Rati o nale f or 
Part B)
Clarifie d mi daz ola m 
w or di n g .
Re m o ve d re d u n da nt te xt.
4. 3. 3. 1 ( Part A 
P F - 0 7 2 5 8 6 6 9 D ose 
Selecti o n)
A d de d Q 8 H d ose le vel 
e x pecte d t o ac hie ve 
t hera pe utic e x p os ures 
f or c o nte xt.
Pr ojecte d t hera pe utic d ose is t wice 
dail y  a n d o utli ne d i n Secti o n 4. 3. 1. 
F or c o nte xt, pr o vi de d a Q 8 H d ose 
e x pecte d t o ac hie ve t hera pe utic 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 2
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
e x p os ures si nce Q 8 H d osi n g is 
bei n g use d i n t his st u d y .
9. 3. 3. 1 ( Deri vati o n of 
P F -0 7 2 5 8 6 6 9 P K 
Para meters [ Part A 
O nl y ])
Re m o ve d Da y  7 fr o m 
Rac, C ma x a n d Rac .
De nse P K sa m ples are n ot bei n g 
c ollecte d o n Da y 7, s o t hese 
para meters ca n n ot be calc ulate d.
1 0. 4. 1 ( A p pe n di x 4 –
Male Partici pa nt 
Re pr o d ucti ve I ncl usi o n 
Criteria) 
U p date d t o re d uce t he 
precl usi o n of s per m 
d o nati o n a n d 
re q uire me nt f or eit her 
a bsti ne nce fr o m 
i nterc o urse or use of 
male c o n d o m fr o m 
2 8 da y s pl us a n 
a d diti o nal 9 0 da ys t o 
c o ver a 
s per mat o ge nesis c ycle 
t o 2 8 da ys o nly. 
P F -0 7 2 5 8 6 6 9 was assesse d i n a 
series of ge netic t o xicit y st u dies a n d 
was n ot ge n ot o xic base d o n t he 
t otalit y of i n vitr o a n d i n vi v o data.
1 0. 1 2 ( A p pe n di x 1 2: 
Pr ot oc ol A me n d me nt 
Hist or y )
M o ve d S u m mar y  of 
C ha n ges f or 
A me n d me nt 1 t o 
A p pe n di x 1 2) .
Si m plifies c urre nt secti o n t o 
S u m mar y  of C ha n ges f or c urre nt 
a me n d me nt o nl y.
1 1 ( Refere nce)
A d de d ne w refere nce .
Refere nce s u p p orts classificati o n of 
p ote ntial c o nc o mita nt me dicati o ns 
as str o n g or m o derate C Y P 3 A 
i n hi bit ors or i n d ucers; or se nsiti ve 
C Y P 3 A s u bstrates; or C Y P 3 A 
s u bstrates wit h narr o w t hera pe utic 
i n de x.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 3
A m e n d me nt 1 ( 1 2 Oct o ber 2 0 2 1)
O ver all R ati o n ale f or t he A me n d me nt: T his a me n d me nt a d de d preca uti o nar y  se nti nel 
d osi n g t o Part A a n d Part B s uc h t hat safet y a n d t olera bilit y ma y be e val uate d i n a s u bset of 
partici pa nts i n eac h c o h ort bef ore d osi n g ot her partici pa nts i n t h ose c o h orts. C o nti n u o us 
p ulse o xi metr y  was als o a d de d as a safety assess me nt o n da ys of mi daz ola m d osi n g i n Part B.
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1. 1 ( S y n o psis), 2. 3 
( Be nefit/ Ris k 
Assess me nt), 2. 3. 1 ( Ris k 
Assess me nt), 4. 1. 1 
( O verall Desi g n Part A), 
4. 2. 1 ( Rati o nale f or 
Part A), 6. 5. 1 ( D ose 
Escalati o n a n d St o p pi n g 
R ules)
A d de d preca uti o nar y  
se nti nel d osi n g t o 
Pa rt A.
Preca uti o nar y  se nti nel d osi n g ma y 
be utilize d w here a p plica ble i n 
Part A t o e ns ure t hat safet y  a n d 
t olera bilit y data i n a s u bset of 
2 partici pa nts wit hi n a c o h ort 
s u p p orts d osi n g a d diti o nal 
partici pa nts.
1. 1 ( S y n o psis), 2. 3 
( Be nefit/ Ris k 
Assess me nt), 2. 3. 1 ( Ris k 
Assess me nt), 4. 1. 2 
( O verall Desi g n Part B), 
4. 2. 2 ( Rati o nale f or Part 
B), 6. 5. 1 ( D ose Escalati o n 
a n d St o p pi n g R ules)
A d de d preca uti o nar y  
se nti nel d osi n g t o 
Part B.
Preca uti o nar y  se nti nel d osi n g ma y 
be utilize d w here a p plica ble i n 
P art B t o e ns ure t hat safet y  a n d 
t olera bilit y data i n a s u bset of 
2 partici pa nts wit hi n a c o h ort 
s u p p orts d osi n g a d diti o nal 
partici pa nts.
1. 1 ( S y n o psis) a n d 
3 ( O bjecti ves a n d 
E n d p oi nts)
A d de d c o nti n u o us p ulse 
o xi metr y  as a n 
a d diti o nal sec o n dar y 
safety e n d p oi nt f or 
Part B.
Res pirat or y  de pressi o n is a 
rec o g nize d p ote ntial si de effect of 
mi daz ola m. C o nti n u o us p ulse 
o xi metr y  was a d de d t o be gi n 
3 0 mi n utes bef ore a n d t o c o nti n ue 
f or at least 6 h o urs after 
mi daz ola m d osi n g as a n a d diti o nal 
safety preca uti o n t o m o n it or 
partici pa nts f or a n y res pirat or y 
de pressi o n.
1. 3. 1 ( Part A – O verall 
Sc he d ule of Acti vities) 
U p date d C O VI D - 1 9 
assess me nts a n d 
f o ot n otes referri n g t o 
baseli ne a n d p ost -d ose 
meas ure me nts of 
 
 
C O VI D -1 9 pa n de mic a n d 
vacci nati o n stat us is e v ol vi n g; 
u p dates reflect e v ol vi n g C R U 
pr oce d ures.
 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 4
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
 
 A d diti o nal f o ot n otes 
were a d de d t o clarif y . 
1. 3. 2 ( Part A – Sc he d ule 
a n d Pr oce d ures f or Da y s 1 
a n d 1 4 O nl y)
Clarifie d ti mi n g of 
assess me nts o utli ne d i n 
f o ot n ote “a”.
P F -0 7 2 5 8 6 6 9 d osi n g d oes n ot 
occ ur o n Da y  1 5.
1. 3. 3 ( Part B – O verall 
Sc he d u le of Acti vities)

U p date d C O VI D - 1 9 
assess me nts.

A d de d c o nti n u o us 
p ulse o xi metr y  o n 
da y s of mi daz ola m 
d osi n g .

Re m o ve d s u pi ne 
vital si g ns fr o m 
scree ni n g, disc har ge, 
f oll o w-u p visit, a n d 
E T/ D C .

U p date d f o ot n otes .

C O VI D -1 9 pa n de mic a n d 
vacci nati o n stat us is e v ol vi n g; 
u p dates reflect e v ol vi n g C R U 
pr oce d ures.

Res pirat or y  de pressi o n is a 
rec o g nize d si de effect of 
mi daz ola m. As a n a d diti o nal 
safety preca uti o n t o m o nit or 
partici pa nts f or a n y res pirat or y 
de pressi o n, c o nti n u o us p ulse 
o xi metr y  was a d de d t o be gi n 
3 0 mi n utes bef ore a n d at least 
6 h o urs after mi daz ola m 
d osi n g.

T he S o A has assess me nts of 
b ot h s u pi ne vital si g ns a n d 
ort h ostatic vital si g ns at t hese 
ti me p oi nts. S u pi ne vitals si g ns 
are part of ort h ostatic vital 
si g ns meas ure me nts, s o t his 
re d u n da nc y was re m ove d.

F o ot n otes were u p date d t o 
reflect c ha n ges i n t he S o A.
2. 2. 6 ( Cli nical O ver vie w)
Clarifie d e x p os ure 
i ncreases o bser ve d 
acr oss d ose ra n ge i n 
C 4 5 4 1 0 0 1 .
Wit hi n eac h c o h ort i n C 4 5 4 1 0 0 1, 
e x p os ure i ncreases were 
a p pr o xi matel y d ose pr o p orti o nal. 
Bet wee n c o h o rts, e x p os ure 
i ncreases were less t ha n d ose 
pr o p orti o nal.
2. 3. 1 ( Ris k Assess me nt)
A d de d ris k assess me nt 
a n d miti gati o n strate gies 
f or mi daz ola m.
Res pirat or y  de pressi o n is a 
rec o g nize d si de effect of 
mi daz ola m i n Part B. C o nti n u o us 
p ulse o xi metr y  will be e m pl o ye d 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 5
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
o n da y s of mi daz ola m d osi n g i n 
Part B as a safet y  preca uti o n. 
4. 1. 1 ( O verall Desi g n 
Part A)
A d de d fle xi bilit y  t o 
all o w n o n-se nti nel 
part ici pa nts t o be gi n 
t heir sta y at t he C R U o n 
t he sa me da y as t he 
se nti nel partici pa nts.
T his e na bles t he C R U t o 
sta n dar dize c o n diti o ns f or all 
partici pa nts of a gi ve n c o h ort.
4. 2. 2 ( Rati o nale f or 
Part B)
A d de d rati o nale f or 
c o nti n u o us p ulse 
o xi metr y .
Asses s me nts a d de d as a n 
a d diti o nal safet y preca uti o n o n 
da y s of mi daz ola m d osi n g.
 
 
U p date d 
 
a n d 
ass ociate d e x p os ures .
P o p ulati o n P K m o del was u p date d 
wit h C 4 5 4 1 0 0 1 data .
4. 3. 3. 2. 2 ( Mi daz ola m i n 
Part B)
U p date d mi daz ola m 
d ose rati o nale a n d a d de d 
mi daz ola m e x p os ure 
li mits.
A c o nce ntrati o n ra n ge of 
mi daz ola m t hat will n ot ha ve 
u n d ue p har mac ol o gical effects was 
n ot defi ne d i n t he d ose selecti o n 
rati o nale. T h us, mi daz ola m 
e x p os ure li mits t hat will n ot be 
e xcee de d i n or der t o ha ve n o 
e x pecte d u n d ue p har mac ol o gical 
effects a n d si de effects ha ve bee n 
defi ne d a n d j ustifie d i n t he 
pr ot oc ol.
5. 2 ( E xcl usi o n Criteria)
Re m o ve d e xcl usi o n f or 
H D L .
H D L was i ncl u de d i n err or, a n d 
t he 1. 2 5 x U LN criteri o n is n ot 
a p plica ble t o t his para meter.
5. 3. 1 ( Meals a n d Dietar y  
Restricti o ns), 6. 1. 1 
( A d mi nistrati o n)
Clarifie d t hat st u d y  
i nter ve nti o n 
a d mi nistrati o n is 
per mitte d d uri n g fasti n g .
Clarificati o n was nee de d t o clearl y 
defi ne t hat b ot h water a n d st u d y 
i nter ve nti o n a d mi nistrati o n is 
per mitte d d uri n g fasti n g ti mes 
pri or t o safet y la b orat or y 
assess me nts.
5. 4 ( Scree n Fail ures)
Scree n fail ures are 
all o we d t o be 
rescree ne d.
If t he pri or reas o n(s) f or n ot 
meeti n g t he eli gi bilit y  criteria ha ve 
bee n res ol ve d, partici pa nts are 
all o we d t o be rescree ne d.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 6
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
6. 2 ( Pre parati o n, 
Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y ), 6. 2. 1 
( Pre parati o n a n d 
Dis pe nsi n g)
A d de d refere nce t o I P 
ma n ual .
I P ma n ual pr o vi des detaile d 
g ui da nce o n d osi n g of st u d y  
i nter ve nti o n.
6. 7 ( Treat me nt of
O ver d ose)
A d de d Le vel 3 secti o ns 
f or P F-0 7 2 5 8 6 6 9 ( 6. 7. 1) 
a n d mi daz ola m ( 6. 7. 2) 
o ver d ose .
A d de d i nf or mati o n f or mi daz ola m 
o ver d ose; treat me nt of o ver d ose is 
differe nt f or P F -0 7 2 5 8 6 6 9 a n d 
mi daz ola m.
6. 8 ( C o nc o mita nt 
T hera p y)
Clarifie d t hat 
c o nc o mita nt 
me dicati o ns are 
pr o hi bite d f or t he 
d urati o n of t he st u d y .
I n a d diti o n t o restricti o ns of 
pri or/c o nc o mita nts me dicati o ns 
pri or t o partici pati o n i n t his st u d y , 
t he restricti o ns s h o ul d be 
mai ntai ne d f or t he d urati o n of t he 
st u d y.
8. 2. 5 ( C o nti n u o us P ulse 
O xi m etr y)
A d de d assess me nt 
descri pti o n .
A d de d i nf or mati o n a b o ut 
pr oce d ure f or c o nti n u o us p ulse 
o xi metr y  t o be e m pl o ye d i n 
Part B, i ncl u di n g e x pecte d 
res p o nse t o a b n or mal o x y ge n 
sat urati o n alerts of p ote ntial 
cli nical c o ncer n.
8. 2. 7 ( C O VI D -1 9 Relate d 
Meas ures)
U p date d secti o n title 
a n d C O VI D- 1 9 
assess me nts.
C O VI D -1 9 pa n de mic a n d 
vacci nati o n stat us is e v ol vi n g; 
u p dates reflect e v ol vi n g C R U 
pr oce d ures.
1 0. 1 1 ( A b bre viati o ns)
A d de d ne w 
a b bre viati o n .
A b bre viati o n a n d defi niti o n of 
I C H a n d I L S a d de d t o pr ot oc ol 
a me nd me nt te xt.
1 1 ( Refere nces)
A d de d refere nces .
Refere nces s u p p ort mi daz ola m 
S m P C a n d mi daz ola m e x p os ure 
data fr o m U ni versit y  of 
Was hi n gt o n Dr u g I nteracti o n 
Data base.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 7
1 0. 1 5. A p pe n di x 1 5 : A b bre vi ati o ns
T he f oll o wi n g is a list of a b bre viati o ns t hat ma y be use d i n t he pr ot oc ol. 
A b bre vi ati o n
Ter m
A bs
a bs ol ute
A D L
acti vities of dail y li vi n g
A E
a d verse e ve nt
A E SI
a d verse e ve nts of s pecial i nterest
Ae ta u
a m o u nt of u nc ha n ge d dr u g rec o vere d i n uri ne d uri n g t he d osi n g 
i nter val
Ae ta u %
p erce nt of d ose rec o vere d i n uri ne as u nc ha n ge d dr u g
A KI
ac ute ki d ne y i nj ur y
A L T
ala ni ne a mi n otra nsferase
A O
al de h y de o xi dase
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n -ti me c ur ve
A U C 8
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 8 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 last
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m 0 t o ti me of last 
meas ura ble c o nce ntrati o n
A U C ta u
area u n der t he c o nce ntrati o n -ti me c ur ve at stea dy state o ver t he 
d osi n g i nter val ta u
A V
A tri o ve ntric ular
B B S
Bi os peci me n Ba n ki n g S yste m
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 v
a vera ge plas ma c o nce ntrati o n
C b, u
u n b o u n d brai n c o nce ntrati o n
C eff
efficaci o us plas ma c o nce ntrati o 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 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
C last
pre dicte d plas ma c o nce ntrati o n at t he last q ua ntifia ble ti me p oi nt 
esti mate d fr o m t he l o g-li near re gressi o n a nalys is
C L / F
a p pare nt cleara nce f or oral d osi n g
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 8
A b bre vi ati o n
Ter m
C L p
plas ma cleara nce
C L r
re nal cleara nce
C ma x
ma xi m u m plas ma co nce ntrati o n
C m i n
mi ni m u m plas ma c o nce ntrati o n
C O 2
car b o n di o xi de ( bicar b o nate)
C O VI D -1 9
c or o na vir us disease 2 0 1 9
C p , u
u n b o u n d plas ma c o nce ntrati o n
C R F
case re p ort f or m
C R O
cli nical researc h or ga nizati o n
C R U
cli nical researc h u nit
C S F
cere br os pi nal fl ui d
C S R
cli nical st u d y re p ort
C -S S R S
C ol u m bia S uici d e Se verit y Rati n g Scale
C T
cli nical trial
C V
c oefficie nt of variati o n
C Y P
c yt oc hr o me P 4 5 0
D C
D isc o nti n uati o n
D DI
dr u g -dr u g i nteracti o n 
DI LI
dr u g -i n d uce d li ver i nj ur y
D M C
data m o nit ori n g c o m mittee
d n
d ose n or malize d
D N A
de o x yri b o n ucleic aci d
E C
et hics c o m mittee
E C C
e mer ge nc y c o ntact car d
E C G
E lectr ocar di o gra m
e Cr Cl
esti mate d creati ni ne cleara nce
e C R F
electr o nic case re p ort f or m
E D B
e x p os ure d uri n g breastfee di n g
E D P
e x p os ure d uri n g pre g na nc y
e G F R
esti mate d gl o mer ular filtrati o n rate
E M A
E ur o pea n Me dici nes A ge nc y
E T
earl y ter mi nati o n
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n Cli nical Trials Data base
F A S
f ull a nal ysis set
F D A
F o o d a n d Dr u g A d mi nistrati o n
F O B
f u ncti o nal o bser vati o nal batter y
F S H
f ollicle-sti m ulati n g h or m o ne
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 4 9
A b bre vi ati o n
Ter m
fu
fracti o n u n b o u n d
G C P
G o o d Cli nical Practice
G G T
ga m ma -gl uta m y l tra nsferase
G L P
G o o d La b orat or y  Practice
G P C R
G -pr otei n c o u ple d rece pt or
H
H o urs
H Bc A b
he patitis B c ore a nti b o d y
H Bs A b
he patitis B s urface a nti b o d y
H Bs A g 
he patitis B s urface a nti ge n
H C H C
hi g h car b o h y drate -hi g h cal orie 
H C V A b
he patitis C a nti b o d y
H D L
hi g h -de nsit y li p o pr otei n
H F H C
h i g h fat-hi g h cal orie 
HI V
h u ma n i m m u n o deficie nc y vir us
H R
heart rate
H R T
h or m o ne re place me nt t hera p y
I B
i n vesti gat or’s br oc h ure
I C5 0
c o nce ntrati o n ass ociate d wit h 5 0 % i n hi biti o n
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 u ncil f or Har m o nisati o n of Tec h nical 
Re q uire me nts f or P har mace uticals f or H u ma n Use
I D
i de ntificati o n
I L S
i m me diate life s u p p ort
I ND
i n vesti gati o nal ne w dr u g 
I N R
i nter nati o nal n or malize d rati o
I P ma n ual
in vesti gati o nal pr o d uct ma n ual
I P A L
I n vesti gati o nal Pr o d uct Acc o u nta bilit y L o g
I RB
i nstit uti o nal re vie w b oar d
I V
i ntra ve n o us
K 2E D T A
di p otassi u m et h y le ne dia mi netetraacetic aci d
K d
diss ociati o n c o nsta nt
K DI G O
Ki d ne y  Disease I m pr o vi n g Gl o bal O utc o mes
k el
ter mi nal p hase eli mi nati o n rate c o nsta nt 
K i
i n hi biti o n c o nsta nt
k i nact
E nz y me i nacti vati o n rate c o nsta nt
L B B B
left b u n dle bra nc h bl oc k
L D L
l o w-de nsit y  li p o pr otei n
L F T
li ver f u ncti o n test
L L O Q
l o wer li mit of q ua ntitati o n
m Bcr p
m o use breast ca ncer resista nce pr otei n
M C 1 R
mela n oc orti n -1 rece pt or
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 5 0
A b bre vi ati o n
Ter m
M C 2 R
mela n oc orti n -2 rece pt or
M C 3 R
mela n oc orti n -3 rece pt or
M C 4 R
mela n oc orti n -4 rece pt or
M C 5 R
mela n oc orti n -5 rece pt or
M C H
mea n c or p usc ular he m o gl o bi n
M C H C
mea n c or p usc ular he m o gl o bi n c o nce ntrati o n
M C V
mea n c or p usc ular v ol u me
M H P
me ntal healt h pr ofessi o nal
m R N A
messe n ger ri b o n ucleic aci d
msec
millisec o n d
M T D
ma xi m u m t olerate d d ose
N/ A
n ot a p plica ble
N O E L
n o -o bser ve d -effect -le vel
N TI
narr o w t hera pe utic i n de x
P B P K
p h y si ol o gically -base d p har mac o ki netics
P C R
p ol y merase c hai n reacti o n
P D
p har mac o d y n a mics
P -g p
P -gl yc o pr otei n
p H
p ote ntial of h y dr o ge n
PI
pri nci pal i n vesti gat or
P K
p har mac o ki netics
p Ka
aci d diss ociati o n c o nsta nt
P K/ P D
p har mac o ki netics/ p har mac o d y na mics
P R
p ulse rate
P T
pr ot hr o m bi n ti me
P T R
pea k -t o-tr o u g h rati o
P V C
pre mat ure v e ntric ular c o ntracti o n/c o m ple x
Q 6 H
e ver y 6 h o urs
Q 8 H
e ver y 8 h o urs
Q 1 2 H
e ver y 1 2 h o urs
Q Tc
c orrecte d Q T i nter val
Q Tc F
Q Tc c orrecte d usi n g Fri dericia’s f or m ula
q ual
q ualitati ve
R ac
o bser ve d acc u m ulati o n rati o
R ac, C ma x
o bser ve d acc u m ulati o n rati o f or C ma x
R B C
re d bl o o d cell
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 5 1
A b bre vi ati o n
Ter m
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 yn dr o me c or o na vir us 2
S C r
ser u m creati ni ne
Sc y s
ser u m c ystati n C
S D
sta n dar d de viati o n
S m P C
S u m mar y  of P r o d uct C haracteristics
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 safety d oc u me nt
S S C
s pecial safet y c o ncer n
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n

ta u; ti me of d osi n g i nter val
t½
ter mi nal half -life
T Bili
t otal bilir u bi n
T DI
ti me-de pe n de nt i n hi biti o n
T H C
tetra hy dr oca n na bi n ol
T ma x
ti me t o reac h C ma x
U L N
u p per li mit of n or mal
U S
U nite d States
U S A
U nite d States of A merica
U V
ultra vi olet
V ss
stea d y-state v ol u me of distri b uti o n 
V z/ F
a p pare nt v ol u me of distri b uti o n f or oral d osi n g
W B C
w hite bl o o d cells
W O C B P
w o ma n/ w o me n of c hil d beari n g p ote ntial
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)
C CI
C CI
C CI


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 5 2
1 1. R E F E R E N C E S
1. 
La n di F, Cal va ni R, T osat o M, et al. A n ore xia of a gi n g: ris k fact ors, c o nse q ue nces, a n d 
p ote ntial treat me nts. N utrie nts. 2 0 1 6; 8( 2): 6 9.
2. 
va n Dr o n kelaar C, Tiela n d M, Aar de n JJ, et al. Decrease d a p petite is ass ociate d wit h 
sarc o pe nia-relate d o utc o mes i n ac ute h os pitalize d ol der a d ults. N utrie nts. 2 0 1 9; 1 1( 4): 
9 3 2.
3.
C o x NJ, I bra hi m K, Sa y er A A, et al. Assess me nt a n d treat me nt of t he a n ore xia of a gi n g: 
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4.
Ts uts u mi m ot o K, D oi T, Ma kiza k o H, et al. T he ass ociati o n bet wee n a n ore xia of a gi n g 
a n d p h ysical frailt y: Res ults fr o m t he nati o nal ce nter f or geriatrics a n d ger o nt ol o g y 
st u d y of geriatric sy n dr o mes. Mat uritas. 2 0 1 7; 9 7: 3 2 - 7.
5. 
La n di F, Li per oti R, Latta nzi o F, et al. Effects of a n ore xia o n m ortalit y  a m o n g ol der 
a d ults recei vi n g h o me care: A n o bser va ti o nal st u d y. J N utr Healt h A gi n g. 
2 0 1 2; 1 6( 1): 7 9 - 8 3.
6.
K ü h ne n P, Kr u de H, a n d Bie ber ma n n H. Mela n oc orti n -4 rece pt or si g nali n g: I m p orta nce 
f or wei g ht re g ulati o n a n d o besit y treat me nt. Tre n ds M ol Me d. 2 0 1 9; 2 5( 2): 1 3 6- 4 8.
7.
Bal di ni G a n d P hela n K D. T he mela n oc orti n pat h wa y  a n d c o ntr ol of a p petite-pr o gress 
a n d t hera pe utic i m plicati o ns. J E n d ocri n ol. 2 0 1 9; 2 4 1( 1): R 1- 3 3.
8.
R o y  M, Ga u drea u P, a n d Pa yette H. A sc o pi n g re vie w of a n ore xia of a gi n g c orrelates 
a n d t heir rele va nce t o p o p ulati o n healt h i nter ve nti o ns. A p petite. 2 0 1 6; 1 0 5: 6 8 8 - 9 9.
9.
W y s o ki ns ki A, S o b ó w T, Kl osze ws ka I, et al. Mec ha nis ms of t he a n ore xia of a gi n g -a 
re vie w. A ge ( D or dr). 2 0 1 5; 3 7( 4): 9 8 2 1.
1 0.
F üre di N, Mi k ó A, Gasz ner B, et al. Acti vit y of t he h y p ot hala mic mela n oc orti n s y ste m 
decreases i n mi d dle -a ge d a n d i ncreases i n ol d rats. J Ger o nt ol A Bi ol Sci Me d Sci, 
2 0 1 8; 7 3( 4): 4 3 8 - 4 5.
1 1.
Péter vári E, Sza ba d Á O, S o ós S, et al. Ce ntral al p ha -M S H i nf usi o n i n rats: dis parate 
a n ore xic vs. meta b olic c ha n ges wit h a gi n g. Re g ul Pe pt. 2 0 1 1; 1 6 6( 1 -3): 1 0 5 - 1 1.
1 2.
W ol de n -Ha ns o n T, Marc k B T, Mats u m ot o A M. Bl u nte d h y p ot hala mic ne ur o pe pti de 
ge ne e x pressi o n i n res p o nse t o fasti n g, b ut preser vati o n of fee di n g res p o nses t o A g R P i n 
a gi n g male Br o w n N or wa y  rats. A m J P h ysi ol Re g ul I nte gr C o m p P h ysi ol. 
2 0 0 4; 2 8 7( 1): R 1 3 8 - 4 6.
1 3.
Mar ks D L, Li n g N, C o ne
R D. R ole of t he ce ntral mela n oc orti n s ys te m i n cac he xia. 
Ca ncer Res. 2 0 0 1; 6 1: 1 4 3 2 - 8. 
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 5 3
1 4.
Scarlett J M, B o we D D, Z h u X, et al. Ge netic a n d p har mac ol o gic bl oc ka de of ce ntral 
mela n oc orti n si g nali n g atte n uates car diac cac he xia i n r o de nt m o dels of heart fail ure. J
E n d ocri n ol. 2 0 1 0; 2 0 6( 1): 1 2 1 - 3 0.
1 5.
C he u n g W W a n d Ma k R H. Mela n oc orti n a nta g o nis m a meli orates m uscle wasti n g a n d 
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3 0 3( 9): 1 3 1 5 - 2 4.
1 6.
J o p pa M A, G o gas K R, F oster A C, et. al. Ce ntral i nf usi o n of t he mela n oc orti n rece pt or 
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i n d uce d by ra diati o n a n d c ol o n - 2 6 t u m ors i n mice. Pe pti des. 2 0 0 7; 2 8( 3): 6 3 6- 4 2.
1 7.
Mar kis o n S, F oster A C, C he n C, et al. T he re g ulati o n of fee di n g
a n d meta b olic rate a n d 
t he pre ve nti o n of m uri ne ca ncer cac he xia wit h a s mall- m olec ule mela n oc orti n- 4 
rece pt or a nta g o nist. E n d ocri n ol o g y. 2 0 0 5; 1 4 6( 6): 2 7 6 6- 7 3. 
1 8.
Aa n dsta d A, H olt ber get K, Ha ge ber g R , et al. Vali dit y  a n d relia bility of bi oelectrical 
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1 9.
Si pers W, D or ge J, Sc h ols J, et al. M ultifre q ue nc y bi oelectrical i m pe da nce a nal ysis ma y 
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2 2.
H uszar D, L y nc h C A, Fairc hil d - H u ntress V, et al. Tar gete d disr u pti o n of t he 
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Q ui n ne y  S K, Malire d d y S R, V u p pala nc hi R, et al. Rate of o nset of i n hi biti o n of g ut -
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Ye h S S, L o vitt S, Sc h uster M W. Usa ge of me gestr ol acetate i n t he treat me nt of 
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0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)


P F -0 7 2 5 8 6 6 9 
Pr ot oc ol C 4 5 4 1 0 0 3
Fi nal Pr ot oc ol A me n d me nt 4 , 0 9 N o ve m ber 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical P har mac ol o g y Pr ot oc ol Te m plate ( 0 1 Marc h 2 0 2 1)
Pa ge 1 5 4
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2 8.
Mi daz ola m -rati o p har m® 2 m g/ m L  oral s ol uti o n S u m mar y of Pr o d uct C haracteristics, 
Dece m ber 2 0 2 0, Versi o n 3.
2 9.
U ni versit y  of Was hi n gt o n, Sc h o ol of P har mac y, Dr u g I nteracti o n S ol uti o ns.  A vaila ble 
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3 0.
U S F D A, 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 n hi bit ors 
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a n d-dr u g -i nteracti o ns-ta ble-s u bstrates-i n hi bit ors-a n d-i n d ucers #ta ble 5-1); accesse d 
1 3 -Ja n uar y- 2 0 2 2.
3 1.
G ui da nce f or I n d ustr y – Dr u g I nteracti o n St u dies: St u d y  Desi g n, Data A nal ysis, 
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Researc h, Fe b 2 0 1 2 .
3 2.
P ur ki n s L, L o ve E R, E ve M D, et al. T he i nfl ue nce of diet u p o n li ver f u ncti o n tests a n d 
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2 0 0 3 ;5 7: 1 9 9 - 2 0 8.
3 3.
I n ker L, E nea nya N, C ores h J, et al. Ne w creati ni ne - a n d c ystati n C- base d e q uati o ns t o 
esti mate G F R wit h o ut race. N E n gl J Me d. 2 0 2 1; 3 8 5( 1 9): 1 7 3 7- 4 9.
3 4.
K DI G O g ui deli nes - htt ps:// k di g o. or g/ g ui deli nes/ . Accesse d o n 0 8 N o ve m ber 2 0 2 2.
0 9 0 1 7 7 e 1 9 b c a 3 7 3 0\ A p pr o v e d\ A p pr o v e d O n: 1 0- N o v- 2 0 2 2 1 2: 2 7 ( G M T)

SAP_001.pdf: 
Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 of 4 6
Pr ot oc ol C 4 5 4 1 0 0 3
A P H A S E 1, R A N D O MI Z E D, D O U B L E- B LI N D, S P O N S O R -O P E N, P L A C E B O -
C O N T R O L L E D S T U D Y T O I N V E S TI G A T E T H E S A F E T Y, T O L E R A BI LI T Y, 
P H A R M A C O KI N E TI C S, A N D P H A R M A C O KI N E TI C I N T E R A C TI O N WI T H 
MI D A Z O L A M O F M U L TI P L E A S C E N DI N G O R A L D O S E S O F P F- 0 7 2 5 8 6 6 9 I N 
H E A L T H Y N O N -J A P A N E S E , J A P A N E S E , A N D O L D E R A D U L T P A R TI CI P A N T S 
St atistic al A n al ysis Pl a n 
( S A P)
Versi o n : 
3
D ate:
0 4 A u g 2 0 2 3
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 of 4 6
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 ..................................................................................................................... 5
LI S T O F FI G U R E S ................................................................................................................... 5
A P P E N DI C E S ........................................................................................................................... 6
1. V E R SI O N HI S T O R Y ............................................................................................................ 6
2. I N T R O D U C TI O N ................................................................................................................. 8
2. 1. M o dificati o ns t o t he A nal y sis Pla n Descri be d i n t he Pr ot oc ol..................................8
2. 2. St u d y  O bjecti ves, E n d p oi nts, a n d Esti ma n ds............................................................ 9
2. 3. St u d y  Desi g n........................................................................................................... 1 1
2. 3. 1. Part A .......................................................................................................... 1 1
2. 3. 2. Part B .......................................................................................................... 1 2
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 ................................................................................................................ 1 3
3. 1. Pri mar y  E n d p oi nt(s)................................................................................................ 1 3
3. 1. 1. Part A: Safet y a n d T olera bilit y ................................................................... 1 3
3. 1. 1. 1. A d verse E ve nts .......................................................................... 1 3
3. 1. 1. 2. Cli nical Safet y  La b orat or y Tests............................................... 1 3
3. 1. 1. 3. Vital Si g ns ................................................................................. 1 4
3. 1. 1. 4. C o nti n u o us Car diac M o nit ori n g ................................................ 1 4
3. 1. 1. 5. 1 2- lea d Electr ocar di o gra ms.......................................................1 5
3. 1. 1. 6. Res pirat or y  Rate........................................................................ 1 5
3. 1. 1. 7. Oral B o d y Te m perat ure ............................................................. 1 5
3. 1. 1. 8. P h y sical a n d Ne ur ol o gical E xa mi nati o ns .................................. 1 5
3. 1. 1. 9. C -S S R S ...................................................................................... 1 6
3. 1. 2. Part B: Mi daz ola m P K Para meters .............................................................1 6
3. 2. Sec o n dar y  E n d p oi nt(s)............................................................................................ 1 6
3. 2. 1. Part A: P F -0 7 2 5 8 6 6 9 Plas ma a n d Uri ne P K Para meters............................ 1 6
3. 2. 2. Part B: Safet y a n d T olera bilit y ................................................................... 1 7
3. 3. Ot her E n d p oi nt(s) .................................................................................................... 1 8
3. 3. 1. Part A .......................................................................................................... 1 8
3. 3. 1. 1. A d dit i o nal P F-0 7 2 5 8 6 6 9 P K Para meters .................................. 1 8
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 of 4 6
3. 3. 1. 2. B o d y Wei g ht ............................................................................. 1 8
3. 3. 1. 7. P ote ntial f or I n d ucti o n of C Y P 3 A ............................................. 2 0
3. 3. 1. 8. Q ualitati ve Meta b olite Pr ofili n g ................................................ 2 0
3. 3. 1. 9. Ot her E n d p oi nts ......................................................................... 2 0
3. 3. 2. Part B .......................................................................................................... 2 1
3. 3. 2. 1. A d diti o nal Mi daz ola m P K Para meters ...................................... 2 1
3. 3. 2. 2. P ote ntial f or I n d ucti o n of C Y P 3 A ............................................. 2 1
3. 4. Baseli ne Varia bles ................................................................................................... 2 2
3. 5. Safet y E n d p oi nts ..................................................................................................... 2 2
3. 5. 1. C O VI D -1 9 .................................................................................................. 2 2
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)................................................... 2 2
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 .................................................... 2 3
5. 1. H y p ot heses a n d Decisi o n R ules .............................................................................. 2 3
5. 2. Ge neral Met h o ds ..................................................................................................... 2 3
5. 2. 1. A nal y ses f or C o nti n u o us E n d p oi nts ........................................................... 2 3
5. 2. 2. A nal y ses f or Cate g orical E n d p oi nts ........................................................... 2 3
5. 2. 3. Mi xe d Effects M o del .................................................................................. 2 3
5. 2. 4. Mi xe d M o del Re peate d Meas ures ..............................................................2 4
5. 2. 5. Ba y esia n E ma x M o del ................................................................................2 4
5. 3. Met h o ds t o Ma na ge Missi n g Data
.......................................................................... 2 5
5. 3. 1. C o nce ntrati o ns Bel o w t he L i mit of Q ua ntificati o n .................................... 2 5
5. 3. 2. De viati o ns, Missi n g C o nce ntrati o ns a n d A n o mal o us Val ues..................... 2 5
5. 3. 3. P har mac o ki netic Para meters ....................................................................... 2 6
6. A N A L Y S E S A N D S U M M A RI E S ...................................................................................... 2 6
6. 1. Pri mar y  E n d p oi nt(s)................................................................................................ 2 6
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
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C CI
C CI
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Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 of 4 6
6. 1. 1. Part A: Safet y a n d T olera bilit y ................................................................... 2 6
6. 1. 1. 1. A d verse E ve nts .......................................................................... 2 6
6. 1. 1. 2. Cli nical Safet y  La b orat or y Tests............................................... 2 6
6. 1. 1. 3. Vital Si g ns ................................................................................. 2 7
6. 1. 1. 4. 1 2- lea d Electr ocar di o gra ms.......................................................2 7
6. 1. 1. 5. Res pirat or y  Rate........................................................................ 2 8
6. 1. 1. 6. Oral B o d y Te m perat ure ............................................................. 2 8
6. 1. 1. 7. C -S S R S ...................................................................................... 2 9
6. 1. 2. Part B: Mi daz ola m P K Para meters ............................................................. 2 9
6. 2. Sec o n dar y  E n d p oi nt(s)............................................................................................ 3 0
6. 2. 1. Part A: P F -0 7 2 5 8 6 6 9 Plas ma a n d Uri ne P K Para meters............................ 3 0
6. 2. 2. Part B: Safet y a n d T olera bilit y ................................................................... 3 2
6. 2. 2. 1. A d verse e ve nts .......................................................................... 3 2
6. 2. 2. 2. Vital si g ns .................................................................................. 3 2
6. 2. 2. 3. E C Gs ......................................................................................... 3 2
6. 2. 2. 4. Cli ni cal Safet y La b orat or y Meas ure me nts ................................ 3 2
6. 2. 2. 5. Res pirat or y  Rate........................................................................ 3 3
6. 2. 2. 6. Oral B o d y Te m perat ure ............................................................. 3 3
6. 3. Ot her E n d p oi nt(s) .................................................................................................... 3 3
6. 3. 1. Part A .......................................................................................................... 3 3
6. 3. 1. 1. A d diti o nal P F -0 7 2 5 8 6 6 9 P K Para meters .................................. 3 3
6. 3. 1. 2. B o d y Wei g ht ............................................................................. 3 4
6. 3. 1. 7. P ote ntial f or I n d ucti o n of C Y P 3 A ............................................. 3 5
6. 3. 2. Part B .......................................................................................................... 3 6
6. 3. 2. 1. A d diti o nal Mi daz ola m P K Para meters ...................................... 3 6
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI
C CI
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 5 of 4 6
6. 3. 2. 2. P ote ntial f or I n d ucti o n of C Y P 3 A ............................................. 3 6
6. 4. S u bset A nal y ses....................................................................................................... 3 7
6. 5. Baseli ne a n d Ot her S u m maries a n d A nal ys es ......................................................... 3 7
6. 5. 1. Baseli ne S u m maries .................................................................................... 3 7
6. 5. 2. St u d y  C o n d uct a n d Partici pa nt Dis p ositi o n................................................ 3 7
6. 5. 3. C o nc o mita nt Me dicati o ns a n d N o n dr u g Treat me nts .................................. 3 7
6. 6. Safet y S u m maries a n d A nal yses ............................................................................. 3 7
6. 6. 1. C O VI D -1 9 .................................................................................................. 3 7
7. I N T E RI M A N A L Y S E S ....................................................................................................... 3 7
7. 1. I ntr o d ucti o n ............................................................................................................. 3 7
7. 2. I nter i m A nalys es a n d S u m maries ............................................................................ 3 8
8. R E F E R E N C E S .................................................................................................................... 3 8
A P P E N DI C E S ......................................................................................................................... 3 9
LI S T O F T A B L E S
Ta ble 1.   S u m mar y  of C ha n ges..................................................................................................6
Ta ble 2.  Mi daz ola m P K Para meters ....................................................................................... 1 6
Ta ble 3. P F -0 7 2 5 8 6 6 9 P K para meters ..................................................................................... 1 7
Ta ble 4. A d diti o nal P F -0 7 2 5 8 6 6 9 P K para meters ................................................................... 1 8
Ta ble 5. A d diti o nal Mi daz ola m P K Para meters ...................................................................... 2 1
Ta ble 6. Mi daz ola m P K Para meters t o be S u m marize d Descri pti vel y .................................... 3 0
Ta ble 7. P F -0 7 2 5 8 6 6 9 P K Para meters t o be S u m marize d Descri pti vel y................................ 3 1
Ta ble 8. A d diti o nal P F -0 7 2 5 8 6 6 9 P K Para meters t o be S u m marize d Descri pti vel y .............. 3 3
Ta ble 9. A d diti o nal Mi daz ola m P K para meters t o be S u m marize d Descri pti vel y .................. 3 6
Ta bl e 1 0. C -S S R S Ma p pe d t o C -C A S A ( S uici dalit y  E ve nts a n d C o des) ............................... 4 0
LI S T O F FI G U R E S
Fi g ure 1. St u d y  Desi g n Part A................................................................................................. 1 2
Fi g ure 2. St u d y Desi g n Part B ................................................................................................. 1 3
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 6 of 4 6
A P P E N DI C E S
A p pe n di x 1. Cate g orical Classes f or E C G a n d Vital Si g ns of P ote ntial Cli nical C o ncer n ..... 3 9
A p pe n di x 2. C -S S R S Ma p pe d t o C -C A S A - S uici dal I deati o n a n d Be ha vi or E ve nts a n d 
C o des ........................................................................................................ 4 0
A p pe n di x 3. E xa m ple S A S C o de f or Statistical A nal yses ....................................................... 4 1
A p pe n di x 4. Ba y esia n E ma x M o del Met h o d ol o g y Details ..................................................... 4 2
A p pe n di x 5. L ist of A b bre viati o ns........................................................................................... 4 5
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
1 /
3 0 N o v 2 0 2 1
Ori gi nal :
2 4 A u g 2 0 2 1
A me n d me nt 1: 
1 2 Oct 2 0 2 1
N/ A  
N/ A
2 / 
0 7 Fe b 2 0 2 3
A me n d me nt 2: 
1 3 Ja n 2 0 2 2
A me n d me nt 3:
0 9 Mar 2 0 2 2
A me n d me nt 4:
0 9 N o v 2 0 2 2
U p dates 
base d o n 
S A P 
te m plate 
u p date, 
pr ot oc ol 
a me n d me nts, 
A & R p la n 
re vie w a n d 
Bli n de d Data 
Re vie ws.
Rati o nale: t he pr ot oc ol has bee n a me n de d 
t o 
1) a d d ol der a d ult c o h ort [ P A 2]
2) a d d 
 
; c ollect uri ne i n P A R T B f or 
meas u re me nt of 6 β-
h y dr o x yc ortis ol/c ortis ol [ P A 3]
3) all o w partici pa nts t o be all ocate d t o 1 of 
3 diets (e g, sta n dar d, H C H C, or H F H C), 
wit h o pti o nal a d diti o nal c o h orts of 
partici pa nts all ocate d t o t he H F H C diet 
( wit h a lar ger sa m ple size). [ P A 4]
T he f oll o wi n g secti o ns were re vise d as part 
of t his rati o nale:

U p date d pr ot oc ol title 

Secti o n 2. 2: u p date d e n d p oi nts t o 
matc h pr ot oc ol a me n d me nts .
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 7 of 4 6

Secti o n 2 .3 : a d de d te xt ver bati m 
fr o m t he pr ot oc ol a me n d me nts t o 
reflect t he c ha n ges t o t he pr ot oc ol
a me n d me nts ; u p date d Sc he ma t o 
reflect pr ot oc ol a me n d me nts

Secti o n s 3 a n d 6: u p date d e n d p oi nts 
t o matc h pr ot oc ol a me n d me nts.

Secti o n 5. 2 ; a d de d re p orti n g by
p o p ulati o n a n d diet ar y al l ocati o n

Secti o n 6: u p date d descri pti o n of 
‘ p o p ulati o ns’ t o i ncl u de ol der 
c o h ort a n d di etar y all ocati o n

A p pe n di x 5: ad de d a b bre viati o n s
Rati o nale: C ha n ges t o reflect c urre nt S A P 
te m plate:

Secti o n 2. 2: a d de d “ T y pe” a n d 
“ Esti ma n d” c ol u m ns t o 
o bjecti ve/ en d p oi nt /esti ma n d ta ble

U p date d li n ks t hr o u g h o ut
Rati o nale: C ha n ges t o reflect u p dates base d 
o n o n g oi n g re vie w of ta bles:

Secti o n 3. 3. 1. 4: re m o ve d relati ve 
c ha n ges w or di n g

Secti o n 3. 3. 1. 5; correcte d 2 4 h o ur 
baseli ne ti me p oi nt

Secti o n 5. 2. 4: u p date d statistical 
m o del d ia g n ostics w or di ng;

Secti o n 5. 2. 5: A d de d clarificati o n 
f or place b o d ose

Se cti o n 6: clarifie d st u d y a n d peri o d 
da y  defi niti o ns
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 8 of 4 6

Secti o n 6. 3. 1. 2: ad de d a d diti o nal 
fle xi bilit y t o d o e x pl orat or y E ma x 
m o delli n g

Secti o n 6. 3. 1. 4: clarifie d M M R M 
a nal ys is met h o d

A p pe n di x 4: u p date d d Tar get a n d 
pre dicte d E D 5 0 (i.e. t o use t he Q 8 H 
d ose) ; u p date d t he Hill S D
3 / 
0 4 A u g 2 0 2 3
N/ A
U p dates 
base d o n 
A & R pla n 
re vie w a n d 
Bli n de d Data 
Re vie ws.

Secti o ns 3. 2. 1, 6. 2. 1 a n d 6. 3. 1. 1: 
a d de d als o f or plas ma M 4 
meta b olite ( P F- 0 7 2 7 5 4 2 8) w here 
p ossi ble. Res ults ma y  n ot be 
i ncl u de d i n t he C S R.

Secti o n s 5. 2. 4 a n d 6: a d de d 
clarificati o n f or rec or ds c ollecte d 
after disc o nti n uati o n of st u d y  dr u g
f or selecte d tertiar y e n d p oi nts

Secti o n 6. 1. 1. 2 - cha n ge fr o m 
baseli ne i n A L T a n d A S T will be 
s u m marize d a n d pl otte d. 

A p pe n di x 5 – a d de d a bre viati o ns
2. I N T R O D U C TI O N
T his statistical a nal ysis 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 4 5 4 1 0 0 3 .  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 n y 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 y sis will als o be reflecte d i n a pr ot oc ol a me n d me nt.
Te xt i n it alics is ta ke n directly fr o m t he pr ot oc ol.
2. 1. M o dific ati o ns
t o t he A n al ysis Pl a n Descri be d i n t he Pr ot oc ol
N ot a p plica ble.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 9 of 4 6
2. 2. St u d y O bjecti ves , E n d p oi nts, a n d Esti m a n ds
T y pe
O bjecti ve
E n d p oi nt
Esti m a n d
P art A
Pri m ar y:
Safet y

T o ev al u ate t he s afety a n d 
t oler a bility of m ulti ple, 
asce n di n g, or al d oses of P F -
0 7 2 5 8 6 6 9 i n he alt hy n o n -
J a p a nese , J a p a nese (if 
e nr olle d), a n d ol der a d ult 
p artici p a nts (if e nr olle d).

Assess me nt of a dverse eve nts, cli nic al 
s afety l a b or at ory tests, vit al si g ns, 
c o nti n u o us c ar di ac m o nit ori n g, 1 2-
le a d E C Gs, res pir at ory r ate, or al b o dy 
te m per at ure, p hysic al ex a mi n ati o ns, 
ne ur ol o gic al ex a mi n ati o n fi n di n gs ,   
C- S S R S, 
 
..
N/ A
Sec o n d ar y:
P K

T o ev al u ate t he pl as m a a n d 
uri ne P K of si n gle a n d 
m ulti ple or al d oses of P F -
0 7 2 5 8 6 6 9 i n he alt hy n o n -
J a p a nese , J a p a nese (if 
e nr olle d), a n d ol der a d ult 
p artici p a nts (if e nr olle d).

P F - 0 7 2 5 8 6 6 9 pl as m a P K o n D ays 1 
a n d 1 4: C m ax , A U C t a u, Tm ax , d ose-
n or m alize d C m ax , a n d d ose-n or m alize d 
A U C t a u

P F - 0 7 2 5 8 6 6 9 uri ne P K o n D ay 1 4: 
Ae t a u, Ae t a u%,  a n d C L r (if d at a per mit)
N/ A
Terti ar y:
P K

T o ev al u ate a d diti o n al P K 
p ar a meters of P F - 0 7 2 5 8 6 6 9 
f oll o wi n g si n gle a n d m ulti ple 
or al d oses t o he alt hy n o n -
J a p a nese , J a p a nese (if 
e nr olle d), a n d ol der a d ult 
p artici p a nts (if e nr olle d).

P F -0 7 2 5 8 6 6 9 pl as m a P K o n D ay 1 4: 
C L/ F, C mi n , C av, P T R, R ac, R ac, C m ax, t½ , 
a n d V z/ F (if d at a per mit)
N/ A
Ot her

T o ev al u ate t he effect of 
m ulti ple, asce n di n g d oses of 
P F -0 7 2 5 8 6 6 9 a d mi nistere d 
f or 1 4 d ays i n he alt hy n o n-
J a p a nese , J a p a nese (if 
e nr olle d), a n d ol der a d ult 
p artici p a nts (if e nr olle d) o n 
b o dy wei g ht .

C h a n ge fr o m b aseli ne i n b o dy wei g ht 
o n D ays 7 a n d 1 4
N/ A
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 0 of 4 6
Bi o mar kers

T o ev al u ate t he p ote nti al f or 
i n d ucti o n of C Y P 3 A wit h 
a d mi nistr ati o n of m ulti ple, 
asce n di n g d oses of P F -
0 7 2 5 8 6 6 9 a d mi nistere d f or 
1 4 d ays i n he alt hy n o n -
J a p a nese , J a p a nese (if 
e nr olle d), a n d ol der a d ult 
p artici p a nts (if e nr olle d).

C h a n ge fr o m b aseli ne o n D ay 1 4:
o
Uri n ary 6 -
hy dr oxyc ortis ol/c ortis ol r ati o;
o
Pl as m a 4 -
hy dr oxyc h olester ol/c h olester ol 
r ati o;
o
Ser u m extr acell ul ar vesicles (if 
a n alyze d).
N/ A
Bi o mar kers

T o c o n d uct ex pl or at ory 
pr ofili n g f or pl as m a 
met a b olites of P F - 0 7 2 5 8 6 6 9 
i n ste a dy-st ate pl as m a 
s a m ples i n he alt hy n o n-
J a p a nese , J a p a nese (if 
e nr olle d), a n d ol der a d ult 
p artici p a nts (if e nr olle d).

Q u alit ative pl as m a levels of p ote nti al 
met a b olites of P F -0 7 2 5 8 6 6 9 at ste a dy -
st ate.:
N/ A
P art B
Pri m ary:
P K

T o ev al u ate t he effects of 
P F -0 7 2 5 8 6 6 9 o n mi d az ol a m 
P K i n he alt hy a d ult 
p artici p a nts

Mi d az ol a m pl as m a P K p ar a meters 
al o ne a n d i n c o m bi n ati o n wit h P F-
0 7 2 5 8 6 6 9 o n Peri o d 1/ D ay 1, Peri o d 
2/ D ay 2, a n d Peri o d 2/ D ay 1 0: C m ax, 
A U Cl ast, a n d A U Ci nf (if d at a per mit).
N/ A
Sec o n d ary:
Safet y

T o ev al u ate t he s afety a n d 
t oler a bility of mi d az ol a m 
al o ne a n d i n c o m bi n ati o n 
wit h P F - 0 7 2 5 8 6 6 9 w he n 
a d mi nistere d t o he alt hy a d ult 
p artici p a nts

A dverse eve nts, vit al si g ns 
me as ure me nts, c o nti n u o us p ulse 
o x i metry, 1 2-le ad E C Gs, p hysic al
ex a mi n ati o n fi n di n gs, a n d cli nic al 
s afety l a b or at ory me as ure me nts
N/ A
Terti ary:
P K

T o ev al u ate t he effects of 
P F - 0 7 2 5 8 6 6 9 o n a d diti o n al 
P K p ar a meters of mi d az ol a m 
i n he alt hy a d ult p artici p a nts

Mi d az ol a m pl as m a P K p ar a meters 
al o ne a n d i n c o m bi n ati o n wit h P F-
0 7 2 5 8 6 6 9 o n Peri o d 1/ D ay 1, Peri o d 
2/ D ay 2, a n d Peri o d 2/ D ay 1 0: T m ax, 
C L/ F, Vz/ F, a n d t ½ (if d at a per mit).
N/ A
Bi o mar kers

T o ev al u ate t he p ote nti al f or 
i n d ucti o n of C Y P 3 A wit h 
a d mi nistr ati o n of m ulti ple, 
asce n di n g d oses of P F -

C h a n ge fr o m b aseli ne:
o
Uri n ary 6 β -
hy dr oxyc ortis ol/c ortis ol r ati o o n 
D ay 7(if a n alyze d);
N/ A
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 1 of 4 6
0 7 2 5 8 6 6 9 i n he alt hy a d ult 
p artici p a nts
o
Pl as m a 4 -
hy dr oxyc h olester ol/c h olester ol 
r ati o;
o
Ser u m extr acell ul ar vesicles (if 
a n alyze d)
2. 3. St u d y Desi g n
T his st u dy c o nsists of 2 p arts. P art A will ev al u ate t he s afety, t oler a bility, a n d P K of m ulti ple  
asce n di n g d oses of P F -0 7 2 5 8 6 6 9. P art B will assess t he effects of P F -0 7 2 5 8 6 6 9 o n 
mi d az ol a m P K. A t ot al of u p t o a p pr ox i m ately 1 5 0 p artici p a nts are pl a n ne d t o be e nr olle d i n 
t his st u dy. P artici p a nts w h o disc o nti n ue pri or t o c o m pleti o n of t he st u dy f or re as o ns 
u nrel ate d t o s afety m ay be re pl ace d at t he discreti o n of t he i nvesti g at or a n d s p o ns or. 
P artici p a nts wit h dr a w n f or s afety re as o ns will n ot be re pl ace d.
2. 3. 1. P art A
P art A of t his st u dy is a r a n d o mize d, i nvesti g at or- a n d p artici p a nt -bli n d, s p o ns or -o pe n, 
pl ace b o -c o ntr olle d ev al u ati o n of t he s afety, t oler a bility, a n d P K of P F -0 7 2 5 8 6 6 9 after 
a d mi nistr ati o n of m ulti ple asce n di n g or al d oses t o he alt hy a d ult p artici p a nts. A n o pti o n al
c o h ort of he alt hy a d ult J a p a nese p artici p a nts m ay als o be ev al u ate d if res ults i n n o n -
J a p a nese p artici p a nts s u p p ort f urt her ev al u ati o n. U p t o 3 differe nt diet ary all oc ati o ns (ie, 
st a n d ar d, hi g h c ar b o hy dr ate-hi g h c al orie, a n d hi g h f at -hi g h c al orie diets) m ay be e m pl oye d. 
A n o pti o n al c o h ort of he alt hy a d ult J a p a nese p artici p a nts m ay als o be ev al u ate d if res ults i n 
n o n- J a p a nese p artici p a nts s u p p ort f urt her ev al u ati o n. I n a d diti o n, a n o pti o n al c o h ort of 
ol de r a d ult p artici p a nts m ay als o be ev al u ate d if res ults i n y o u n ger p artici p a nts s u p p ort 
f urt her ev al u ati o n. T he c o h ort of ol der p artici p a nts will o nly be ev al u ate d after t he res ults of 
P art B of t his st u dy are av ail a ble.  
A p pr oxi m ately 1 3 8 he alt hy a d ult p artici p a nts m ay be e nr olle d i n P art A, of w hic h 
a p pr oxi m ately 8 m ay be J a p a nese a n d 8- 1 0 m ay be ol der p artici p a nts.  
Prec a uti o n ary se nti nel d osi n g will be use d i n e ac h c o h ort of P art A i n w hic h P F -0 7 2 5 8 6 6 9
ex p os ures ( C m ax a n d/ or A U C 2 4) are pr ojecte d t o be hi g her t h a n t he ex p os ures ev al u ate d i n
t he si n gle asce n di n g d ose cli nic al st u dy C 4 5 4 1 0 0 1 or at t he discreti o n of t he i nvesti g at or i n 
res p o nse t o s afety si g n als o bserve d i n a previ o us c o h ort. If t he pr ojecte d ex p os ures h ave 
bee n ev al u ate d i n a previ o us c o h ort of t he c urre nt st u dy, se nti nel d osi n g m ay be o mitte d. 
W h e n se nti nel d osi n g is e m pl oye d, 2 p artici p a nts ( 1 receivi n g P F -0 7 2 5 8 6 6 9 a n d 1 receivi n g 
pl ace b o) will be d ose d bef ore t he re m ai ni n g p artici p a nts of t h at c o h ort are d ose d.   S afety 
a n d t oler a bility d at a t hr o u g h at le ast 4 8 h o urs after t he first d ose of st u dy i nterve nti o n f or t he 
se nti nel p artici p a nts will be revie we d pri or t o d osi n g t he re m ai ni n g p artici p a nts of t h at
c o h ort.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 2 of 4 6
A d diti o n al o pti o n al c o h orts m ay be e nr olle d t o re pe at a d ose or t o ex p a n d t he d ose/ex p os ure 
r a n ge or better c h ar acterize a p artic ul ar s afety or t oler a bility si g n al or cli nic al bi o m arker of 
i nterest (e g, b o dy wei g ht).
Fi g ure 1 . St u d y Desi g n P art A
2. 3. 2. P art B
P art B will be c o n d ucte d if t he res ults of P art A s u p p ort f urt her ev al u ati o n of P F -0 7 2 5 8 6 6 9. 
P art B is a 2 -peri o d, fixe d -se q ue nce, m ulti ple-d ose, o pe n -l a bel desi g n t o ev al u ate t he effect 
of P F -0 7 2 5 8 6 6 9 o n mi d az ol a m P K i n he alt hy a d ult p artici p a nts. A t ot al of a p pr oxi m ately 1 2 
he alt hy a d u lt p artici p a nts per c o h ort will be e nr olle d i n P art B. All p artici p a nts i n P art B
will be all oc ate d t o st a n d ar d diet.
Prec a uti o n ary se nti nel d osi n g m ay be use d i n P art B if a ut oi n hi biti o n of P F -0 7 2 5 8 6 6 9 P K is
o bserve d i n P art A of t he st u dy, or at t he dis creti o n of t he i nvesti g at or. B ase d o n p ote nti al
ti me-de pe n de nt i n hi biti o n of C Y P 3 A 4/ 5 at hi g h d oses of P F 0 7 2 5 8 6 6 9, ne ar m axi m al
i n hi biti o n of C Y P 3 A 4/ 5 is pre dicte d t o occ ur o n Peri o d 2/ D ay 2. T heref ore, if se nti nel d osi n g
is e m pl oye d, 2 p artici p a nts will be d ose d, a n d if n o u nt o w ar d effects are o bserve d t hr o u g h at
le ast 2 4 h o urs after mi d az ol a m d osi n g i n Peri o d 2/ D ay 2 f or t he se nti nel p artici p a nts, t he
re m ai ni n g p artici p a nts of t h at c o h ort will t he n be d ose d. If u nt o w ar d effects are o bserve d, a
l o wer d ose of P F-0 7 2 5 8 6 6 9 m ay be ev al u ate d i n a n ot her c o h ort.
I niti ally, a P F-0 7 2 5 8 6 6 9 d ose/ex p os ure level si mil ar t o t he M T D deter mi ne d i n P art A is
pl a n ne d t o be use d t o m axi mize t he p ossi bility of detecti n g a P K i nter acti o n wit h mi d az ol a m
i n P art B. H o wever, a l o wer d ose level m ay be ev al u ate d b ase d o n t he res ults of P art A.
A d diti o n al o pti o n al c o h orts m ay be a d de d if it is necess ary t o ev al u ate t he effect of 
a d diti o n al d ose levels of P F -0 7 2 5 8 6 6 9 o n mi d az ol a m P K. If t he P F -0 7 2 5 8 6 6 9/ mi d az ol a m 
c o m bi n ati o n use d i n t he first c o h ort of P art B is well t oler ate d, se nti nel d osi n g m ay n ot be 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 3 of 4 6
use d i n s u bse q ue nt c o h orts if t he P F-0 7 2 5 8 6 6 9 d ose use d i n a ny a d diti o n al c o h ort of P art B 
is less t h a n t he P F-0 7 2 5 8 6 6 9 d ose ev al u ate d i n t he first c o h ort of P art B.
Fi g ure 2 . St u d y Desi g n P art B
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)
3. 1. 1. P art A: S afet y a n d T oler a bilit y
Assess me nt of a dverse eve nts, cli nic al s afety l a b or at ory tests, vit al si g ns, c o nti n u o us c ar di ac 
m o nit ori n g, 1 2 -le a d E C Gs, res pir at ory r ate, or al b o dy te m per at ure, p hysic al ex a mi n ati o ns, 
ne ur ol o gic al ex a mi n ati o n fi n di n gs , C-S S R S , 
 
.
3. 1. 1. 1. A d verse E ve nts
A n y  e ve nts occ urri n g f oll o wi n g t he start of treat me nt, or i ncreasi n g i n se verit y , will be 
c o u nte d as treat me nt e mer ge nt. E ve nts t hat occ ur i n a n o n -treat me nt peri o d (f or e xa m ple 
F oll o w -u p) will be c o u nte d as treat me nt e mer ge nt a n d attri b ute d t o t he m ost rece nt treat me nt 
ta ke n. 
A 3 -tier a p pr oac h f or s u m marizi n g a d verse e ve nts ( A Es) will n ot be use d d ue t o t he l o w 
n u m ber of partici pa nts pla n ne d t o be recr uite d.
3. 1. 1. 2. Cli nic al S afet y L a b or at or y Tests
Safet y  la b orat or y tests will be perf or me d as descri be d i n t he pr ot oc ol.
Baseli ne will be defi ne d as t he assess me nts o n Da y  -2.  H o we ver, at t he discreti o n of t he 
i nvesti g at or, n o n-se nti nel p artici p a nts m ay be gi n t heir st ay at t he C R U o n t he s a me d ay as 
t he se nti nel p artici p a nts i n or der t o st a n d ar dize c o n diti o ns f or all p artici p a nts of a give n 
c o h ort. I n t h at c ase, a d m issi o n a n d b aseli ne activities c a n be st arte d eit her o n t heir first d ay 
i n t he C R U or o n D ay -2 of t heir st ay , i n w hic h case baseli ne will be t he last pre-d ose 
meas ure me nt .
A n y  cli nical la b orat or y a b n or malities of p ote ntial cli nical c o ncer n will be descri be d. T o 
deter mi ne if t here are a n y cli nicall y  si g nifica nt la b orat or y a b n or malities, t he hae mat ol o gical, 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 4 of 4 6
cli nical c he mistr y, uri nal y sis a n d ot her safet y tests will be assesse d a gai nst t he criteria 
s pecifie d i n t he s p o ns or re p orti n g sta n dar ds.  T he assess me nt will ta ke i nt o acc o u nt w het her 
eac h partici pa nt’s baseli ne test res ult is wit hi n or o utsi de t he la b orat or y  refere nce ra n ge f or 
t he partic ular la b orat or y para meter.
3. 1. 1. 3. Vit al Si g ns
Tri plicate s u pi ne a n d si n gle ort h ostatic bl o o d press ure ( B P) a n d p ulse rate meas ure me nts will 
be ta ke n as descri be d i n t he pr ot oc ol.  N ote t hat s o me of t he s u pi ne meas ure me nts are 
c ollecte d as part of t he ort h ostatic assess me nt. W he n ti mi n g of ort h ostatic assess me nts 
c oi nci des wit h ti mi n g of tri plicate s u pi ne assess me nts, t he last of t he tri plicate s u pi ne 
rea di n gs will be use d as t he s u pi ne rea di n g f or t he ort h ostatic assess me nt.  T he a vera ge of t he 
tri plicate meas ure me nts ( w he n a p pr o priate) will be calc ulate d f or eac h vital si g ns para meter.
Baseli ne f or s u pi ne B P a n d p ulse rate will be defi ne d as t he a vera ge of t he tri plicate 
meas ure me nts c ollecte d at t he pre -d ose ( 0 h o ur) assess me nt o n Da y 1.  Baseli ne f or sta n di n g 
B P a n d p ulse rate (as part of t he ort h ostatic vital si g ns) will be defi ne d as t he pre -d ose ( 0 
h o ur) assess me nt o n Da y 1.
T he f oll o wi n g e n d p oi nts will be deter mi ne d:

P ost ural differe nces (s u pi ne - sta n di n g) f or s yst olic a n d diast olic B P a n d f or p ulse rate
(at eac h ort h ostatic assess me nt ti me p oi nt)

C ha n ge fr o m baseli ne ( C F B) i n s u pi ne, sta n di n g a n d p ost ural differe nces f or s yst olic 
a n d diast olic B P a n d f or p ulse rate

T he mi ni m u m a n d ma xi m u m p ost -d ose s u pi ne a n d sta n di n g f or s yst olic a n d diast olic 
B P a n d f or p ul se rate

T he ma xi m u m p ost -d ose p ost ural differe nces f or s y st olic a n d diast olic B P

T he mi ni m u m p ost -d ose p ost ural differe nces f or p ulse rate

T he ma xi m u m decrease a n d i ncrease fr o m baseli ne o ver all meas ure me nts ta ke n p ost -
d ose f or s u pi ne, sta n di n g a n d p ost ural differe nces f or s ys t olic a n d diast olic B P a n d 
p ulse rate.
T he ma xi m u m i ncrease fr o m baseli ne will be calc ulate d b y selecti n g t he ma xi m u m c ha n ge 
fr o m baseli ne o ver t he res pecti ve peri o d, e xce pt i n t he case w here a partici pa nt d oes n ot 
s h o w a n i ncrease.  I n s uc h a n i nsta nce, t he mi ni m u m decrease s h o ul d be ta ke n.  Si milarl y, t he 
ma xi m u m decrease fr o m baseli ne will be deter mi ne d b y selecti n g t he mi ni m u m val ue of t he 
c ha n ges fr o m baseli ne.  I n cases w here a partici pa nt d oes n ot s h o w a decrease, t he mi ni m u m 
i ncrease s h o ul d be ta ke n.
3. 1. 1. 4. C o nti n u o us C ar di ac M o nit ori n g
C o nti n u o us car diac m o nit ori n g will be perf or me d usi n g tele metr y as o utli ne d i n t he pr ot oc ol.
All a b n or mal r h yt h ms will be rec or de d a n d re vie we d b y  t he i n vesti gat or f or t he prese nce of 
r h yt h ms of p ote ntial cli nical c o ncer n.  T he ti me, d urati o n, a n d descri pti o n of t he cli nically 
si g nifica nt e ve nt will be rec or de d i n t he C R F.  E ve nts dee me d of cli nical c o ncer n will be 
rec or de d as A Es a n d will be s u m marize d as part of t he sta n dar d A E o ut p uts.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 5 of 4 6
3. 1. 1. 5. 1 2 -le a d E lectr oc ar di o gr a ms
A si n gle s u pi ne 1 2 -lea d E C G will be o btai ne d o n all partici pa nts at scree ni n g, disc har ge a n d 
f oll o w- u p.  1 2 -lea d E C Gs will be rec or de d i n tri plicate o n all partici pa nts at all ot her ti mes 
detaile d i n t he pr ot oc ol.  T he a vera ge of t he tri plic ate rea di n gs ( w he n a p pr o priate) will be 
calc ulate d f or eac h E C G para meter.
T he Q T, Q Tc F, P R, R R, Q R S i nter val a n d heart rate will be rec or de d at eac h assess me nt ti me.  
If n ot s u p plie d, Q Tc F will be deri ve d usi n g Fri dericia’s heart rate c orrecti o n f or m ula:
Q Tc F = Q T / ( R R) 1/ 3
w here R R = 6 0/ H R (if n ot pr o vi de d).
T he a vera ge of t he tri plicate E C G meas ure me nts o ver t he 3 pre -d ose meas ure me nt ti mes 
(-1 H, -0. 5 H, a n d pre d ose 0 H; t otal of 9 E C G meas ure me nts) c ollecte d bef ore m or ni n g d ose 
a d mi nistrati o n o n Da y 1 will ser ve as eac h partici pa nt’s baseli ne val ue.
T he f oll o wi n g e n d p oi nts will be deter mi ne d: -

c ha n ge fr o m baseli ne i n Q T, Q Tc F, P R, Q R S i nter val a n d heart rate

m a xi m u m p ost - d ose Q Tc F, P R a n d Q R S i nter val

ma xi m u m i ncrease fr o m baseli ne o ver all meas ure me nts ta ke n p ost -d ose f or Q Tc F , 
P R a n d Q R S val ues
T he ma xi m u m i ncrease fr o m baseli ne will be calc ulate d b y selecti n g t he ma xi m u m c ha n ge 
fr o m baseli ne o ver t he res pecti ve peri o d, e xce pt i n t he case w here a partici pa nt d oes n ot 
s h o w a n i ncrease.  I n s uc h a n i nsta nce, t he mi ni m u m decrease s h o ul d be ta ke n.
3. 1. 1. 6. Res pir at or y R ate
Res pirat or y  rate will be meas ure d at ti mes s pecifie d i n t he pr ot oc ol.
Baseli ne will be t he pre -d ose ( 0 h o ur) assess me nt o n Da y  1.
C ha n ge fr o m baseli ne i n res pirat or y rate will be deter mi ne d, as well t he ma xi m u m i ncrease 
a n d decrease fr o m baseli ne o ver all meas ure me nts ta ke n p ost -d ose.
3. 1. 1. 7. Or al B o d y Te m per at ure
Oral b o d y te m perat ure will be meas ure d at ti mes s pecifie d i n t he pr ot oc ol.
Baseli ne will b e t he pre -d ose ( 0 h o ur) assess me nt o n Da y  1.
C ha n ge fr o m baseli ne i n b o d y  te m perat ure will be deter mi ne d, as well t he ma xi m u m i ncrease 
a n d decrease fr o m baseli ne o ver all meas ure me nts ta ke n p ost -d ose.
3. 1. 1. 8. P h ysic al a n d Ne ur ol o gic al E x a mi n ati o ns
P h y sical a n d ne u r ol o gical e xa mi nati o ns will be perf or me d as descri be d i n t he pr ot oc ol.  
P hysic al ex a mi n ati o n, a n d ne ur ol o gic al ex a mi n ati o n i nf or m ati o n, as a p plic a ble, c ollecte d 
d uri n g t he c o urse of t he st u dy will be c o nsi dere d s o urce d at a a n d will n ot be re q uire d t o be 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 6 of 4 6
rep orte d, u nless ot her wise n ote d. H o wever, a ny u nt o w ar d fi n di n gs i de ntifie d o n p hysic al 
a n d/ or ne ur ol o gic al ex a mi n ati o ns c o n d ucte d d uri n g t he active c ollecti o n peri o d will be 
c a pt ure d as A Es, if t h ose fi n di n gs meet t he defi niti o n of a n A E.
3. 1. 1. 9. C- S S R S
T he C - S S R S is a vali date d t o ol t o e val uate s uici dal i deati o n a n d be ha vi o ur.  T he 
‘ Baseli ne/ Lifeti me’ assess me nt is t o be perf or me d at S cree ni n g.  All ot her assess me nts 
s h o ul d use t he ‘Si nce Last Visit ’ assess me nt.  Data rele va nt t o t he assess me nt of s uici d alit y 
will be ma p pe d t o t he C ol u m bia - Classificati o n Al g orit h m of S uici de Assess me nt ( C-C A S A) 
c o des as gi ve n i n A p pe n di x 2 .
3. 1. 2. P art B: Mi d az ol a m P K P ar a meters

Mi d az ol a m pl as m a P K p ar a meters al o ne a n d i n c o m bi n ati o n wit h P F -0 7 2 5 8 6 6 9 o n 
Peri o d 1/ D ay 1, Peri o d 2/ D ay 2, a n d Peri o d 2/ D ay 1 0 : Cm ax , A U Cl ast, a n d A U Ci nf (if d at a 
per mit).
Bl o o d sa m ples f or P K a nal y sis of mi daz ola m will be c ollecte d acc or di n g t o t he pr ot oc ol.  
Plas ma P K para meters ( o n Peri o d 1/ Da y  1, Peri o d 2/ Da y 2 a n d Peri o d 2/ Da y 1 0 ) f or 
mi daz ola m will be de ri ve d fr o m t he plas ma c o nce ntrati o n-ti me pr ofiles usi n g sta n dar d n o n-
c o m part me ntal met h o ds, as data per mit.  
Ta ble 2 s h o ws t he a nal ysis scale a n d met h o d f or eac h para meter.
T a ble 2 .  Mi d az ol a m P K P ar a meters
P ar a meter
A n al ysis 
Sc ale
Peri o d 1/ D a y 1
(Mi d az ol a m )
Peri o d 2/ D a y 2
(Mi d az ol a m
+
P F -0 7 2 5 8 6 6 9 )
Peri o d 2/ D a y 1 0
(Mi d az ol a m
+
P F -0 7 2 5 8 6 6 9 )
C ma x
l n
A, D
A, D
A, D
A U C last
l n
A, D
A, D
A, D
A U C i nf*
l n
A, D
A, D
A, D
* =if data per mit. A b bre viati o ns: A =a nal yz e d usi n g a statistical m o del; D = dis pla ye d wit h 
descri pti ve statistics as o utli ne d i n Ta ble 6 i n Secti o n 6. 1. 2 ; l n = nat ural-l o g tra nsf or me d.  
3. 2. Sec o n d ar y E n d p oi nt(s)
3. 2. 1. P art A: P F - 0 7 2 5 8 6 6 9 Pl as m a a n d Uri ne P K P ar a meters

P F - 0 7 2 5 8 6 6 9 pl as m a P K o n D ays 1 a n d 1 4: C m ax, A U Ct a u, T m ax, d ose-n or m alize d 
C m ax, a n d d ose -n or m alize d A U Ct a u
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 7 of 4 6

P F -0 7 2 5 8 6 6 9 uri ne P K o n D ay 1 4: Ae t a u, Aet a u%, a n d C Lr (if d at a per mit)
Plas ma P K para meters will als o be calc ulate d f or t he M 4 meta b olite ( P F -0 7 2 7 5 4 2 8) w here 
p ossi ble a n d as a p plica ble. Bl o o d a n d uri ne sa m ples f or P K a nal y sis of P F - 0 7 2 5 8 6 6 9 will be 
c ollecte d acc or di n g t o t he pr ot oc ol.
Plas ma P K para meters ( o n Da ys 1 a n d 1 4) a n d uri ne P K para meters ( o n Day 1 4) f or 
P F - 0 7 2 5 8 6 6 9 will be deri ve d fr o m t he plas ma a n d uri ne c o nce ntrati o n- ti me pr ofiles usi n g 
sta n dar d n o n-c o m part me ntal met h o ds , as data per mit.
Ta ble 3 s h o ws t he a nal ysis scale a n d met h o d f or eac h para meter.
T a ble 3. P F -0 7 2 5 8 6 6 9 P K p ar a meters
P ar a meter
A n al ysis Sc ale
P F - 0 7 2 5 8 6 6 9
Plas ma Para meters
C ma x
l n
D
A U C ta u
l n
D
T ma x
R
D
C ma x ( d n)
l n
D
A U C ta u ( d n)
l n
D
Uri ne Para meters
Ae ta u
l n
D
Ae ta u%
l n
D
C L r
l n
D
A b bre viati o ns: ( d n) = D ose n or malize d; D = dis pla ye d wit h descri pti ve statistics as o utli ne d i n 
Ta ble 7 i n Secti o n 6. 2. 1 ; l n= nat ural -l o g tra nsf or me d; R =ra w ( u ntra nsf or me d).
3. 2. 2. P art B: S afet y a n d T oler a bilit y

A dverse eve nts, vit al si g ns me as ure me nts, c o nti n u o us p ulse oxi metry, 1 2 -le a d E C Gs, 
p hysic al ex a mi n ati o n fi n di n gs, a n d cli nic al s afety l a b or at ory me as ure me nts
See secti o n s 3. 1. 1. 1 , 3. 1. 1. 2 , 3. 1. 1. 3 , 3. 1. 1. 5 a n d 3. 1. 1. 8 f or details o n t he safety e n d p oi nts.  
See sec ti o ns 3. 1. 1. 6 a n d 3. 1. 1. 7 f or details o n a d diti o nal safet y e n d p oi nts (res pirat or y rate 
a n d oral b o d y te m perat ure).
C o nti n u o us p ulse o xi metr y  will be perf or me d as o utli ne d i n t he pr ot oc ol.  E ve nts dee me d of 
cli nical c o ncer n will be rec or de d as A Es a n d will be s u m marize d as part of t he sta n dar d A E 
o ut p uts.
F or Part B vital si g ns , E C G , cli nical safety la b orat or y meas ure me nts, res pirat or y  rate a n d oral 
b o d y  te m perat ure data , baseli ne will be defi ne d as t he last pre -d ose assess me nt o n Da y  1,
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 8 of 4 6
Peri o d 1. W here a p pr o priate , as o utli ne d i n t he pr ot oc ol, t he a vera ge of tri plicate meas ures 
will be use d f or t h is baseli ne.  
3. 3. Ot her E n d p oi nt (s)
3. 3. 1. P art A
3. 3. 1. 1. A d diti o n al P F -0 7 2 5 8 6 6 9 P K P ar a meters

P F - 0 7 2 5 8 6 6 9 pl as m a P K o n D ay 1 4: C L/ F, C mi n, C av, P T R, R ac, R ac, C m ax, t ½, a n d 
Vz/ F (if d at a per mits).
T hese P K para meters will als o be calc ulate d f or M 4 meta b ol ite ( P F-0 7 2 7 5 4 2 8) w here 
p ossi ble .
A d diti o nal plas ma P K para meters ( o n Da y 1 4) f or P F - 0 7 2 5 8 6 6 9 will be deri ve d fr o m t he 
plas ma c o nce ntrati o n-ti me pr ofiles usi n g sta n dar d n o n -c o m part me ntal met h o ds , as data 
per mit.
Ta ble 4 s h o ws t he a nal ysis scale a n d met h o d f or eac h of t hese a d diti o nal para meters.
T a ble 4 . A d diti o n al P F -0 7 2 5 8 6 6 9 P K p ar a meters
* =if data per mits. A b bre viati o ns: D = dis pla y e d wit h descri pti ve statistics as o utli ne d i n Ta ble 
8 i n Secti o n 6. 3. 1. 1 ; l n= nat ural -l o g tra nsf or me d; R =ra w ( u ntra nsf or me d) .
3. 3. 1. 2. B o d y W ei g ht

C h a n ge fr o m b aseli ne i n b o dy wei g ht o n D ays 7 a n d 1 4.
B o d y wei g ht will be meas ure d at ti mes s pecifie d i n t he pr ot oc ol.
Baseli ne will be defi ne d as t he pre -d ose ( 0 h o ur) assess me nt o n Da y  1. 
C ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m baseli ne will be calc ulate d f or eac h p ost-
baseli ne ti me p oi nt. 
P ar a meter
A n al ysis 
Sc ale
P F -0 7 2 5 8 6 6 9
C L / F
l n
D
C mi n
l n
D
C a v
l n
D
P T R
l n
D
R ac
l n
D
R ac,C ma x
l n
D
t ½*
R
D
Vz/ F *
l n
D
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 1 9 of 4 6
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 0 of 4 6
3. 3. 1. 7. P ote nti al f or I n d ucti o n of C Y P 3 A

C h a n ge fr o m b aseli ne o n D ay 1 4:
•
Uri n ary 6 -hy dr oxyc ortis ol/c ortis ol r ati o;
•
Pl as m a 4 - hy dr oxyc h olester ol/c h olester ol r ati o;
•
Ser u m extr acell ul ar vesicles (if a n alyze d).
Bl o o d sa m ples f or t he meas ure me nt of 4 -h y dr o x y c h olester ol, c h olester ol a n d e xtracell ular 
vesicles, a n d uri ne sa m ples f or t he meas ur e me nt of 6-h y dr o x yc o rtis ol a n d c ortis ol will be 
c ollecte d at ti mes s pecifie d i n t he pr ot oc ol.
Baseli ne f or u ri nar y 6-h y d r o xyc ortis ol/c ortis ol rati o will be t he sa m ple o n Da y  - 1. Baseli ne 
f or p las ma 4-h y dr o x yc h olester ol/c h olester ol rati o a n d ser u m e xtracell ular vesicles (if 
a nal ys e d) will be t he pre -d ose ( 0 h o ur) sa m ple o n Da y  1. 
C ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m baseli ne will be calc ulate d at eac h p ost -
baseli ne ti me p oi nt.  
3. 3. 1. 8. Q u alit ati ve M et a b olite Pr ofili n g

Q u alit ative pl as m a levels of p ote nti al met a b olites of P F - 0 7 2 5 8 6 6 9 at ste a dy-st ate.
Meta b olite pr ofili n g ma y be c o n d ucte d as part of t his st u d y  a n d use d f or i nter nal e x pl orat or y  
p ur p oses .  T hese data will n ot be i ncl u de d i n t he C S R.
3. 3. 1. 9. Ot her E n d p oi nts
 
 
Retai ne d Researc h Sa m ples f or bi o mar kers a n d ge netics will be c ollecte d as par t of t his st u d y
an d ma y  be use d f or i nter nal e x pl orat or y p ur p oses.  T hese data will n ot be i ncl u de d i n t he 
C S R.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 1 of 4 6
3. 3. 2. P art B
3. 3. 2. 1. A d diti o n al Mi d az ol a m P K P ar a meters 

Mi d az ol a m pl as m a P K p ar a meters al o ne a n d i n c o m bi n ati o n wit h P F -0 7 2 5 8 6 6 9 o n 
Peri o d 1/ D ay 1, Peri o d 2/ D ay 2, a n d Peri o d 2/ D ay 1 0: T m ax, C L/ F, Vz/ F, a n d t ½ (if d at a 
per mit).
A d diti o nal plas ma P K para meters ( o n Peri o d 1/ Da y  1, Peri o d 2/ Da y 2 a n d Peri o d 2/ Da y 1 0 ) 
f or mi daz ola m will be deri ve d fr o m t he plas ma c o nce ntrati o n-ti me pr ofiles usi n g sta n dar d 
n o n- c o m part me ntal met h o ds, as data per mit.
Ta ble 5 s h o ws t he a nal ysis scale a n d met h o d f or eac h of t hese a d diti o nal para meters.
T a ble 5. A d diti o n al Mi d az ol a m P K P ar a meters
P ar a meter
A n al ysis 
Sc ale
Peri o d 1/ D a y 1 
(Mi d az ol a m )
Peri o d 2/ D a y 2
(Mi d az ol a m
+
P F -0 7 2 5 8 6 6 9 )
Peri o d 2/ D a y 1 0
(Mi d az ol a m
+
P F -0 7 2 5 8 6 6 9 )
T ma x
R
D
D
D
C L / F*
l n
D
D
D
Vz/ F *
l n
D
D
D
t ½*
R
D
D
D
* =if data per mits. A b bre viati o ns: D = dis pla y e d wit h descri pti ve statistics as o utli ne d i n Ta ble 
9 i n Secti o n 6. 3. 2. 1 ; l n= nat ural -l o g tra nsf or me d; R =ra w ( u ntra nsf or me d)
3. 3. 2. 2. P ote nti al f or In d ucti o n of C Y P 3 A

C h a n ge fr o m b aseli ne o n D ay 1 0:
o
Uri n ary 6 β -hy dr oxyc ortis ol/c ortis ol r ati o o n D ay 7(if a n alyze d);
o
Pl as m a 4 - hy dr oxyc h olester ol/c h olester ol r ati o
o
Ser u m extr acell ul ar vesicles (if a n alyze d)
Bl o o d sa m ples f or t he meas ure me nt of uri nar y  6-h y dr o x y c ortis ol, c ortis ol, plas ma 
4 -h y dr o x y c h olester ol, c h olester ol a n d e xtracell ular vesicles will be c ollecte d at ti mes 
s pecifie d i n t he pr ot oc ol.
Baseli ne will be t he sa m ple o n Da y  1 Peri o d 1, pri or t o m or ni n g d osi n g. 
C ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m baseli ne will be calc ulate d f or Da y  1 0 Peri o d 
2.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 2 of 4 6
3. 4. B aseli ne V ari a bles
N ot a p plica ble.
3. 5. S afet y E n d p oi nts
See S ecti o n 3. 2. 1 f or safet y e n d p oi nts f or Part A. 
See S ecti o n 3. 2. 2 f or safet y e n d p oi nts f or Part B.
3. 5. 1. C O VI D -1 9
Partici pa nts will u n der g o C O VI D -1 9 relate d meas ures per C R U pr oce d ures.
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 )
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.
P artici p a nt A n alysis Set
Descri pti o n
E nr olle d/ R a n d o mly 
assi g ne d t o st u dy 
i nterve nti o n
" E nr olle d" me a ns a p artici p a nt's a gree me nt t o p artici p ate i n a 
cli nic al st u dy f oll o wi n g c o m pl eti o n of t he i nf or me d c o nse nt 
pr ocess a n d scree ni n g.  P ote nti al p artici p a nts w h o are 
scree ne d f or t he p ur p ose of deter mi ni n g eli gi bility f or t he st u dy, 
b ut d o n ot p artici p ate i n t he st u dy, are n ot c o nsi dere d e nr olle d, 
u nless ot her wise s pecifie d by t he pr ot oc ol. A p artici p a nt will be 
c o nsi dere d e nr olle d if t he i nf or me d c o nse nt is n ot wit h dr a w n 
pri or t o p artici p ati n g i n a ny st u dy activity after scree ni n g.
F ull A n alysis Set ( F A S)
All p artici p a nts r a n d o mly assi g ne d t o st u dy i nterve nti o n a n d 
w h o t ake at le ast 1 d ose of st u dy i nterve nti o n, f or t he give n p art 
of t he st u dy ( P art A or B) .
S afety A n alysis Set
All p artici p a nts r a n d o mly assi g ne d t o st u dy i nterve nti o n a n d 
w h o t ake at le ast 1 d ose of st u dy i nterve nti o n, f or t he give n p art 
of t he st u dy ( P art A or B). P ar tici p a nts will be a n alyze d 
acc or di n g t o t he pr o d uct t hey act u ally receive d.
P K C o nce ntr ati o n Set
All p artici p a nts r a n d o mly assi g ne d t o st u dy i nterve nti o n a n d 
w h o t ake at le ast 1 d ose of mi d az ol a m a n d/ or st u dy i nterve nti o n 
a n d i n w h o m at le ast 1 pl as m a or uri ne c o nce ntr ati o n v al ue is 
re p orte d, f or t he give n p art of t he st u dy ( P art A or B).
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 3 of 4 6
P artici p a nt A n alysis Set
Descri pti o n
P K P ar a meter Set
All p artici p a nts r a n d o mly assi g ne d t o st u dy i nterve nti o n a n d 
w h o t ake at le ast 1 d ose of mi d az ol a m a n d/ or st u dy i nterve nti o n 
a n d h ave at le ast 1 of t he P K p ar a meters of i nterest c alc ul ate d,
f or t he give n p art of t he st u dy ( P art A or B).
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
5. 1. H y p ot heses a n d Decisi o n R ules
T here is n o statistical h y p ot hesis testi n g pla n ne d f or t his st u d y  a n d n o statistical decisi o n 
r ules will be a p plie d.
5. 2. Ge ner al Met h o ds
P art A a n d P art B of t he st u dy will be prese nte d se p ar ately.
U nless ot her wise state d, all s u m maries a n d pl ots will be prese nte d b y treat me nt gr o u p, wit h 
data fr o m differe nt p o p ulati o ns (e. g. n o n -Ja pa nese, Ja pa nese a n d ol der a dult partici pa nts), if 
a p pr o priate, re p orte d se parately. Eac h dietar y  all ocati o n (ie, sta n dar d, hi g h car b o hy drate -hi g h 
cal orie, a n d hi g h fat-hi g h cal orie diets) will als o be re p orte d se paratel y.
If a d ose le vel is re peate d acr oss 2 or m ore c o h orts ( wit hi n a diet), t he data ma y be c o m bi ne d 
a n d/ or re p orte d se paratel y.
5. 2. 1. A n al yses f or C o nti n u o us E n d p oi nts
U nless ot her wise state d, c o nti n u o us varia bles will be prese nte d usi n g s u m mar y statistics: 
n u m ber of o bser vati o ns, arit h metic 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 val ues.
L o g tra nsf or me d c o nti n u o us varia bles will be prese nte d usi n g s u m mar y statistics: n u m ber of 
o bser vati o ns, arit h metic mea n, me dia n, c v %, sta n dar d de viati o n, mi ni m u m, ma xi m u m, 
ge o metric mea n a n d ge o metric c v % .
5. 2. 2. A n al yses f or C ate g oric al E n d p oi nts
Cate g orical varia bles will be prese nte d usi n g s u m mar y  statistics: n u m ber of o bser vati o ns a n d 
perce nta ges.
5. 2. 3. Mi xe d Effects M o del 
A mixe d effect s m o del wit h tre at me nt as a fixe d effect a n d p artici p a nt as a r a n d o m effect will
be use d . Esti m ates of t he a dj uste d me a n differe nces ( Test-Refere nce) a n d c orres p o n di n g 
9 0 % c o nfi de nce i nterv als will be o bt ai ne d fr o m t he m o del. T he a dj uste d me a n differe nces 
a n d 9 0 % c o nfi de nce i nterv als f or t he differe nces will be ex p o ne nti ate d t o pr ovi d e esti m ates 
of t he r ati o of a dj uste d ge o metric me a ns ( Test/ Refere nce) a n d 9 0 % c o nfi de nce i nterv als f or 
t he r ati os.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 4 of 4 6
E xa m ple S A S c o de is pr o vi de d i n A p pe n di x 3 .
5. 2. 4. Mi xe d M o del Re pe ate d Me as ures
A n M M R M m o del will be use d wit h treat me nt, ti me (as a fact or), treat me nt-b y -ti me
i nteracti o n, baseli ne a n d baseli ne -b y -ti me i nteracti o n as fi xe d effects. Partici pa nt will be 
fitte d as a ra n d o m effect i n t he m o del wit h ti me as a re peate d effect wit hi n eac h partici pa nt.  
A n u nstr uct ure d c o varia nce matri x will be fitte d t o t he re peate d ti mes wit hi n partici pa nt 
( ot her c o varia nce matrices will be c o nsi dere d if necessar y, e. g. if t he m o del d oes n ot 
c o n ver ge ). Rec or ds c ollecte d after disc o nti n uati o n of st u d y  dr u g will be e xcl u de d.  
T he Least S q uares ( L S) mea ns  (a n d sta n dar d err ors, 9 0 % c o nfi de nce i nter vals a n d 2 -si de d p-
val ues) will be o btai ne d f or eac h treat me nt at eac h ti me p oi nt. Differe nces (a n d sta n dar d 
err ors, 9 0 % c o nfi de nce i nter vals a n d 2-si de d p-val ues) bet wee n L S mea ns will als o be 
o btai ne d , c o m pari n g eac h d ose of P F - 0 7 2 5 8 6 6 9 vers us place b o. If data ha ve bee n l o g ge d, 
L S mea ns a n d differe nces (i ncl u di n g CI’s) will be bac k tra nsf or me d t o gi ve perce nt c h a n ges 
fr o m baseli ne ([relati ve c ha n ge fr o m baseli ne -1] * 1 0 0) a n d perce nt c ha n ge fr o m place b o 
([rati o of relati ve c ha n ge fr o m baseli ne -1] * 1 0 0) , as a p pr o priate.  
Sta n dar d S A S o ut p ut will be pr o vi de d t o s u p p ort t he statistical s u m mar y ta ble f or t he 
a nal ys is m o del, b ut will n ot be i ncl u de d i n t he C S R.
E xa m ple S A S c o de is pr o vi de d i n A p pe n di x 3 .
Statistical M o del Dia g n ostics
T he prese nce of o utliers will be i n vesti gate d f or t his m o del. A n o utlier will be defi ne d as a n y  
res p o nse data val ue wit h a st u de ntize d (c o n diti o nal) resi d ual greater t ha n 3, or less t ha n -3. A 
listi n g will be prese nte d of a n y partici pa nts meeti n g t hese criteria a n d will be i ncl u de d wit h 
sta n dar d S A S o ut p ut. T he ass u m pti o ns of n or malit y will be verifie d gra p hicall y usi n g 
resi d ual pl ots. F or eac h fitte d m o del, a set of c o n diti o nal st u de ntize d resi d ual pl ots will be 
pr o d uce d, i ncl u di n g resi d ual pl ot, hist o gra m of n or malit y , q uartile-q uartile ( Q Q) pl ot a n d 
s u m mar y of fit statistics. T he resi d ual pl ots will n ot be i ncl u de d i n t he C S R.
If t here are o utliers or maj or de viati o ns fr o m n or malit y, t he n t he effect of t hese o n t he 
c o ncl usi o ns ma y be i n vesti gate d t hr o u g h alter nati ve tra nsf or mati o ns a n d/ or a nalys es 
e xcl u di n g o utliers. J ustificati o n f or a ny alter nati ve t o t he pla n ne d a nal ys is will be gi ve n i n 
t he re p ort of t he st u dy.
5. 2. 5. B a yesi a n E m a x M o del
A f o ur - para meter E ma x m o del will be use d, wit h d ose as a c o nti n u o us varia ble. T he m o del 
str uct ure will ta ke t he f or m: -
   =   +
    ∗              0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 5 of 4 6
E 0 is t he place b o effect, d ose is t he tar get ra n d o mize d d ose ( place b o d ose = 0), E m ax is t he 
ma xi m u m effect, E D 5 0 is t he d ose pr o d uci n g 5 0 % of t he ma xi m u m effect a n d Hill is t he 
sl o pe para meter. T he m o del will utilize a Ba yesia n met h o d ol o g y a p pr oac h wit h wea kly 
i nf or mati ve pri ors as descri be d i n A p pe n di x 4 .
Esti mates of t he m o del para meters of E 0, E m ax , E D 5 0 a n d Hill a n d t heir 9 5 % cre di ble i nter vals 
will be pr o d uce d.
T he p osteri or me dia ns a n d 9 0 % cre di ble i nter vals ( 5t h a n d 9 5t h perce ntiles of t he rele va nt 
p osteri or distri b uti o n) will be re p orte d f or eac h tar get ra n d o mize d d ose (i ncl u di n g place b o) 
a n d t heir differe nces relati ve t o place b o.  
If c o n ver ge nce ca n n ot be o btai ne d, a p osteri or pre dicti ve c hec k f or n o n-m o n ot o ne d ose 
res p o nse pr o d uces a pre dicti ve fit pr o ba bilit y < 0. 0 5, or vis ual i ns pecti o n of t he data d oes n ot 
s u p p ort a d ose-res p o nse E ma x relati o ns hi p, t he m o del ma y be si m plifie d or t he a nalys is ma y 
n ot be perf or me d .
5. 3.
Met h o ds t o M a n a ge Missi n g D at a
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 n dar d r ules f or i m p utati o n will be 
a p plie d.
5. 3. 1. 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 P K 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. 
I n all e x pl orat or y bi o mar ker 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 t he l o wer li mit of q ua ntificati o n ( L L Q).
I n 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 wit h t he 
val ue f or t he L L Q.
5. 3. 2. 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
I n P K a n d e x pl orat or y bi o mar ker s u m mar y ta bles a n d pl ots of me dia n pr ofiles, 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 (i.e. n ot d o ne) or N S (i.e. n o sa m ple), 
2.
A de viati o n i n sa m pli n g ti me is of s ufficie nt c o ncer n or a c o nce ntrati o n has b ee n 
fla g ge d a n o mal o us by t he p har mac o ki neticist/statisticia n.
N ote t hat s u m mar y  statistics will n ot be prese nte d at a partic ular ti me p oi nt if m ore t ha n 5 0 % 
of t he data are missi n g. 
Partici pa nts w h o e x perie nce e ve nts t hat ma y  affect t heir P K pr ofile (e. g. lac k of c o m plia nce 
wit h d osi n g or v o miti n g) ma y be e xcl u de d fr o m t he P K a nal ys is. At t he discreti o n of t he 
p har mac o ki neticist a c o nce ntrati o n val ue ma y  als o be e xcl u de d if t he de viati o n i n sa m pli n g 
ti me is of s ufficie nt c o ncer n or if t he c o nce ntrati o n is a n o mal o us f or a n y ot her reas o n. 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 6 of 4 6
A f ull list of pr ot oc ol de viati o ns will be c o m pile d a n d re vie we d t o i de ntif y  maj or a n d mi n or 
de viati o ns pri or t o data base cl os ure.
5. 3. 3. P h ar m ac o ki netic P ar a meters
Act ual P K sa m pli n g ti mes will be use d i n t he deri vati o n of P K para meters.  F or P K 
para meter calc ulati o ns, t he s p o ns or ’s sta n dar d r ules will be a p plie d.
If a P K para meter ca n n ot be deri ve d fr o m a partici pa nt’s c o nce ntrati o n data, t he para meter 
will be c o de d as N C (i.e. n ot calc ulate d). ( N ote t hat N C val ues will n ot be ge nerate d be y o n d 
t he da y t hat a partici pa nt disc o nti n ues.)
I n s u m mar y ta bles, statistics will be calc ulate d by setti n g N C val ues t o missi n g; a n d statistics 
will be prese nte d f or a partic ular tr eat me nt gr o u p/a nal yte wit h ≥3 e val ua ble meas ure me nts. 
F or statistical a nal ys es (i.e. mi xe d effects m o del), P K para meters c o de d as N C will als o be 
set t o missi n g; a n d a nalyses will n ot be perf or me d f or a partic ular para meter if m ore t ha n 
5 0 % of t he data are N C.
If a n i n di vi d ual partici pa nt has a k n o w n biase d esti mate of a P K para meter ( d ue f or e xa m ple 
t o a n u ne x pecte d e ve nt s uc h as v o miti n g bef ore all t he c o m p o u n d is a de q uatel y a bs or be d i n 
t he b o d y), t his will be f o ot n ote d i n s u m mar y ta bles a n d will n ot be i ncl u de d i n t he calc ulati o n 
of s u m mar y  statistics or statistical a nal yses.
6. A N A L Y S E S A N D S U M M A RI E S
F or all prese ntati o ns, st u d y da y is relati ve t o start of st u d y treat me nt ( Da y 1); peri o d da y is 
relati ve t o t he start of treat me nt peri o d, u nless ot her wise s pecifie d.
F or e n d p oi nts B o d y Wei g ht, 
, 
, 
 
t he rec or ds c ollecte d after disc o nti n uati o n of st u d y dr u g will be e xcl u de d fr o m all s u m maries, 
fi g ures a n d a nalys is ta bles. Data will be liste d o nl y.  
6. 1. Pri m ar y E n d p oi nt (s)
6. 1. 1. P art A: S afet y a n d T oler a bilit y
6. 1. 1. 1. A d verse E ve nts
A d verse e ve nts will be liste d a n d s u m marize d b y  treat me nt a n d o verall, i n acc or da nce wit h 
s p o ns or re p orti n g sta n dar ds usi n g t he safet y p o p ulati o n defi ne d i n Secti o n 4 .
6. 1. 1. 2. Cli nic al S afet y L a b or at or y Tests
La b orat or y  data will be liste d a n d s u m marize d b y treat me nt, i n acc or da nce wit h t he s p o ns or 
re p orti n g sta n dar ds usi n g t he safety p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n 
Secti o n 3. 1. 1. 2 .
C ha n ge fr o m baseli ne i n A LT a n d A S T will be s u m marize d de scri pti vel y b y treat me nt a n d 
ti me p oi nt, as descri be d i n Secti o n 5. 2. 1 . T he safet y a nalys is set (as defi ne d i n Secti o n 4) will 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 7 of 4 6
be use d. Mea n c ha n ge fr o m baseli ne wi ll be pl otte d a gai nst ti me p ost-d ose. O n eac h pl ot 
t here will be o ne li ne f or eac h treat me nt a n d 9 0 % CIs.  
6. 1. 1. 3. Vit al Si g ns
A bs ol ute val ues a n d c ha n ges fr o m baseli ne i n s u pi ne, sta n di n g a n d p ost ural c ha n ges f or 
s yst olic a n d diast olic bl o o d press ure ( B P) a n d p ulse rate will be liste d a n d s u m marise d b y 
treat me nt a n d ti me p oi nt, acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he safety 
p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 1. 1. 3 .
Mea n c ha n ges fr o m baseli ne f or s u pi ne, sta n di n g a n d p ost ural c ha n ges f or s y st olic a n d 
diast olic B P a n d p ulse rate will be pl ott e d a gai nst ti me p ost - d ose.  O n eac h pl ot t here will be 
o ne li ne f or eac h treat me nt.  C orres p o n di n g i n di vi d ual pl ots of c ha n ges fr o m baseli ne will 
als o be pr o d uce d f or eac h treat me nt.
Ma xi m u m decrease fr o m baseli ne f or s u pi ne
a n d sta n di n g s yst olic a n d diastolic B P,
ma xi m u m i ncrease fr o m baseli ne f or s u pi ne a n d sta n di n g p ulse rate , ma xi m u m i ncrease fr o m 
baseli ne f or p ost ural differe nces i n s y st olic a n d diast olic B P, a n d ma xi m u m decrease fr o m 
baslei ne f or p ost ural differe nce i n p ulse rate will be s u m marize d b y treat me nt, acc or di n g t o 
s p o ns or re p orti n g sta n dar ds. 
Ma xi m u m/ mi ni m u m a bs ol ute val ues a n d c ha n ges fr o m baseli ne f or vital si g ns (f or s u pi ne, 
sta n di n g a n d p ost ural) will als o be s u m marise d descri pti vel y b y treat me nt usi n g cate g ories as 
defi ne d i n A p pe n di x 1 . 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. All pla n ne d a n d u n pla n ne d p ost- d ose ti me p oi nt s will be c o u nte d i n 
t hese cate g orical s u m maries.  
6. 1. 1. 4. 1 2 -le a d Electr oc ar di o gr a ms
A bs ol ute val ues a n d c h a n ges fr o m b aseli ne f or t he E C G p ar a meters (ie, 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 c o m plex) will be s u m m arize d by tre at me nt a n d 
ti mep oi nt acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he safet y p o p ulati o n defi ne d i n 
Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 1. 1. 5 .
Mea n c ha n ges fr o m baseli ne f or Q T i nter val, heart rate a n d Q Tc F i nter val will be pl otte d 
a gai nst ti me p ost- d ose. O n eac h pl ot t here will be o ne li ne f or eac h treat me nt.  C orres p o n di n g 
i n di vi d ual pl ots of c ha n ges fr o m baseli ne will als o be pr o d uce d f or eac h treat me nt. 
Ma xi m u m i ncrease fr o m baseli ne f or Q Tc F will be s u m marize d b y  treat me nt, acc or di n g t o 
s p o ns or re p orti n g sta n dar ds.
Ma xi m u m/ mi ni m u m a bs ol ute val ues a n d c ha n ges fr o m baseli ne
f or Q Tc F, P R a n d Q R S 
i nter vals will als o be s u m marize d descri pti vely b y treat me nt usi n g cate g ories as defi ne d i n 
A p pe n di x 1 . 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. All pla n ne d a n d u n pla n ne d p ost d ose ti me p oi nts will be c o u nte d i n t hese 
cate g orical s u m maries. 
I n a d diti o n, t he n u m ber of p artici p a nts wit h u nc orrecte d Q T v al ues > 5 0 0 msec will be 
s u m m arize d.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 8 of 4 6
If m ore t h an 1 E C G is c ollecte d at a n o mi n al ti me after d ose a d mi nistr ati o n (f or ex a m ple, 
tri plic ate E C Gs), t he me a n of t he re plic ate me as ure me nts will be use d t o re prese nt a si n gle 
o bserv ati o n at t h at ti me p oi nt. If a ny of t he 3 i n divi d u al E C G tr aci n gs h as a Q Tc F v a l ue 
> 5 0 0 msec, b ut t he me a n of t he tri plic ates is n ot > 5 0 0 msec, t he d at a fr o m t he p artici p a nt’s 
i n divi d u al tr aci n g will be descri be d i n a s afety secti o n of t he C S R i n or der t o pl ace t he 
> 5 0 0 msec v al ue i n a p pr o pri ate cli nic al c o ntext. H o wever, v al ues fr o m i n divi d u al tr aci n gs 
wit hi n tri plic ate me as ure me nts t h at are > 5 0 0 msec will n ot be i ncl u de d i n t he c ate g oric al 
a n alysis u nless t he aver a ge fr o m t he tri plic ate me as ure me nts is als o > 5 0 0 msec. C h a n ges 
fr o m b aseli ne will be defi ne d as t he c h a n ge bet wee n t he p ost d ose Q Tc F v al ue a n d t he 
aver a ge of t he pre d ose tri plic ate v al ues o n D ay 1 .
C ha n ges fr o m baseli ne i n Q Tc F will be pl otte d se paratel y a gai nst dr u g c o nce ntrati o ns.  T his 
will be a scatter pl ot f or all o bser vati o ns w here Q Tc F a n d dr u g c o nce ntrati o n are rec or de d.  
Place b o data will als o be i ncl u de d ( wit h dr u g c o nce ntrati o n set t o zer o).   Differe nt s y m b ols 
will be use d f or eac h treat me nt.  I n a d diti o n, a n atte m pt will be m a de t o ex pl ore a n d 
c h ar acterize t he rel ati o ns hi p bet wee n pl as m a c o nce ntr ati o n a n d Q T i nterv al le n gt h usi n g a 
P K/ P D m o deli n g a p pr o ac h. If a P K/ P D rel ati o ns hi p is f o u n d, t he i m p act of p artici p a nt 
f act ors (c ov ari ates) o n t he rel ati o ns hi p will be ex a mi ne d. T he res ults of s uc h a n alyses m ay 
n ot be i ncl u de d i n t he C S R.
6. 1. 1. 5. Res pir at or y R ate
A bs ol ute val ues a n d c ha n ges fr o m baseli ne i n res pirat or y  rate will be liste d a n d s u m marize d 
b y  treat me nt a n d ti me p oi nt, acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he safety 
p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 1. 1. 6 .
Mea n c ha n ge fr o m baseli ne will be pl otte d a gai nst ti me p ost -d ose.  O n eac h pl ot t here will be 
o ne li ne f or eac h treat me nt. C orres p o n di n g i n di vi d ual pl ots of c ha n ges fr o m baseli ne will 
als o be pr o d uce d f or eac h treat me nt.
Ma xi m u m i ncrease a n d decrease fr o m baseli ne f or res pirat or y rate will be s u m marize d b y  
treat me nt, acc or di n g to s p o ns or re p orti n g sta n dar ds.
6. 1. 1. 6. Or al B o d y Te m per at ure
A bs ol ute val ues a n d c ha n ges fr o m baseli ne i n oral b o d y  te m perat ure will be liste d a n d 
s u m marize d b y treat me nt a n d ti me p oi nt, acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he 
safety p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 1. 1. 7 .
Mea n c ha n ge fr o m baseli ne will be pl otte d a gai nst ti me p ost -d ose.  O n eac h pl ot t here will be 
o ne li ne f or eac h treat me nt. C orres p o n di n g i n di vi d ual pl ots of c ha n ges fr o m baseli ne will 
als o be pr o d uce d f or eac h treat me nt.
Ma xi m u m i ncrease a n d decrease fr o m baseli ne f or ora l b o d y te m perat ure will be s u m marize d 
b y  treat me nt, acc or di n g t o s p o ns or re p orti n g sta n dar ds. 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 2 9 of 4 6
6. 1. 1. 7. C- S S R S
Scree ni n g (“ L ifeti me”) a n d p ost-scree ni n g (“Si nce Last Visit ”) C-S S R S data ( ma p pe d t o C -
C A S A sc ores, as descri be d i n Secti o n 3. 1. 1. 9 ) will be liste d a n d s u m marize d cate g oricall y, as 
o utli ne d i n Secti o n 5. 2. 2 , b y treat me nt an d ti me p oi nt, usi n g t he safet y p o p ulati o n defi ne d i n 
Secti o n 4 .
6. 1. 2. P art B: Mi d az ol a m P K P ar a meters
Pl as m a c o nce ntr ati o ns of mi d az ol a m will be liste d a n d s u m m arize d descri ptively by n o mi n al 
P K s a m pli n g ti me a n d tre at me nt ( mi d az ol a m al o ne o n Peri o d 1/ D ay 1, c o -a d mi nistr ati o n o n 
Peri o d 2/ D ay 2, a n d c o -a d mi nistr ati o n o n Peri o d 2/ D ay 1 0) usi n g t he P K C o nce ntrati o n Set 
(as defi ne d i n Secti o n 4 ). Prese ntati o ns will i ncl u de:

a listi n g of all c o nce ntrati o ns s orte d b y  partici pa nt I D, treat me nt a n d n o mi nal ti me 
p ost -d ose. T he c o nce ntrati o n listi n g will als o i ncl u de t he act ual ti mes. De viati o ns 
fr o m t he n o mi nal ti me will be gi ve n i n a se parate listi n g. 

a s u m mar y of c o nce ntrati o ns b y treat me nt a n d n o mi nal ti me p ost-d ose, w here t he set 
of statisti cs will i ncl u de n, mea n, me dia n, sta n dar d de viati o n, c oefficie nt of variati o n 
(c v), mi ni m u m, ma xi m u m a n d t he n u m ber of c o nce ntrati o ns a b o ve t he l o wer li mit of 
q ua ntificati o n.

i n di vi d ual c o nce ntrati o n-ti me pl ots b y treat me nt ( o n b ot h li near a n d se mi-l o g scales) 
a gai nst act ual ti me p ost - d ose (t here will be se parate s pa g hetti pl ots f or eac h treat me nt, 
wit h a li ne f or eac h partici pa nt per scale). 

i n di vi d ual c o nce ntrati o n-ti me pl ots b y partici pa nt ( o n b ot h li near a n d se mi-l o g scales) 
a gai nst act ual ti me p ost - d ose (t here will be se parate s pa g hetti pl ots f or eac h 
partici pa nt, wit h a li ne f or eac h treat me nt per scale). 

me dia n c o nce ntrati o n -ti me pl ots ( o n b ot h li near a n d se mi-l o g scales) a gai nst n o mi nal 
ti me p ost-d ose b y  treat me nt (all treat me nts o n t he sa me pl ot p er scale, base d o n t he 
s u m mar y of c o nce ntrati o ns b y treat me nt a n d ti me p ost -d ose) .

mea n c o nce ntrati o n -ti me pl ots ( o n b ot h li near a n d se mi-l o g scales) a gai nst n o mi nal 
ti me p ost-d ose b y  treat me nt (all treat me nts o n t he sa me pl ot per scale, base d o n t he 
s u m mar y of c o nce ntrati o ns b y treat me nt a n d ti me p ost -d ose) .
T he n o mi nal P K sa m pli n g ti me will be use d f or s u m mar y  statistics a n d rele va nt me dia n 
pl ots, w hereas f or i n di vi d ual partici pa nt pl ots b y  ti me, t he act ual P K sa m pli n g ti me will be 
use d.
T he mi daz ola m P K para meters , detaile d i n Secti o n 3. 1. 2 , will be liste d, s u m marize d 
descri pti vel y a n d a nal yz e d b y treat me nt f or partici pa nts i n t he P K Para meter set (as defi ne d 
i n Secti o n 4 ). Missi n g val ues will be ha n dle d as detaile d i n Secti o n 5. 3 .
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 0 of 4 6
Ea c h P K para meter will be s u m marize d f or eac h treat me nt usi n g t he s u m mar y  statistics as 
s pecifie d i n t he ta ble bel o w: -
T a ble 6. M i d az ol a m P K P ar a meters t o be S u m m arize d Descri pti vel y
P ar a meter
S u m m ar y St atisticis
C ma x ,  A U C last,A U C i nf
N, arit h metic mea n, me dia n, c v %, sta n dar d de viati o n, mi ni m u m, 
ma xi m u m, ge o metric mea n a n d ge o metric c v %.
S u p p orti n g data fr o m t he esti mati o n of A U Ci nf will be liste d b y  treat me nt: ter mi nal p hase 
rate c o nsta nt ( kel); g o o d ness of fit statistic fr o m t he l o g-li near re gressi o n (r 2 ); t he perce nt of 
A U Ci nf base d o n e xtra p olati o n ( A U Ce xtra p %); a n d t he first, last, a n d n u m ber of ti me p oi nts 
use d i n t he esti mati o n of kel. T hese data ma y  be i ncl u de d i n t he cli nical st u d y re p ort.
B o x a n d w his ker pl ots f or i n di vi d ual P K para meters ( C ma x, A U Ci nf a n d A U Clast) will be 
prese nte d b y treat me nt a n d o verlai d wit h ge o metric mea ns a n d i n di vi d ual data p oi nts . 
N at ur al l o g tr a nsf or me d A U C i nf, A U Cl ast a n d C m ax of mi daz ola m will be a n alyze d usi n g a 
mixe d effect s m o del as descri bed i n Secti o n 5. 2. 3 .  Mi d az ol a m al o ne ( Peri o d 1) will be t he 
Refere nce tre at me nt, w hile t he mi d az ol a m c o- a d mi nistere d wit h P F - 0 7 2 5 8 6 6 9 ( o n D ay 2 or 
1 0 i n Peri o d 2) will be t he Test tre at me nts.
A d diti o n al P K a n aly ses m ay be perf or me d if dee me d a p pr o pri ate a n d m ay n ot be i ncl u de d i n 
t he C S R.
If a d diti o n al c o h orts are i ncl u de d i n t he st u dy, all s u m m aries a n d a n alyses will als o i ncl u de 
c o h ort/ d ose.
6. 2. Sec o n d ar y E n d p oi nt(s)
6. 2. 1. P art A: P F - 0 7 2 5 8 6 6 9 Pl as m a a n d Uri ne P K P ar a meters
Pl as m a a n d uri ne c o nce ntr ati o ns of P F - 0 7 2 5 8 6 6 9 a n d plas ma c o nce ntrati o ns of M 4 
meta b olite ( P F- 0 7 2 7 5 4 2 8) w here p ossi ble will be liste d a n d s u m m arize d descri ptively by 
d ose, p o p ul ati o n ( n o n-Ja pa nese, Ja pa nese [if e nr olle d], a n d ol der a d ult partici pa nts [if 
e nr olle d]), diet ary all oc ati o n, d ay a n d n o m i n al P K s a m pli n g ti me usi n g t he P K 
C o nce ntrati o n Set defi ne d i n Secti o n 4 .  Prese ntati o ns will i ncl u de:

a listi n g of all c o nce ntrati o ns s orte d b y  partici pa nt I D a n d n o mi nal ti me p ost -d ose.  T he 
c o nce ntrati o n listi n g will als o i ncl u de t he act ual ti mes.  De viati o ns fr o m t he n o mi nal ti me 
will be gi ve n i n a se parate listi n g.

a s u m mar y of c o nce ntrati o ns b y d ose, p o p ulati o n, d ietar y all ocati o n, d a y a n d n o mi nal 
ti me p ost-d ose, w here t he set of statistics will i ncl u de n, mea n, me dia n, sta n dar d 
de viati o n, c oefficie nt of variati o n (c v), mi ni m u m, ma xi m u m a n d t he n u m ber of 
c o nce ntrati o ns a b o ve t he l o wer li mit of q ua ntificati o n.

i n di vi d ual c o nce ntrati o n-ti me pl ots b y d ose, p o p ulati o n ( o n b ot h li near a n d se mi-l o g 
scales) a n d dietar y  all ocati o n, a gai nst act ual ti me p ost -d ose (t here will be se parate 
s pa g hetti pl ots f or eac h d ose per scale), pa ge d b y da y a n d c ol o ure d b y d ose .
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 1 of 4 6

me dia n c o nce ntrati o ns -ti me pl ots ( o n b ot h li near a n d se mi-l o g scales) a gai nst n o mi nal 
ti me p ost-d ose b y  d ose, p o p ulati o n a n d dietar y all ocati o n (all d oses o n t he sa me pl ot per 
scale, base d o n t he s u m mar y of c o nce ntrati o ns b y d ose, p o p ulati o n, dietar y all ocati o n a n d 
ti me p ost-d ose) , pa ge d b y d a y a n d c ol o ure d b y d ose .

mea n c o nce ntrati o ns -ti me pl ots ( o n b ot h li near a n d se mi-l o g scales) a gai nst n o mi nal ti me 
p ost -d ose b y  d ose, p o p ulati o n a n d dietar y all ocati o n (all d oses o n t he sa me pl ot per scale, 
base d o n t he s u m mar y of c o nce ntrati o ns b y  d ose a n d ti me p ost-d ose) , pa ge d b y da y a n d 
c ol o ure d b y d ose .

Me dia n a n d mea n pre -d ose c o nce ntrati o n -ti me pl ots ( o n b ot h li near a n d se mi-l o g scales) 
a gai nst da y b y d ose, p o p ulati o n a n d dietar y all ocati o n (all d oses o n t he sa me pl ot per
scale), base d o n t he s u m mar y of c o nce ntrati o ns b y d ose a n d ti me p ost-d ose) , c ol o ure d b y 
d ose .
T he n o mi nal P K sa m pli n g ti me will be use d f or s u m mar y statistics a n d rele va nt me dia n 
pl ots, w hereas f or i n di vi d ual partici pa nt pl ots b y  ti me, t he act ual P K sa m pli n g ti me will be 
use d.
T he pl as m a a n d uri ne P F- 0 7 2 5 8 6 6 9 P K p ar a meters a n d plas ma M 4 meta b olite ( P F -
0 7 2 7 5 4 2 8) w here p ossi ble a n d as a p plica ble, detaile d i n Secti o n 3. 2. 1 , will be liste d a n d 
s u m m arize d descri ptively by d ose, p o p ul ati o n , diet ary all oc ati o n a n d d ay, as a p plic a ble, f or 
partici pa nts i n t he P K Para meter set (as defi ne d i n Secti o n 4 ). Missi n g val ues will be ha n dle d 
as detaile d i n Secti o n 5. 3 .
Eac h P K para meter will be s u m marize d b y  d ose, p o p ulati o n, dietar y all ocati o n a n d da y 
( Da ys 1 or 1 4, as a p pr o priate) usi n g t he s u m mar y statistics as s pecifie d i n t he ta ble bel o w: -
T a ble 7. P F- 0 7 2 5 8 6 6 9 P K P ar a meters t o be S u m m arize d Descri pti vel y 
P ar a meter
St atistic al S u m m aries
C ma x, A U C ta u, C ma x ( d n), A U C ta u ( d n)
N, arit h metic mea n, me dia n, c v %, sta n dar d 
de viati o n, mi ni m u m, ma xi m u m, ge o metric mea n 
a n d ge o metric c v %.
T ma x
N, me dia n, mi ni m u m, ma xi m u m.
Ae ta u, Ae ta u%, C L r
N, arit h metic mea n, me dia n, c v %, sta n dar d 
de viati o n, mi ni m u m, ma xi m u m, ge o metric mea n 
a n d ge o metric c v %
T o assess t he relati o ns hi p bet wee n t he P K para meters a n d d ose, d ose n or m alize d A U C t a u a n d 
C m ax m ay be pl otte d a g ai nst d ose ( usi n g a l o g arit h mic sc ale) f or e ac h d ay se paratel y, a n d will 
i ncl u de i n divi d u al p artici p a nt v al ues a n d t he ge o metric me a ns f or e ac h d ose.  T he d at a fr o m 
t he J a p a nese p artici p a nts (if e nr olle d) a n d ol der a d ult p artici p a nts (if e nr olle d) a n d diet , will 
be i de ntifie d by differe nt sy m b ols/c ol ors.   Ge o metric mea ns will ha ve a differe nt s y m b ol t ha n 
t he i n di vi d ual val ues.  T he val ues will be d ose n or malize d (t o a 1 m g d ose) b y di vi di n g t he 
i n di vi d ual val ues a n d ra w ge o metric mea ns by d ose.  
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 2 of 4 6
A d diti o n al P K a n alyses m ay be perf or me d if dee me d a p pr o pri ate a n d m ay n ot be i ncl u de d i n 
t he C S R. Res ults fr o m M 4 meta b olite ( P F- 0 7 2 7 5 4 2 8) ma y  n ot be i ncl u de d i n t he C S R.
6. 2. 2. P art B: S afet y a n d T oler a bilit y
6. 2. 2. 1. A d verse e ve nts
See secti o n 6. 1. 1. 1 .  
6. 2. 2. 2. V it al si g ns
A bs ol ute val ues a n d c ha n ges fr o m baseli ne i n s u pi ne, sta n di n g a n d p ost ural c ha n ges f or 
s yst olic a n d diast olic bl o o d press ure ( B P) a n d p ulse rate will be liste d a n d s u m marise d b y 
treat me nt a n d ti me p oi nt, acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he safety 
p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 2. 2 .
Mea n c ha n ges fr o m baseli ne f or s u pi ne, sta n di n g a n d p ost ura l c ha n ges f or s yst olic a n d 
diast olic B P a n d p ulse rate will be pl otte d a gai nst ti me p ost- d ose. C orres p o n di n g i n di vi d ual 
pl ots of c ha n ges fr o m baseli ne ma y  als o be pr o d uce d, or c o m bi ne d wit h t he mea n pl ot. 
Ma xi m u m/ mi ni m u m a bs ol ute val ues a n d c ha n ges fr o m b aseli ne f or (f or s u pi ne, sta n di n g a n d 
p ost ural) vital si g ns will als o be s u m marise d descri pti vel y  b y treat me nt usi n g cate g ories as 
defi ne d i n A p pe n di x 1 . 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. All pla n ne d a n d u n pla n ne d p ost d ose ti me p oi nts will be c o u nte d i n 
t hese cate g orical s u m maries.
6. 2. 2. 3. E C Gs
A bs ol ute val ues a n d c ha n ges fr o m baseli ne f or t he E C G para meters (ie, Q T i nter val, heart 
rate, Q Tc F i nter val, P R i nter val a n d Q R S c o m ple x ) will be liste d a n d s u m marize d b y 
treat me nt a n d ti me p oi nt, acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he safety 
p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 2. 2 .
Mea n c ha n ges fr o m baseli ne f or Q T i nter val, heart rate a n d Q Tc F i nter val will be pl otte d 
a gai nst ti me p ost- d ose. C orres p o n di n g i n di vi d ual pl ots of c ha n ges fr o m baseli ne ma y  als o be 
pr o d uce d, or c o m bi ne d wit h t he mea n pl ot. 
Ma xi m u m a bs ol ute val ues a n d c ha n ges
fr o m baseli ne f or Q Tc F, P R a n d Q R S i nter vals will 
als o be s u m marize d descri pti vel y  b y treat me nt usi n g cate g ories as defi ne d i n A p pe n di x 1 . 
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. 
All pla n ne d a n d u n pla n ne d p ost d ose ti me p oi nts will be c o u nte d i n t hese cate g orical 
s u m maries.
6. 2. 2. 4. Cli nic al S afet y L a b or at or y Me as ure me nts
La b orat or y  data will be liste d a n d s u m marize d b y treat me nt, i n acc or da nce wit h t he s p o ns or 
re p orti n g sta n dar ds, usi n g t he safet y p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n 
Secti o n 3. 2. 2 .
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 3 of 4 6
6. 2. 2. 5. Res pir at or y R ate
A bs ol ute val ues a n d c ha n ges fr o m baseli ne i n res pirat or y  rate will be liste d a n d s u m marize d 
b y  treat me nt a n d ti me p oi nt , acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he safety 
p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 2. 2 .
Mea n c ha n ge fr o m baseli ne will be pl otte d a gai nst ti me p ost -d ose.  C orres p o n di n g i n di vi d ual 
pl ots of c ha n ges fr o m baseli ne ma y  als o be pr o d uce d or c o m bi ne d wit h t he mea n pl ot.
6. 2. 2. 6. Or al B o d y Te m per at u re
A bs ol ute val ues a n d c ha n ges fr o m baseli ne i n oral b o d y  te m perat ure will be liste d a n d 
s u m marize d b y treat me nt a n d ti me p oi nt, acc or di n g t o s p o ns or re p orti n g sta n dar ds, usi n g t he 
safety p o p ulati o n defi ne d i n Secti o n 4 . Baseli ne is as defi ne d i n Secti o n 3. 2. 2 .
Mea n c ha n ge fr o m baseli ne will be pl otte d a gai nst ti me p ost - d ose.  C orresp o n di n g i n di vi d ual 
pl ots of c ha n ges fr o m baseli ne ma y als o be pr o d uce d or c o m bi ne d wit h t he mea n pl ot.
6. 3. Ot her E n d p oi nt(s)
6. 3. 1. P art A
6. 3. 1. 1. A d diti o n al P F -0 7 2 5 8 6 6 9 P K P ar a meters 
A d diti o nal plas ma P K para meters f or P F -0 7 2 5 8 6 6 9 a n d M 4 plas ma meta b olite ( P F -
0 7 2 7 5 4 2 8) w here p ossi ble a n d as a p plica ble, as descri be d i n Secti o n 3. 3. 1. 1 , will be liste d 
a n d s u m marize d descri pti vel y  b y d ose, p o p ulati o n , da y, a n d dietar y all ocati o n, as a p plica ble, 
f or partici pa nts i n t he P K Para meter set (as defi ne d i n Secti o n 4 ). Missi n g val ues will be 
ha n dle d as detaile d i n Secti o n 5. 3 .
Eac h P K para meter (if data per mit) will be s u m marize d b y  d ose, p o p ulati o n a n d dietar y 
all ocati o n o n Da y  1 4 usi n g t he s u m mar y statistics as s pecifie d i n t he ta ble bel o w: -
T a ble 8 . A d diti o n al P F- 0 7 2 5 8 6 6 9 P K P ar a meters t o be S u m m arize d Descri pti vel y
P ar a meter
S u m m ar y St atisitics 
C L / F, Vz/ F , Cmi n , C a v, P T R ,
R ac, R ac C ma x
N, arit h metic mea n, me dia n, c v %, sta n dar d de viati o n,
mi ni m u m, ma xi m u m, ge o metric mea n a n d ge o metric c v %.
t ½
N, arit h metic mea n, me dia n, c v %, sta n dar d de viati o n, 
mi ni m u m, ma xi m u m.
S u p p orti n g data fr o m t he esti mati o n of t ½ will be liste d b y  treat me nt:  ter mi nal p hase rate 
c o nsta nt ( kel); g o o d ness of fit statistic fr o m t he l o g- li near re gressi o n (r 2); t he perce nt of 
A U Ci nf base d o n e xtra p olati o n ( A U Ce xtra p %); a n d t he first, last, a n d n u m ber of ti me p oi nts 
use d i n t he esti mati o n of kel.  T hese data ma y  be i ncl u de d i n t he cli nical st u d y re p ort.
A d diti o n al P K a n alyses m ay be perf or me d if dee me d a p pr o pri ate a n d m ay n ot be i ncl u de d i n 
t he C S R. Res ults fr o m plas ma M 4 meta b olite ( P F - 0 7 2 7 5 4 2 8) m a y  n ot be i ncl u de d i n t he 
C S R.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 4 of 4 6
6. 3. 1. 2. B o d y W ei g ht
C ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m baseli ne b o d y  wei g ht will be liste d a n d 
s u m marize d descri pti vel y by treat me nt a n d ti me p oi nt, as descri be d i n Secti o n 5. 2. 1 . T he F A S 
(as defi ne d i n Secti o n 4 ) will be use d. 
Mea n c ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m baseli ne will be pl otte d a gai nst ti me 
p ost -d ose. O n eac h pl ot t here will be o ne li ne f or eac h treat me nt.
C orres p o n di n g i n di vi d ual 
pl ots of c ha n ges fr o m baseli ne will als o be pr o d uce d f or eac h treat me nt.
C ha n ge fr o m baseli ne will be a nal yz e d usi n g a n M M R M m o del as descri be d i n Secti o n 5. 2. 4 . 
Se parate m o dels will be fitte d t o t he differe nt p o p ulati o ns (e. g. n o n -Ja pa nese, Ja pa nese a n d 
ol der a d ult partici pa nts), a n d dietar y all ocati o n if a p pr o priate.  Eac h m o del will i ncl u de all 
pla n ne d ti me p oi nts u p t o Da y  1 6.  Pl ots of L S mea n s a n d differe nces (i ncl u di n g CIs f or b ot h) 
will be pr o d uce d o ver ti me (all treat me nts o n t he sa me pl ot wit h differe nt c ol o urs/s y m b ols 
f or eac h treat me nt).  A d diti o nall y , pl ots of  L S mea ns a n d differe nces (i ncl u di n g c o nfi de nce 
i nter vals f or b ot h), f or D a y  1 4 o nly, will be pr o d uce d o ver treat me nt.  T hese pl ots of L S 
mea ns a n d differe nces ma y  be c o m bi ne d acr oss t he differe nt p o p ulati o ns, as a p pr o priate.
A Ba y esia n E ma x m o del will als o be a p plie d t o t he sta n dar d diet, n o n- Ja pa nese L S mea ns f or
D a y 1 4 o nl y , as descri be d i n Secti o n 5. 2. 5 .  Pl ots of p osteri or me dia ns a n d differe nces 
(i ncl u di n g cre di ble i nter vals f or b ot h), f or Da y 1 4 o nl y, will be pr o d uce d vers us d ose.  T his 
a nal ys is ma y use t otal dail y d ose a n d/ or ma y o nl y i ncl u de a s u bset of treat me nts (e. g. all 
d oses f or a si n gle d osi n g re gi me n).  
F urt her e x pl orat or y  a nalysis ma y  be perf or me d (e. g. wit h all p o p ulati o ns i ncl u de d), if 
dee me d a p pr o priate a n d ma y  n ot be incl u de d i n t he C S R.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 5 of 4 6
6. 3. 1. 7. P ote nti al f or I n d ucti o n of C Y P 3 A
A bs ol ute val ues, c ha n ge fr o m baseli ne, a n d perce nt c ha n ge fr o m baseli ne i n u ri nar y 6-
h y dr o x yc ortis ol/c ortis ol rati o a n d p las ma 4-h y dr o x y c h olester ol/c h olester ol rati o will be 
s u m marize d descri pti vel y by treat me nt a n d ti me p oi nt, as descri be d i n Secti o n 5. 2. 1 .  T he 
F A S (as defi ne d i n Secti o n 4 ) will be use d.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 6 of 4 6
B o x a n d w his ker pl ot s f or c ha n ge fr o m baseli ne i n uri nar y 6-h y dr o x yc ortis ol/c ortis ol rati o 
a n d plas ma 4 -h y dr o x yc h olester ol/c h olester ol rati o will be prese nte d b y treat me nt a n d 
o verlai d wit h ge o metric mea ns a n d i n di vi d ual data p oi nts.
 
6. 3. 2. P art B
6. 3. 2. 1. A d diti o n al M i d az ol a m P K P ar a meters 
A d diti o nal plas ma P K para meters f or M i daz ola m as descri be d i n Secti o n 3. 3. 2. 1 will be 
liste d a n d s u m marize d descri pti vel y b y treat me nt f or partici pa nts i n t he P K Para meter set (as 
defi ne d i n Secti o n 4 ). Missi n g val ues will be ha n dle d as detaile d i n Secti o n 5. 3 .
Eac h P K para meter (if data per mit) will be s u m marize d f or eac h treat me nt usi n g t he 
s u m mar y statistics as s pecifie d i n t he ta ble bel o w: -
T a ble 9. A d diti o n al Mi d az ol a m P K p ar a meters t o be S u m m arize d Descri pti vel y
* =if data per mit
S u p p orti n g data fr o m t he esti mati o n of t ½ will be liste d b y  treat me nt:  ter mi nal p hase rate 
c o nsta nt ( kel); g o o d ness of fit statistic fr o m t he l o g -li near re gressi o n (r 2); t he perce nt of 
A U Ci nf base d o n e xtra p olati o n ( A U Ce xtra p %); a n d t he first, last, a n d n u m ber of ti me p oi nts 
use d i n t he esti mati o n of kel.  T hese data ma y  be i ncl u de d i n t he cli nical st u d y re p ort.
A d diti o n al P K a n alyses m ay be perf or me d if dee me d a p pr o pri ate a n d m ay n ot be i ncl u de d i n 
t he C S R.
If a d diti o n al c o h orts are i ncl u de d i n t he st u dy, all s u m m aries a n d a n alyses will als o i ncl u de 
c o h ort/ d ose.
6. 3. 2. 2. P ote nti al f or I n d ucti o n of C Y P 3 A
A bs ol ute val ues a n d c ha n ge fr o m baseli ne i n p las ma 4-h y dr o x y c h olester ol/c h olester ol rati o
will be s u m marize d descri pti vel y  b y treat me nt, as descri be d i n Secti o n 5. 2. 1 . T he F A S (as 
defi ne d i n Secti o n 4 ) will be use d.
B o x a n d w his ker pl ots f or c ha n ge fr o m baseli ne i n plas ma 4 -h y dr o x y c h olester ol/c h olester ol 
rati o will be prese nte d by treat me nt a n d o verlai d wit h ge o metric mea ns a n d i n di vi d ual 
data p oi nts.
P ar a meter
S u m m ar y St atisticis
C L / F* , Vz/ F*
N, arit h metic mea n, me dia n, c v %, sta n dar d de viati o n, mi ni m u m, 
ma xi m u m, ge o metric mea n a n d ge o metric c v %.
T ma x
N, me dia n, mi ni m u m, ma xi m u m.
t ½*
N, arit h metic mea n, me dia n, c v %, sta n dar d de viati o n, 
mi ni m u m, ma xi m u m.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 7 of 4 6
 
6. 4. S u bset A n al yses
N o s u bset a nal ys es will be perf or me d.
6. 5. B aseli ne a n d Ot her S u m m aries a n d A n al yses
6. 5. 1. B aseli ne S u m m aries
De m o gra p hic data (a ge, bi ol o gical se x, race, et h nicit y , b o d y wei g ht, b o dy mass i n de x a n d 
hei g ht) will be s u m marize d b y  treat me nt a n d o verall, f or partici pa nts i n t he safety 
p o p ulati o ns f or Part A a n d Part B ( as defi ne d i n Secti o n 4 ), se parately, as descri be d i n 
Secti o ns 5. 2. 1 o r 5. 2. 2 (as a p pr o priate).
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
Partici pa nt e val uati o n gr o u ps will s h o w e n d of st u d y  partici pa nt dis p ositi o n b y treat me nt a n d 
o verall, f or Part A a n d Part B se paratel y, a n d will s h o w w hic h partici pa nts were a nal yz e d f or 
P K a n d safet y. Fre q ue nc y c o u nts a n d perce nta ges will be s u p plie d f or partici pa nt 
disc o nti n uati o n(s) b y  treat me nt.
6. 5. 3. C o nc o mit a nt Me dic ati o ns a n d N o n dr u g Tre at me nts
Al l pri or a n d c o nc o mita nt me dicati o n(s) as well as n o n-dr u g treat me nt(s) will be pr o vi de d i n 
listi n gs.
6. 6. S afet y S u m m aries a n d A n al yses
See Secti o n 6. 1. 1 f or Part A safety s u m maries.
See Secti o n 6. 2. 2 f or Part B safet y s u m maries.
6. 6. 1. C O VI D -1 9
P ositi ve C O VI D- 1 9 stat us will be liste d.  A d diti o nal ta bles ma y  be pr o d uce d, i n acc or da nce 
wit h s p o ns or re p orti n g sta n dar ds, usi n g t he safet y p o p ulati o n defi ne d i n Secti o n 4 .
7. I N T ERI M A N A L Y S E S
7. 1. I ntr o d ucti o n
N o f or m al i nteri m a n alysis will be c o n d ucte d f or t his st u dy. As t his is a s p o ns or -o pe n st u dy, 
t he s p o ns or m ay c o n d uct u n bli n de d revie ws of t he d at a d uri n g t he c o urse of t he st u dy f or t he 
p ur p ose of s afety assess me nt, f acilit ati n g d ose -esc al ati o n decisi o ns, f acilit ati n g P K/ P D 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 8 of 4 6
m o deli n g, a n d/ or s u p p orti n g cli nic al devel o p me nt. A li mite d n u m ber of t he s p o ns or’s te a m 
me m bers (excl u di n g site st aff) m ay c o n d uct t he u n bli n de d re vie ws.
7. 2. I nteri m A n al yses a n d S u m m aries
N ot A p plica ble.
8. R E F E R E N C E S
1.
cli n D R: Si m ulati o n a n d A nal y sis T o ols f or Cli nical D ose Res p o nse M o deli n g .  
htt ps:// C R A N. R -pr oject. or g/ pac ka ge =cli n D R
2.
T h o mas, N., S wee ne y , K., a n d S o ma yaji, V. ( 2 0 1 4). Meta-a nal ys is 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, 
V ol. 6, N o. 4, 3 0 2 - 3 1 7. < d oi: 1 0. 1 0 8 0/ 1 9 4 6 6 3 1 5. 2 0 1 4. 9 2 4 8 7 6 >
3.
T h o mas, N., a n d R o y, D. ( 2 0 1 6). A nal ys is of cli nical d ose-res p o nse i n s mall-m olec ule 
dr u g de ve l o p me nt: 2 0 0 9-2 0 1 4. Statistics i n Bi o p har mace utical Researc h, V ol. 6, N o. 4, 
3 0 2 - 3 1 7 < d oi: 1 0. 1 0 8 0/ 1 9 4 6 6 3 1 5. 2 0 1 6. 1 2 5 6 2 2 9 >
4.
W u, J., Ba nerjee, A., Ji n, B., Me n o n, S., Marti n, S., a n d Heat heri n gt o n, A. ( 2 0 1 7). 
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 ys is. V ol. 9, 2 6 9 4-2 7 2 1.  < d oi: 1 0. 1 1 7 7/ 0 9 6 2 2 8 0 2 1 6 6 8 4 5 2 8? >
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 3 9 of 4 6
A P P E N DI C E S
A p pe n di x 1. C ate g oric al Cl asses f or E C G a n d Vit al Si g ns of P ote nti al Cli nic al C o ncer n
C ate g ories f or Q Tc F
De gree of Pr ol o n g ati o n
Mil d ( msec)
M o der ate ( msec)
Se ver e ( msec)
A bs ol ute val ue
> 4 5 0 -4 8 0
> 4 8 0 -5 0 0
> 5 0 0
I ncrease fr o m baseli ne
3 0 -6 0
> 6 0
C ate g ories f or P R a n d Q R S
P R ( ms)
ma x. ≥3 0 0
P R ( ms) i ncrease fr o m baseli ne
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
Q R S ( ms)
ma x. ≥1 4 0
Q R S ( ms) i ncrease fr o m baseli ne
≥5 0 % i ncrease
C ate g ories f or Vit al Si g ns
S y st olic B P ( m m H g)
mi n. < 9 0
ma x. ≥1 6 0
S y st olic B P ( m m H g) c ha n ge fr o m baseli ne
ma x. decrease ≥3 0
ma x. i ncrease ≥3 0
S y st olic B P ( m m H g) p ost ural differe nce (s u pi ne – sta n di n g)
ma x. ≥ 2 0
Diast olic B P ( m m H g)
mi n. < 5 0
ma x. ≥9 0
Diast olic B P ( m m H g) c ha n ge fr o m baseli ne
ma x. decrease ≥2 0
ma x. i ncrease ≥2 0
Diast olic B P ( m m H g) p ost ural differe nce (s u pi ne – sta n di n g) ma x. ≥ 1 0
S u pi ne p ulse rate ( b p m)
mi n. < 4 0
ma x. > 1 2 0
Sta n di n g p ulse rate ( b p m)
mi n. < 4 0
ma x. > 1 4 0
P ulse rate ( b p m) p ost ural differe nce (s u pi ne – sta n di n g)
mi n. ≤ -3 0
Meas ure me nts t hat f ulfill t hese criteria are t o be liste d i n t he re p ort.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 0 of 4 6
A p pe n di x 2. C- S S R S M a p pe d t o C- C A S A - S uici d al I de ati o n a n d Be h a vi or E ve nts a n d 
C o des
T a ble 1 0. C- S S R S M a p pe d t o C- C A S A ( S uici d alit y E ve nts a n d C o des)
E ve nt 
C o de
C -C A S A E ve nt
C -S S R S Res p o nse
S uici dal I deati o n
1
Passi ve
“ Yes” o n “ Wis h t o be dea d”
2
Acti ve: N o ns pecific ( n o met h o d, i nte nt, 
or pla n)
“ Yes” o n “ N o n -S pecific Acti ve S uici dal 
T h o u g hts ”
3
Acti ve: Met h o d, b ut n o i nte nt or pla n
“ Yes” o n “ Acti ve S uici dal I deati o n wit h A n y 
Met h o ds ( N ot Pla n) wit h o ut I nte nt t o Act ”
4
Acti ve: Met h o d a n d i nte nt, b ut n o pla n
“ Yes” o n “ Acti ve S uici dal I deati o n wit h 
S o me I nte nt t o Act, wit h o ut S pecific Pla n ”
5
Acti ve: Met h o d, i nte nt, a n d pla n *
“ Yes” o n “ Acti ve S uici dal I deati o n wit h 
S pecific Pla n a n d I nte nt ”
S uici dal Be ha vi or
1
C o m plete d s uici de
“ Yes” o n “ C o m plete d S uici de”
2 
S uici de atte m pt
“ Yes” o n “ Act ual Atte m pt ”
3
I nterr u pte d atte m pt 
“ Yes” o n “ I nterr u pte d atte m pt”
4
A b orte d atte m pt
“ Yes” o n “ A b orte d atte m pt ”
5
Pre parat or y  acti o ns t o war d i m mi ne nt 
s uici dal be ha vi ors
“ Yes” o n “ Pre parat or y Acts or Be ha vi or ”
Self -i nj uri o us be ha vi or, n o s uici dal i nte nt
Self -i nj uri o us be ha vi or, n o s uici dal 
i nte nt
“ Yes” o n “ Has s u bject e n ga ge d i n N o n -
s uici dal Self-I njuri o us Be ha vi or?”
*Acc or di n g t o C -S S R S, t he defi niti o n of pl a n i ncl u des i nte nt (i.e., i nte nt t o c o m plete t he s uici de is i m plicit wit h 
t he c o nce pt of pla n). T h us, t here is n o nee d f or t he cate g or y met h o d a n d pl a n, b ut n o i nte nt .
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 1 of 4 6
A p pe n di x 3. E x a m ple S A S C o de f or St atistic al A n al yses
Mi xe d Effects M o del :
pr oc mi xe d data = i n p ut _ dataset;
class trt s u bject;
m o del var = trt / d df m = kr;
ra n d o m s u bject / s u bject = s u bject;
ls mea ns trt / diff cl al p ha = 0. 1; 
r u n;
M M R M:
pr oc mi xe d data = i n p ut _ dataset met h o d = re ml;
class s u bject trt ti me;
m o del var = trt base ti me base *ti me trt *ti me / d df m = kr resi d ual;
re peate d ti me / s u bject = s u bject t y pe = u n;
ls mea ns trt *ti me / diff cl al p ha = 0. 1;
r u n;
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 2 of 4 6
A p pe n di x 4. B a yesi a n E m a x M o del Met h o d ol o g y Det ails
Data Pr o vi de d b y Pr o gra m mer
A dataset (eit her .t xt or .cs v) of L S mea ns fr o m t he M M R M a nal y sis s ho ul d be pr o d uce d b y 
pr o gra m mi n g f or use i n R b y  t he re p orti n g statisticia n a n d Q C statisticia n.  T he file s h o ul d be 
i n t he f oll o wi n g f or mat ( N ote t hat c ol u m n hea ders s h o ul d be la belle d as s pecifie d bel o w 
(i ncl u di n g ca pitalizati o n), as R is case se nsiti ve): -
d ose
mea n
se
0 
0 
0. 3
2. 5  
0. 2 
0. 4
1 0 
0. 4 
0. 5
4 0 
0. 3 
0. 3
8 0 
1. 6 
0. 4
1 2 0 
1. 8 
0. 5
N ote: d ose m a y  re prese nt t he t otal dail y d ose if a p pr o priate.
T he resi d ual sta n dar d de viati o n o n Da y  1 4 fr o m t he u nstr uct ure d c o varia nce matri x fr o m t he 
M M R M will als o be pr o vi de d t o t he statisticia ns.
Fitti n g t he E ma x M o del
T he 4 -para meter E ma x m o del will be fitte d usi n g t he latest versi o n (c urre ntl y  2. 3. 5) of t he 
cli n D R pac ka ge (1 ). T his a nalys is will be c o n d ucte d b y t he st u d y statisticia n. A differe nt 
statisticia n will c o n d uct Q C of t he a nalys is. T he o ut p uts of t he a nalys is will be pr o vi de d as 
.t xt files t o t he pr o gra mmi n g tea m f or creati o n of pr o gra m mi n g ta bles a n d fi g ures.
T he defa ult b ur n -i n a n d n u m ber of sa m ples will be utilize d al o n g wit h t hi n ni n g of 2 0, w hic h 
will i ncl u de 3 c hai ns t o assess c o n ver ge nce.
M o del dia g n ostics will be e xa mi ne d,
i ncl u di n g trace a n d a ut o-c orrelati o ns pl ots. If t hese raise
c o ncer ns o ver m o del c o n ver ge nce, a d diti o nal b ur n -i ns, sa m ples a n d t hi n ni n g will be 
i n vesti gate d t o i m pr o ve c o n ver ge nce. C ha n ges t o t he pri ors bel o w m a y  als o be c o nsi dere d 
(e. g. i ncrease precisi o n of E 0 a n d dif T ar get ) t o i m pr o ve c o n ver ge nce, if dee me d necessar y. 
T he fi nal dia g n ostic pl ots will n ot be i ncl u de d i n t he cli nical st u d y  re p ort.
Pri ors
P ri or distri b uti o ns will be s pecifie d f or t he place b o res p o nse (E 0), t he differe nce i n res p o nse 
(dif T ar get ) bet wee n t he hi g he st d ose st u die d (e. g. d T ar get = 2 0 0 m g ) a n d place b o, a n d t he 
resi d ual sta n dar d de viati o n (si g m a).  N ote t hat E ma x is deri ve d fr o m ot her para meters a n d is 
t h us n ot e x plicitl y s u p plie d.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 3 of 4 6
Para meter
Pri or
E 0
t( Mea n = 0, S D = 1 7, df = 5)
dif T ar get
t( Mea n = 0 , S D = 1 7 , df = 5)
si g m a
U nif or m(l b = 0, u b = 3. 5)
E 0: T here is i ns ufficie nt hist orical data t o f or mall y calc ulate a place b o pri or.  T heref ore, a 
n o n- i nf or mati ve t-distri b uti o n will be use d f or t he place b o c ha n ge fr o m baseli ne o n Da y  1 4, 
wit h a mea n of 0 a n d a sta n dar d de viati o n e q ual t o 1 0 ti mes t he pre dicte d sta n dar d de viati o n 
( 1. 7 k g).
dif T ar get :  A n o n- i nf or mati ve t-distri b uti o n will be use d f or t he hi g hest d ose place b o -
c orrecte d c ha n ge fr o m baseli ne o n Da y  1 4 wit h a mea n of 0 a n d a sta n dar d de viati o n e q ual t o 
1 0 ti mes t he pre dicte d sta n dar d de viati o n ( 1. 7 k g).
si g m a:  A u nif or m pri or will be use d, wit h a ra n ge we are c o nfi de nt will i ncl u de t he 
p o p ulati o n val ue.  Base d o n a meta -a nal ys is of hist orical data t he sta n dar d de viati o n is n ot 
e x pecte d t o be greater t ha n 3. 5 k g.  
Cli n D R defa ult setti n gs will be use d t o s pecif y  pri or distri b uti o ns f or t he Hill para meter a n d 
t he E D 5 0. T he defa ult distri b uti o ns i n t he c urre nt versi o n of cli n D R ( versi o n 2. 3. 5) are base d 
o n a meta -a nal ys is of d ose res p o nse data (fr o m refere nces: 2 , 3 a n d 4 ) a n d are liste d bel o w.  
T hese defa ult distri b uti o ns will be u p date d if t he meta -data , a n d t heir a nal ysis , are u p date d 
bef ore t he c o m pleti o n of t he c urre nt st u d y .
Para meter
Pri or
l o g( E D5 0/ P5 0)
t( Mea n = 0, S D = 1. 7 3, df = 5)
l o g( Hill)
t( Mea n = 0, S D = 0.8 5 , df = 5)
T he c orrelati o n bet wee n t hese t w o para meters is c urre ntl y -0. 4 5 base d o n t he a nal ys is of t he 
meta - data, w hic h als o w o ul d be u p date d if t he hist orical a nalys is is u p date d.
T he pre dicte d E D 5 0 f or t he c o m p o u n d (P 5 0) =
, base d o n data 
fr o m t he C 4 5 4 1 0 0 1 st u d y.
R C o de
T he f oll o wi n g R c o de is i ncl u de d as a n e xa m ple t hat will be use d as a basis f or t he a nal ysis: -
li brar y(cli n D R) 
m mr m Res < - rea d.cs v(“ L S mea ns.cs v", hea der = T, stri n gs As Fact ors = F) 
# Deter mi ne 'effecti ve' s u bject n u m bers base d o n M M R M S D at Da y 1 4: 
m mr m _s d < - 0. 8 2 5 
# Pr o vi de d b y pr o gra m mi n g 
m mr m Res $ n <- tr u nc(( m mr m _s d/ m mr m Res $se) ^ 2, 0) 
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 4 of 4 6
# Set -u p pri ors a n d M C M C o pti o ns: 
pri or _ m mr m < - e ma x Pri or.c o ntr ol( e p mu = 0, e psca = 1 7,
             dif Tar get m u = 0, dif Tar getsca = 1 7 ,
             d Tar get = 6 0 0 ,
            
             si g mal o w =0, si g ma u p = 3. 5) 
mc mc _ m mr m < - mc mc.c o ntr ol(c hai ns = 3, t hi n = 2 0, see d = 1 6 9)
# R u n E ma x m o del: # 
e ma x M M R M < - fit E ma x B( m mr m Res $mea n , m mr m Res $ d ose, pri or _ m mr m, m o d T y pe = 4,
c o u nt = m mr m Res $ n , ms Sat = m mr m _s d ^ 2, mc mc = mc mc _ m mr m) 
# Dia g n ostics a n d o ut p ut: 
sta n _trace(e ma x M M R M $esta nfit) 
# L o o k at trace 
sta n _ de ns(e ma x M M R M $esta nfit) 
# L o o k at de nsities 
sta n _ac(e ma x M M R M $esta nfit) 
# L o o k at a ut oc orrelati o n 
s u m mar y(e ma x M M R M) 
# S u m mar y of m o del para meters 
pl ot(e ma x M M R M) 
# L o o k at fitte d vs. o bser ve d data t o c hec k m o del fit
e ma x M M R M o ut < - pre dict(e ma x M M R M, d ose vec = m mr m Res $ d ose, cle v = 0. 9 0) 
# Get d ose pre dicti o ns 
# P osteri or pre dicti ve c hec k f or n o n -m o n ot o ne d ose res p o nse
p ost C hec k < -c hec k M o n o E ma x( y = m mr m Res $ mea n , d ose = m mr m Res $ d ose,
                par m =c oef(e ma x M M R M),si g ma 2 =(si g ma(e ma x M M R M)) ^ 2, n vec = m mr m Res $ n)
Data Pr o vi de d b y Statisticia n
M o del para meters, p osteri or me dia ns a n d cre di ble i nter vals, as s pecifie d i n Secti o n 5. 2. 5 , 
will be o ut p ut a n d pr o vi de d bac k t o pr o gra m mi n g a fter Q C is c o m plete.
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 5 of 4 6
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
A E
a d verse e ve nt
Ae ta u
a m o u nt of u nc ha n ge d dr u g rec o vere d i n uri ne d uri n g t he d osi n g
i nter val
Ae ta u %
perce nt of d ose rec o vere d i n uri ne as u nc ha n ge d dr u g
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n -ti me c ur ve
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 Ce xtra p %
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 base d 
o n e xtra p olati o n
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 last
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m 0 t o ti me of last
meas ura ble c o nce ntrati o n
A U C ta u
area u n der t he c o nce ntrati o n -ti me c ur ve at stea dy state o ver t he 
d osi n g i nter val ta u
A & R
a nal ys is a n d re p orti n g
B L Q
bel o w t he li mit of q ua ntitati o n
B P
bl o o d press ure
b p m
beats per mi n ute
C a v
a vera ge plas ma c o nce ntrati o n
C -C A S A
C ol u m bia -Classificati o n Al g orit h m of S uici de Assess me nt
C F B
c ha n ge fr o m baseli ne
CI
c o nfi de nce i nter val
C L / F
a p pare nt cleara nce f or oral d osi n g
C L r
re nal cleara nce
C ma x
ma xi m u m plas ma c o nce ntrati o n
C mi n
mi ni m u m plas ma c o nce ntrati o n
C O VI D -1 9
c or o na vir us disease 2 0 1 9
C R F
case re p ort f or m
C R U
cli nical researc h u nit
C -S S R S
C ol u m bia S uici de Se verit y  Rati n g Scale
C S R
cli nical st u d y re p ort
c v
c oefficie nt of variati o n
C Y P
c yt oc hr o me P 4 5 0
E C G
electr ocar di o gra m
E 0
place b o effect
E D 5 0
d ose t hat pr o d uces half -ma xi mal effect
E ma x
t he ma xi mal effect
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI


Pr ot oc ol C 4 5 4 1 0 0 3 (P F -0 7 2 5 8 6 6 9 ) Statistical A nal ysis Pla n
D M B 0 2 -G S O P -R F 0 2 7. 0 St atistic al A n alysis Pl a n Te m pl ate 3 1 -Ja n-2 0 2 2
P FI Z E R C O N FI D E N TI A L
T M F D oc I D: 9 8. 0 3
Pa ge 4 6 of 4 6
A b bre vi ati o n
Ter m
F A S
f ull a nal ysis set
H
h o ur
H C H C
hi g h car b o h y drate, hi g h cal orie
H F H C
hi g h fat, hi g h cal orie
H R
heart rate
I D
i de ntificati o n
kel
ter mi nal p hase eli mi nati o n rate c o nsta nt
L
litres
L L Q
l o wer li mit of q ua ntitati o n
L S
least-s q uares
M M R M
mi xe d -effects m o del wit h re peate d meas ures
m m H g
milli metre of merc ur y
ms
millisec o n d
msec
millisec o n d
M T D
ma xi m u m t olerate d d ose
N
n u m ber of o bser vati o ns
N/ A
n ot a p plica ble
N C
n ot calc ulate d
N D
n ot d o ne
N S
n o sa m ple
P A 2
pr ot oc ol a me n d me nt 2
P A 3
pr ot oc ol a me n d me nt 3
P A 4
pr ot oc ol a me n d me nt 4
P K
p har mac o ki netic(s)
P K/ P D
p har mac o ki netics/ p har mac o d y na mics
P T R
pea k -t o-tr o u g h rati o
Q 8 H
e ver y 8 h o urs
Q C
q ualit y  c o ntr ol
Q Q
q uartile -q uartile
Q Tc F
c orrecte d Q T ( Fri dericia met h o d)
R ac
o bser ve d acc u m ulati o n rati o
R ac, C ma x
o bser ve d acc u m ulati o n rati o f or C ma x
S A P
statistical a nal ysis pla n
S D
sta n dar d de viati o n
t½
ter mi nal half-life
T ma x
ti me f or Cma x
V z/ F
a p pare nt v ol u me of distri b uti o n f or oral d osi n g
0 9 0 1 7 7 e 1 9 e 6 0 6 e 0 6\ Fi n al\ Fi n al O n: 2 2- A u g- 2 0 2 3 2 0: 1 1 ( G M T)
C CI
C CI
C CI
C CI