Clinical trial NCT05671653
Conditions: Obesity
Keywords: Midazolam Omeprazole PF-07081532
Sponsor: Pfizer
Start date: 2023-01-19; Completion date: 2023-11-03
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Two different groups of healthy volunteers will be chronically treated with GLP-1 drugs PF-07081532 or alternatively Semaglutide. The effect of these GLP-1 drugs on a single dose of the common sedative medication midazolam blood levels will be measured. The effect of chronic PF-07081532 on single doses of the common stomach acid medication omeprazole, and common birth control medication blood levels will also be measured. The hypothesis is that chronic administration of the GLP-1 drugs will minimally affect blood levels from these common medications.

Detailed description:

Arms: arm 1: Cohort 1 is an open-label, 9 period, fixed-sequence design to evaluate the effect of 2 steady state dose levels of PF-07081532 on the SD pharmacokinetics of midazolam and omeprazole, administered simultaneously, and an OC (LE/EE) in otherwise healthy obese adult female participants with a BMI ≥30 kg/m2. arm 2: Cohort 2 is an open label, 4-period, fixed-sequence design to evaluate the effect of steady state semaglutide on the SD PK of midazolam in obese adult female participants with a BMI ≥30 kg/m2
Interventions: intervention 1: PF-07081532 intervention 2: Semaglutide
Intervention descriptions: intervention 1: Experimental oral GLP-1 drug intervention 2: Approved and marketed GLP-1 drug for subcutaneous injection.

Protocol documents:
Prot_000.pdf: 
P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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, O P E N -L A B E L, FI X E D -S E Q U E N C E S T U D Y T O E V A L U A T E T H E 
E F F E C T O F T W O S T E A D Y -S T A T E D O S E L E V E L S O F P F - 07 0 8 1 5 3 2 O N T H E 
P H A R M A C O KI N E TI C S O F SI N G L E -D O S E MI D A Z O L A M , O M E P R A Z O L E A N D 
A N O R A L C O N T R A C E P TI V E, A N D T H E E F F E C T O F S T E A D Y -S T A T E 
S E M A G L U TI D E O N T H E P H A R M A C O KI N E T I C S O F SI N G L E-D O S E 
MI D A Z O L A M , I N O B E S E A D U L T F E M A L E 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 - 07 0 8 1 5 3 2
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 6 0 2 9 6 ( P F-0 7 0 8 1 5 3 2)
E u dr a C T N u m ber:
N/ A
Cli nic al Tri als. g o v I D:  
N/ A
Pr ot oc ol N u m ber:
C 3 9 9 1 0 4 0
P h ase:
1
Brief Title : A P hase 1 , 2-C o h ort , Fi xe d-Se q ue nce St u d y  to E val uate the Effect o f 2
Stea d y -State D oses of P F - 07 0 8 1 5 3 2 o n Si n gle -D ose Mi daz ola m , O me praz ole , a n d Oral 
C o ntrace pti ve P har mac o ki netics , a n d t he Effect of S e ma gl uti de o n Si n gle -D ose 
Mi daz ola m
P har mac o ki netics , i n O bese A d ult Fe male Partici pa nt s.
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 os es. 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
Ori gi nal Pr ot oc ol
0 7 N o ve m ber 2 0 2 2
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
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 .....................................................................................................................8
1. P R O T O C O L  S U M M A R Y...................................................................................................1 0
1. 1. S y n o psis ..................................................................................................................1 0
1. 2. Sc he ma ....................................................................................................................1 5
1. 3. Sc he d ule of Acti vities .............................................................................................1 5
2. I N T R O D U C TI O N ...............................................................................................................3 0
2. 1. St u d y  Rati o nale .......................................................................................................3 0
2. 2. Bac k gr o u n d .............................................................................................................3 0
2. 2. 1. N o ncli nical P har mac ol o g y ..........................................................................3 1
2. 2. 2. N o ncli nical P har mac o ki netics a n d Meta b olis m ......................................... 3 1
2. 2. 3. N o ncli nical Safet y ...................................................................................... 3 2
2. 2. 4. Cli nical O ver vie w a n d Safet y..................................................................... 3 2
2. 2. 4. 1. Cli nical P har mac o ki netics .........................................................3 3
2. 3. Be nefit/ Ris k Assess me nt................................ .........................................................3 3
2. 3. 1. Ris k Assess me nt......................................................................................... 3 4
2. 3. 2. Be nefit Assess me nt .....................................................................................3 6
2. 3. 3. O verall Be nefit/ Ris k C o ncl usi o n ................................................................3 7
3. O BJ E C TI V E S A N D E N D P OI N T S .....................................................................................3 7
4. S T U D Y D E SI G N .................................................................................................................3 9
4. 1. O verall Desi g n .........................................................................................................3 9
4. 1. 1. C o h ort 1 ......................................................................................................4 0
4. 1. 2. C o h ort 2 ......................................................................................................4 0
4. 2. Scie ntific Rati o nale f or St u d y  Desi g n.....................................................................4 1
4. 2. 1. C o h ort 1 ......................................................................................................4 1
4. 2. 1. 1. Mi daz ola m A d mi nistrati o n .......................................................4 1
4. 2. 1. 2. O me praz ole A d mi nistrati o n ......................................................4 3
4. 2. 1. 3. Oral C o ntrace pti ve A d mi nistrati o n................................ ...........4 3
4. 2. 1. 4. P F -0 7 0 8 1 5 3 2 A d mi nistrati o n ....................................................4 4
4. 2. 2. C o h ort 2 ......................................................................................................4 4
4. 2. 2. 1. Se ma gl uti de a n d Mi daz ola m A d mi nistrati o n............................ 4 4
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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. 2. 3. Safet y Assess me nts ( C o h orts 1 a n d 2) ........................................................4 6
4. 2. 4. Di versit y  of St u d y P o p ulati o n ....................................................................4 7
4. 2. 5. C h oice of C o ntrace pti o n/ Barrier Re q uire me nts .........................................4 7
4. 2. 6. C ollecti o n of Retai ne d Researc h Sa m ples ..................................................4 7
4. 3. J ustificati o n f or D ose ..............................................................................................4 7
4. 4. E n d of St u d y  Defi niti o n ..........................................................................................4 9
5. S T U D Y P O P U L A T I ON................................ ......................................................................4 9
5. 1. I ncl usi o n Criteria .....................................................................................................4 9
5. 2. E xcl usi o n Criteria ....................................................................................................5 0
5. 3. L ifest yle C o nsi derati o ns..........................................................................................5 4
5. 3. 1. Meals a n d Dietar y  Restricti o ns...................................................................5 4
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. C o ntrace pti o n ..............................................................................................5 6
5. 4. Scree n Fail ures ........................................................................................................5 6
6. S T U D Y I N T E R V E N TI O N( S) A N D C O N C O MI T A N T T H E R A P Y .................................5 6
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. Assi g n me nt t o St u d y I nter ve nti o n ...........................................................................6 0
6. 4. Bli n di n g................................ ...................................................................................6 2
6. 5. St u d y  Inter ve nti o n C o m plia nce ...............................................................................6 2
6. 6. D ose M o dificati o n ...................................................................................................6 2
6. 7. 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 2
6. 8. Treat me nt of O ver d ose................................ ............................................................6 3
6. 9. C o nc o mita nt T hera p y ..............................................................................................6 3
6. 9. 1. Resc ue Me dici ne .........................................................................................6 4
6. 9. 1. 1. Ma na ge me nt of Na usea a n d V o miti n g ......................................6 4
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 5
7. 1. Disc o nti n uati o n of St u d y  Inter ve nti o n ....................................................................6 5
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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. 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 5
7. 2. 1. Wit h dra wal of C o nse nt ...............................................................................6 6
7. 3. L ost t o F oll o w - u p....................................................................................................6 7
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 7
8. 1. A d mi nistrati ve Pr oce d ures ......................................................................................6 7
8. 2. Efficac y  Assess me nts..............................................................................................6 8
8. 3. Safet y Assess me nts .................................................................................................6 8
8. 3. 1. P h y sical E xa mi nati o ns ................................................................................6 8
8. 3. 2. Vital Si g ns ..................................................................................................6 9
8. 3. 2. 1. T e m perat ure ..............................................................................7 0
8. 3. 3. Electr ocar di o gra ms..................................................................................... 7 0
8. 3. 4. Cli nical Safet y  La b orat or y Assess me nts....................................................7 1
8. 3. 4. 1. Alter nati ve Facilities f or Cli nical Safet y  La b orat or y 
Assess me nt ........................................................................................7 1
8. 3. 5. C O VI D - 1 9 S pecific Assess me nts...............................................................7 2
8. 3. 6. Ma na ge me nt of H y p o gl y ce mia ...................................................................7 2
8. 3. 6. 1. Defi niti o n a n d Se verit y of Cate g orizati o n of 
H y p o gl yc e mic A d verse E ve nt ( H A E) ...............................................7 2
8. 3. 6. 2. Gl uc o meter M o nit ori n g of Gl uc ose ................................ ..........7 3
8. 3. 7. Pre g na nc y  Testi n g ......................................................................................7 4
8. 3. 8. S uici dal I deati o n a n d Be ha vi or Ris k M o nit ori n g .......................................7 4
8. 3. 8. 1. C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S) .................7 4
8. 3. 8. 2. Patie nt Healt h Q uesti o n naire- 9 ( P H Q - 9) ..................................7 5
8. 3. 8. 3. Referral t o a Me ntal Healt h Pr ofessi o nal ..................................7 5
8. 4. 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 5
8. 4. 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 6
8. 4. 1. 1. Re p orti n g S A Es t o Pfizer Safet y ...............................................7 7
8. 4. 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 7
8. 4. 2. Met h o d of Detecti n g A Es a n d S A Es ..........................................................7 7
8. 4. 3. F oll o w -U p of A Es a n d S A Es ......................................................................7 7
8. 4. 4. Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...........................................7 8
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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. 4. 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 .....................................................7 8
8. 4. 5. 1. E x p os ure D uri n g Pre g na nc y ......................................................7 8
8. 4. 5. 2. E x p os ure D uri n g Breastfee di n g ................................................ 8 0
8. 4. 5. 3. Occ u pati o nal E x p os ure ............................................................. 8 0
8. 4. 6. Car di o vasc ular a n d Deat h E ve nts ...............................................................8 0
8. 4. 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 0
8. 4. 8. A d verse E ve nts of S pecial I nterest ............................................................. 8 0
8. 4. 8. 1. Lac k of Efficac y ........................................................................ 8 1
8. 4. 9. Me dical De vice Deficie ncies ...................................................................... 8 1
8. 4. 1 0. Me dicati o n Err ors ..................................................................................... 8 1
8. 5. P har mac o ki netics .................................................................................................... 8 1
8. 5. 1. P K of Mi daz ola m a n d 1- h y dr o x y m i daz ola m ............................................. 8 3
8. 5. 2. P K of O me praz ole a n d 5 -h y dr o x y o me praz ole ........................................... 8 3
8. 5. 3. P K of Le v o n or gestrel .................................................................................. 8 3
8. 5. 4. P K of Et hi n y l Estra di ol............................................................................... 8 3
8. 5. 5. P K of P F -0 7 0 8 1 5 3 2 .................................................................................... 8 3
8. 5. 6. P K of Se ma gl uti de ...................................................................................... 8 3
8. 6. Ge netics ................................................................................................................... 8 4
8. 6. 1. S pecifie d Ge netics ...................................................................................... 8 4
................................................... 8 4
8. 7. Bi o mar kers .............................................................................................................. 8 4
8. 7. 1. S pecifie d Pr otei n Researc h .........................................................................8 4
8. 7. 2. S pecifie d Ge ne E x pressi o n ( R N A) Researc h .............................................8 4
8. 7. 3. S pecifie d Meta b ol o mic Researc h ...............................................................8 4
8. 7. 4. Retai ne d Researc h Sa m ples f or Bi o mar kers ...............................................8 4
8. 7. 5. Plas ma f or A nal ys is of 4-h y dr o x y c h olester ol/c h olester ol ........................ 8 5
8. 8. I m m u n o ge nicit y Assess me nts ................................................................................. 8 5
8. 9. Healt h Ec o n o mics ................................................................................................... 8 5
9. S T A TI S TI C A L C O N SI D E R A TI O N S ................................................................................8 5
9. 1. Statistical H y p ot heses ............................................................................................. 8 5
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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. 2. A nal y sis Sets ...........................................................................................................8 5
9. 3. Statistical A nal y ses .................................................................................................8 6
9. 3. 1. Ge neral C o nsi derati o ns ...............................................................................8 6
9. 3. 1. 1. Deri vati o n of P har mac o ki netic Para meters ...............................8 6
9. 3. 2. Statistical Met h o ds f or P har mac o ki netic Data ........................................... 8 8
9. 3. 3. Safet y A nal ys es ..........................................................................................9 0
9. 3. 3. 1. Electr ocar di o gra m A nal y ses......................................................9 1
9. 3. 4. Ot her A nal ys e(s) .........................................................................................9 1
9. 4. I nteri m A nalys es .....................................................................................................9 1
9. 5. Sa m ple Size Deter mi nati o n .....................................................................................9 1
9. 6. Data M o nit ori n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee .............9 2
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 3
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 3
1 0. 1. 1. Re g ulat or y a n d Et hical C o nsi derati o ns ....................................................9 3
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 3
1 0. 1. 2. Fi na ncial Discl os ure .................................................................................9 4
1 0. 1. 3. I nf or me d C o nse nt Pr ocess ........................................................................9 4
1 0. 1. 4. Data Pr otecti o n .........................................................................................9 5
1 0. 1. 5. C o m mittees Str uct ure ...............................................................................9 5
1 0. 1. 5. 1. Data M o nit ori n g C o m mittee ...................................................9 5
1 0. 1. 6. Disse mi nati o n of Cli nical St u d y  Data ......................................................9 5
1 0. 1. 7. Data Q ualit y Ass ura nce ............................................................................9 7
1 0. 1. 8. S o urce D oc u me nts ....................................................................................9 8
1 0. 1. 9. St u d y  a n d Site Start a n d Cl os ure ..............................................................9 8
1 0. 1. 1 0. P u blicati o n P olic y ...................................................................................9 9
1 0. 1. 1 1. S p o ns or’s Q ualifie d Me dical P ers o n nel ............................................... 1 0 0
1 0. 2. A p pe n di x 2: Cli nical La b orat or y  Tests...............................................................1 0 1
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 3
1 0. 3. 1. Defi niti o n of A E .....................................................................................1 0 3
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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 0. 3. 2. Defi ni ti o n of a n S A E.............................................................................. 1 0 4
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 0 6
1 0. 3. 4. Re p orti n g of S A Es .................................................................................. 1 0 9
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 0
1 0. 4. 1. Male ........................................................................................................ 1 1 0
1 0. 4. 2. Fe male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria ............................... 1 1 0
1 0. 4. 3. W o ma n of C hil d beari n g P ote ntial .......................................................... 1 1 0
1 0. 4. 4. C o ntrace pti o n Met h o ds ........................................................................... 1 1 1
.......................................................................................... 1 1 3
1 0. 6. A p pe n di x 6: L i ver Safet y: S u g geste d Acti o ns a n d F oll o w-U p Assess me nts ..... 1 1 4
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 1 6
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 1 6
1 0. 7. 2. A g e-S pecific Ki d ne y  F u ncti o n Calc ulati o n Rec o m me n dati o ns............. 1 1 6
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..... 1 1 6
1 0. 7. 3. A d verse E ve nt Gra di n g f or Ki d ne y  Safety La b orat or y  
A b n or malities ................................................................................................. 1 1 6
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 1 7
1 0. 9. A p pe n di x 9 A b bre viati o ns .................................................................................. 1 1 9
1 1. R E F E R E N C E S ................................................................................................................ 1 2 4
LI S T O F T A B L E S
Ta ble 1.
C o h ort 1 - O verall Sc he d ule of Acti vities Scree ni n g t o Peri o d 5 ............. 1 6
Ta ble 2.
C o h ort 1 - O verall Sc he d ule of Acti vities Peri o d 6 t o E T ........................ 1 9
Ta ble 3.
Sc he d ule of Acti vities – Da y  1 of Peri o d 1 ( Mi daz ola m + 
O me praz ole O N L Y), Peri o d 4 ( Mi daz ola m + O me praz ole + 
P F - 0 7 0 8 1 5 3 2 8 0 m g Q D), Peri o d 7 ( Mi daz ola m + O me praz ole + 
P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D), a n d Peri o d 9 ( Mi daz ola m O N L Y) ............... 2 2
Ta ble 4.
Sc he d ule of Acti vities – Da y  1 of Peri o d 2 ( O C O N L Y), Peri o d 5 
( O C + P F- 0 7 0 8 1 5 3 2 8 0 m g Q D) a n d Peri o d 8 ( O C + P F - 0 7 0 8 1 5 3 2 
2 6 0 m g Q D) ..............................................................................................2 3
Ta ble 5.
Sc he d ule of Acti vities – Da y  2 8 of Peri o d 3 a n d Da y 6 3 of Peri o d 6 
( P F- 0 7 0 8 1 5 3 2 o nly) .................................................................................. 2 4
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
Ta ble 6.
C o h ort 2: Sc he d ule of Acti vities ...............................................................2 5
Ta ble 7.
Sc he d ule of Acti vities – Da y  1 of Peri o d 1 ( Mi daz ola m O N LY), 
Peri o d 3 ( Mi daz ola m + Se ma gl uti de 2. 4 m g), a n d Peri o d 4 
( Mi daz ola m O N L Y) .................................................................................2 9
Ta ble 8.
C o h ort 1 D osi n g ........................................................................................5 8
Ta ble 9.
C o h ort 2 D osi n g ........................................................................................5 9
Ta ble 1 0.
P F -0 7 0 8 1 5 3 2 D osi n g Re gi me ns i n C o h ort 1 ............................................6 1
Ta ble 1 1.
Se ma gl uti de D osi n g Re gi me ns i n C o h ort 2 ..............................................6 2
Ta ble 1 2.
Plas ma P K Para meters f or Mi daz ola m, 1- O H -Mi daz ola m, 
O me praz ole, 5 -O H -O me praz ole, Le v o n or gestrel a n d Et hi n y l 
Estra di ol ....................................................................................................8 7
Ta ble 1 3.
Plas ma P K Para meters f or P F- 0 7 0 8 1 5 3 2 ................................................. 8 8
Ta ble 1 4.
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 a n d Para meters of I nterest .......9 2
Ta ble 1 5.
Pr ot oc ol -Re q uire d Safet y L a b orat or y Assess me nts ...............................1 0 1
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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. P R O T O C O L S U M M A R Y 
1. 1. S y n o psis 
Brief Title: A P hase 1 , 2-C o h ort, Fi xe d -Se q ue nce St u d y  to E val uate the Effect o f 
2 Stea d y -State D oses of P F - 0 7 0 8 1 5 3 2 o n Si n gle - D ose Mi daz ola m, O me praz ole, a n d Oral 
C o ntrace pti ve P har mac o ki netics , a n d t he Effect of Se ma gl uti de o n Si n gle - D ose Mi daz ola m 
P har mac o ki netics, i n O bese A d ult Fe male Partici pa nts .
R ati o n ale
T his is a P hase 1, o pe n -la bel, fi xe d-se q ue nce, 2- c o h ort st u d y t o e val uate t he effect of 
1) 2 stea dy- state d ose le vels of P F - 0 7 0 8 1 5 3 2 o n t he S D p har mac o ki netics of mi daz ola m , 
o me praz ole, a n d a n O C ( L E/ E E), a n d 2) stea d y-state se ma gl uti de o n t he S D 
p har mac o ki netics of mi daz ola m, i n ot her wise healt h y  o bese a d u lt fe male partici pa nts . T he 
i nte nt of t his st u d y is t o ge nerate safet y, t olera bilit y, a n d P K data f or f urt her cli nical 
de vel o p me nt .
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
C o h ort 1
Pri m ar y: 
Pri m ar y: 

T o e val uate t he effects of P F -0 7 0 8 1 5 3 2 o n t he 
p har mac o ki netics of mi daz ola m, o me praz ole, 
a n d a n oral c o ntrace pti ve ( O C; L E/ E E) i n o bese 
a d ult fe male partici pa nts.

Mi daz ola m plas ma p har m ac o ki netic para meters: 
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o ds 1, 4 a n d 7.

O m e praz ole plas ma p har mac o ki netic 
para meters: A U C i nf (if data per mit* ot her wise 
A U C last) i n Peri o ds 1, 4 a n d 7.

L E plas ma p har mac o ki netic para meters: A U C i nf
(if data per mit* ot her w ise A U Clast) i n Peri o ds 2, 
5 a n d 8.

E E plas ma p har mac o ki netic para meters: A U C i nf
(if data per mit* ot her wise A U C last) i n i n Peri o ds 
2, 5 a n d 8.
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 
P F - 07 0 8 1 5 3 2 a d mi nistere d se paratel y a n d i n 
c o m bi nati o n wit h mi daz ola m, o me praz ole, a n d 
a n O C ( L E/ E E) i n o bese a d ult fe male 
partici pa nts .

Assess me nt of T E A Es , cli nical la b orat or y 
a b n or malities, a n d b o d y wei g ht .

Assess me nt of me ntal healt h as deter mi ne d b y 
C- S S R S a n d P H Q - 9. 

T o e val uate t he p har mac o ki netics of S D 
mi daz ola m f oll o wi n g t he disc o nti n uati o n of 
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n i n o bese a d ult 
fe male partici pa nts.  

Mi daz ola m plas ma p har mac o ki netic para meters:
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o d 9.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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

T o e val uate t he effects of P F - 07 0 8 1 5 3 2 o n 
a d diti o nal p har mac o ki netic para meters of 
mi daz ola m , o me praz ole, a n d a n O C ( L E/ E E) i n 
o bese a d ult fe male partici pa nts.

A d diti o nal plas ma p har mac o ki netic para meters 
f or mi daz ola m a n d o me praz ole ( Peri o ds 1, 4 a n d 
7) , a n d L E a n d E E ( Peri o ds 2, 5 a n d 8): Cma x a n d 
T ma x ; a n d C L/ F, Vz/ F, t½ , as data per mit.

T o e val uate t he effects of P F - 07 0 8 1 5 3 2 o n t he 
meta b olite/ p are nt rati os f or mi daz ola m a n d 
o m e praz ole i n o bese a d ult fe male partici pa nts.

M R A U C
i nf ( 1-h y dr o x y mi daz ola m 
A U C i nf/ mi daz ola m A U Ci nf).

M R A U C
i nf ( 5-h y dr o x y o m e praz ole
A U C i nf/o m e praz ole A U C i nf).

T o e val uate t he M D p har mac o ki netics of 
P F - 07 0 8 1 5 3 2 i n o bese a d ult fe male partici pa nts.

P F - 07 0 8 1 5 3 2 plas ma p har mac o ki netic 
para meters at Da ys 3 4 a n d 1 0 3: A U C 2 4, Cma x , 
T ma x .
C o h ort 2
Pri m ar y: 
Pri m ar y: 

T o e val uate t he effects of se ma gl uti de 
(s u bc uta ne o us se ma gl uti de) o n t he S D P K of 
mi daz ola m i n o bese a d ult fe male partici pa nts.

Mi daz ola m plas ma p har mac o ki netic para meters: 
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o ds 1 a n d 3.
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 
se ma gl uti de a d mi nistere d se paratel y a n d i n 
c o m bi nati o n wit h mi daz ola m i n o bese a d ult 
fe male partici pa nts.

Assess me nt of T E A Es , cli nical la b orat or y 
a b n or malities, a n d b o d y wei g ht .

Assess me nt of me ntal healt h as deter mi ne d b y 
C- S S R S a n d P H Q -9.

T o e val uate t he p har mac o ki netics of S D 
mi daz ola m f oll o wi n g t he disc o nti n uati o n of 
se ma gl uti de a d mi nistrati o n i n o bese a d ult 
fe male partici pa nts.

Mi daz ola m plas ma p har mac o ki netic para meters: 
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o d 4.

T o e val uate t he effects of se ma gl uti de o n 
a d diti o nal p har mac o ki netic para meters of 
mi daz ola m i n o bese a d ult fe male partici pa nts.

A d diti o nal plas m a p har m ac o ki netic para meters 
f or mi daz ola m (i n Peri o ds 1 a n d 3): Cma x , Tma x ,
a n d C L/ F, Vz/ F, t ½ as data per mit.

T o e val uate t he effects of se ma gl uti de o n t he 
meta b olite/ pare nt rati o f or mi daz ola m i n o bese 
a d ult fe male partici pa nts.

M R A U C
i nf ( 1-h y dr o x y mi daz ola m 
A U C i nf/ mi daz ola m A U Ci nf).
* S h o ul d it be dee me d t hat t o o fe w A U C i nf esti mates (e g, less t ha n 1 2 f or a si n gle treat me nt) are o btai ne d 
fr o m t he e val ua ble partici pa nts, A U Clast ma y be selecte d as t he pri mar y e n d p oi nt f or C S R re p orti n g.  T his 
will be c o nsi dere d f or t he mi daz ola m, 1 -h y dr o x y mi daz ola m, o me praz ole, 5 -h y dr o x y o me pr az ole, L E, a n d E E 
o bjecti ves se paratel y.
O ver all Desi g n
Brief S u m m ar y
T his st u d y  is a P hase 1, o pe n-la bel st u dy t hat will be c o n d ucte d i n 2 c o h orts; b ot h c o h orts 
will e nr oll ot her wise healt h y , o bese , a d ult fe male partici pa nts . C o h ort 1 is a n o pe n-la bel, 
9 -peri o d, fi xe d-se q ue nce desi g n t o e val uate t he effect of 2 stea dy-state d ose le vels of 
P F - 0 7 0 8 1 5 3 2 o n t he S D p har mac o ki netics of mi daz ola m a n d o me praz ole, a d mi nistere d
si m ulta ne o usl y, a n d a n O C ( LE/ E E) . C o h ort 2 is a n o pe n-la bel, 4 -peri o d, fi xe d-se q ue nce
desi g n t o e val uate t he effect of stea dy- state se ma gl uti de o n t he S D p har mac o ki netics of
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
m i daz ola m. A d diti o nall y, partici pa nts i n b ot h c o h orts will be disc har ge d fr o m t he cli nical 
site f or 2 wee ks f oll o wi n g t he fi nal P K sa m ple c ollecti o n of O C ( L E/ E E) i n Peri o d 8, Da y 2 
( C o h ort 1) or mi daz ola m i n Peri o d 3, Da y 2 ( C o h ort 2), a n d disc o nti n ue all f urt her 
P F - 0 7 0 8 1 5 3 2 or se ma gl uti de d osi n g at t hat ti me.  F oll o wi n g t he 2-wee k o ut -patie nt d urati o n, 
partici pa nts will ret ur n t o t he cli nical site f or a fi nal mi daz ol a m assess me nt ( wit h o ut eit her 
P F -0 7 0 8 1 5 3 2 or se ma gl uti de c oa d mi nistrati o n ).
Partici pa nts will partici pate i n eit her C o h or t 1 or C o h ort 2 ( n ot b ot h), a n d C o h ort 1 a n d 
C o h ort 2 are preferre d t o be c o n d ucte d i n parallel, if p ossi ble. F or partici pa nts i n C o h ort 1, 
t he t otal d urati o n of partici pati o n fr o m t he Scree ni n g Visit t o t he F/ U c o ntact will be 
a p pr o xi matel y 1 8 8 d a y s or 2 7 wee ks. F or partici pa nts i n C o h ort 2, t he t otal d urati o n of 
partici pati o n fr o m t he Scree ni n g Visit t o t he F/ U c o ntact will be a p pr o xi matel y 2 2 8 d a y s or 
3 3 wee ks.
N u m ber of P artici p a nts
A sa m ple size of a p pr o xi matel y 1 6 partici pa nts i n C o h ort 1 a n d a p pr o xi matel y
1 6 partici pa nts i n C o h ort 2 will be e nr olle d s uc h t hat a p pr o xi matel y  1 2 e val ua ble partici pa nts 
c o m plete eac h c o h ort of t he st u d y.  
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 by t he pr ot oc ol.
N ote: " E nr olle d" mea ns a partici pa n t'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 scre e ni n g. 
I nter ve nti o n Gr o u ps a n d D ur ati o n
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 0 8 1 5 3 2, mi daz ola m, 
o me praz ole, O C a n d se ma gl uti de .
T he p ur p ose of t his st u d y is t o c haracterize t he effect of P F - 0 7 0 8 1 5 3 2, a d mi nistere d at 
2 stea d y-state d ose le vels, o n t he P K of si n gle d oses of mi daz ola m ( 2 m g oral ) a n d 
o me praz ole ( 2 0 m g oral ), a d mi nistere d si m ulta ne o usl y, a n d a n O C ( L E 0. 1 5 m g/ E E 0. 0 3 m g
oral ) i n ot her wise healt h y , o bese , a d ult fe male partici pa nts i n C o h ort 1.  A d diti o nall y , 
C o h ort 2 will c haracterize t he effect of se ma gl uti de ( 2. 4 m g s u bc uta ne o us) a d mi nistere d t o 
stea d y state o n t he P K of si n gle d oses of mi daz ola m ( 2 m g) i n ot her wise healt h y , o bese , a d ult 
fe male partici pa nts. Titrati o n of P F - 0 7 0 8 1 5 3 2 a n d se ma gl uti de d oses will be utilize d t o 
ac hie ve a ma xi m u m d ose of 2 6 0 m g Q D i n C o h ort 1 (Ta ble 8 ) a n d 2. 4 m g ( gi ve n o nce 
wee kl y) i n C o h ort 2 (Ta ble 9 ), res pecti vel y.
A d diti o nall y , partici pa nts i n b ot h c o h orts will be disc har ge d fr o m t he cli nical site f or 2 wee ks 
f oll o wi n g t he fi nal P K sa m ple c ollecti o n of O C ( L E/ E E) i n Peri o d 8, Da y 2 ( C o h ort 1) or 
mi daz ola m i n Peri o d 3, Da y  2 ( C o h ort 2), a n d disc o nti n ue all f urt her P F-0 7 0 8 1 5 3 2 or 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
se ma gl uti de d osi n g at t hat ti me.  F oll o wi n g t he 2-wee k o ut -patie nt d urati o n, partici pa nts will 
ret ur n t o t he cli nical site f or a fi nal mi daz ola m assess me nt ( wit h o ut eit her P F-0 7 0 8 1 5 3 2 or 
se ma gl uti de c oa d mi nistrati o n).  I n C o h ort 1, the dr u g - dr u g i nteracti o n effect will be assesse d 
at P F - 0 7 0 8 1 5 3 2 d oses of 8 0 m g Q D a n d 2 6 0 m g Q D , as 8 0 m g Q D is pr ojecte d as a p ote ntial 
t hera pe utic d ose f or T 2 D M a n d 2 6 0 m g Q D is t he ma xi m u m d ose bei n g st u die d i n P hase 2 
f or T 2 D M a n d o besit y . I n C o h ort 2, t he D DI effect will be assesse d at a se ma gl uti de d ose of 
2. 4 m g as t his is t he ma xi m u m a p pr o ve d d ose f or wei g ht l oss. I n b ot h c o h orts, t he i m pact of 
disc o nti n uati o n f or 2 wee ks of eit her P F - 0 7 0 8 1 5 3 2 ( C o h ort 1) or se ma gl uti de ( C o h ort 2) o n 
t he P K of mi daz ola m will be assesse d. 
P F - 0 7 0 8 1 5 3 2 will be pr o vi de d as ta blets f or oral a d mi nistrati o n.  St u d y i nter ve nti o n 
(P F - 0 7 0 8 1 5 3 2), mi daz ola m a n d o me praz ole or t he O C m ust be a d mi nistere d wit hi n 
a p pr o xi matel y 1 0 mi n utes of c o m pleti o n of t he m or ni n g meal w he n ta ke n al o ne .  
P F - 0 7 0 8 1 5 3 2 will be a d mi nistere d first a n d mi daz ola m a n d o me praz ole or t he O C will be 
a d mi nistere d wit hi n 5 mi n utes of P F - 0 7 0 8 1 5 3 2 d uri n g t he D DI assess me nt peri o ds.
S e ma gl uti de ( Oze m pic a n d/ or We g o v y) will be pr o vi de d as pre -fille d, si n gle-d ose pe ns / d ose 
le vel f or s u bc uta ne o us i njecti o n.  Dr u g a d mi nistrati o n will f oll o w t he i nstr ucti o ns pr o vi de d i n 
t he a p pr o ve d Hi g hli g hts of Prescri bi n g I nf or mati o n as o utli ne d i n t he U S PI .  St u d y  
i nter ve nti o n (se ma gl uti de) m ust be a d mi nistere d o nce wee kl y , prefera bl y i n t he m or ni n g,
wit h o ut re gar d t o ti mi n g of t he brea kfast meal d uri n g o ut patie nt visits t o t he C R U f or d ose 
a d mi nistrati o n.  D uri n g t he D DI assess me nt i n patie nt visit ( Peri o d 3) , se ma gl uti de a n d 
mi daz ola m m ust be a d mi nistere d wit hi n a p pr o xi matel y 1 0 mi n utes of c o m pleti o n of t he 
m or ni n g meal.  S e ma gl ut i de will be a d mi nistere d first a n d mi daz ola m will be a d mi nistere d 
wit hi n 5 mi n utes of se ma gl uti de.
C o h ort 1 : 11 2 da y s will be i n-patie nt as f oll o ws: Peri o d 1 ( S D mi daz ola m a n d o me praz ole): 
1 da y ; Peri o d 2 ( S D O C): 5 da y s; Peri o d 3 (P F -0 7 0 8 1 5 3 2 titrate d t o 8 0 m g Q D) : 28 d a y s; 
Peri o d 4 ( 8 0 m g P F -0 7 0 8 1 5 3 2 + S D mi daz ola m a n d o me praz ole ): 1 da y; Peri o d 5 ( 8 0 m g 
P F -0 7 0 8 1 5 3 2 + S D O C ): 5 da y s; Peri o d 6 ( P F -0 7 0 8 1 5 3 2 titrate d t o 2 6 0 m g Q D) : 6 3 d a y s; 
Peri o d 7 ( 2 6 0 m g P F -0 7 0 8 1 5 3 2 + S D mi daz ola m a n d o me praz ole ): 1 da y; Peri o d 8 ( 2 6 0 m g  
P F -0 7 0 8 1 5 3 2 + S D O C ): 6 da ys; Peri o d 9 ( S D mi daz ola m o nl y): 2 da ys.
C o h ort 2 : 6 da y s will be i n-patie nt as f oll o ws: Peri o d 1 ( S D mi daz ola m ): 1 da y ; Peri o d 2 
(fi nal da y of se ma gl uti de titrate d t o 2. 4 m g o nce wee kl y ): 1 da y ; Peri o d 3 ( 2. 4 m g 
se ma gl uti de o nce wee kl y + S D mi daz ola m ) 2 da y s; Peri o d 4 ( S D mi daz ola m): 2 da y s.  
Partici pa nts will als o be re q uire d t o ret ur n t o t he cli nic d uri n g o ut- patie nt visits , prefera bly i n 
t he m or ni n g, t o recei ve t heir o nce wee kly se ma gl uti de i njecti o ns ( Peri o d 2).
T h e F/ U visit will occ ur 7 -1 0 da y s fr o m t he last d ose of st u d y i nter ve nti o n a n d a tele p h o ne 
F/ U c o ntact will occ ur 2 8- 3 5 d a y s fr o m t he last d ose of st u d y i nter ve nti 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 : 
T his st u d y will n ot use a D M C .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
St atistic al Met h o ds
T he P K data f or P F -0 7 0 8 1 5 3 2 , mi daz ola m , 1 -h y r o x ymi daz ola m, o me praz ole,
5 -h y dr o x y o me praz ole, L E , a n d E E will be a nal yz e d a n d re p orte d se paratel y.
C o h ort 1
Nat ural l o g e tra nsf or me d A U Ci nf (as data per mit), Cma x a n d A U C last of o me praz ole 
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c oa d mi nistere d wit h P F - 0 7 0 8 1 5 3 2 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 ( Tes t- Refere nce) a n d c orres p o n di n g 
9 0 % CI s will be o btai ne d fr o m t he m o dels.  T he a dj uste d mea n differe nces a n d 9 0 % CI s f or 
t he differe nces will be e x p o ne ntiate d t o pr 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 % CI s f or t he rati os.  T he 2 test treat me nts will be 
‘ o mepraz ole a n d P F -0 7 0 8 1 5 3 2 8 0 m g Q D ’ ( Peri o d 4) a n d ‘o me praz ole a n d P F - 0 7 0 8 1 5 3 2
2 6 0 m g Q D ’ ( Peri o d 7), w hic h will be re p orte d se parately i n c o m paris o n t o t he refere nce 
treat me nt of ‘o me praz ole wit h o ut P F - 0 7 0 8 1 5 3 2’ ( Peri o d 1).  
Nat ural l o g e-tra nsf or me d A U C i nf (as data per mit), Cma x a n d A U C last of mi daz ola m 
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c oa d mi nistere d wit h P F - 0 7 0 8 1 5 3 2 will be a nal y ze d 
a n d re p orte d se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or 
o me praz ole .  T he 2 test treat me nts will be ‘ mi daz ola m a n d P F - 0 7 0 8 1 5 3 2 80 m g Q D ’ 
( Peri o d 4 )’ a n d ‘ mi daz ola m a n d P F - 0 7 0 8 1 5 3 2 2 60 m g Q D ’ ( Peri o d 7 ), w hic h will be 
re p orte d se parately i n c o m paris o n t o t he refere nce treat me nt of ‘ mi daz ola m wit h o ut 
P F - 0 7 0 8 1 5 3 2’ ( Peri o d 1 ).
Nat ural l o g e-tra nsf or me d A U C i nf (as data per mit), Cma x a n d A U C last of L E a n d E E
a d mi nistere d al o ne or c oa d mi nistere d wit h P F -0 7 0 8 1 5 3 2 will be a nal yz e d a n d re p orte d 
se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or o me praz ole .  F or L E , 
t he 2 test treat me nts will be ‘L E a n d P F - 0 7 0 8 1 5 3 2 80 m g Q D ’ ( Peri o d 5 ) a n d ‘L E a n d 
P F - 0 7 0 8 1 5 3 2 26 0 m g Q D ’ ( Peri o d 8 ), w hic h will be re p orte d se parately i n c o m paris o n t o t he 
refere nce treat me nt of ‘L E al o ne’ ( Peri o d 2 ). Si milarl y f or E E , t he 2 test treat me nts will be 
‘E E a n d P F - 0 7 0 8 1 5 3 2 80 m g Q D ’ ( Peri o d 5 ) a n d ‘E E a n d P F - 0 7 0 8 1 5 3 2 2 60 m g Q D ’ 
( Peri o d 8 ), w hic h will be re p orte d se parately i n c o m paris o n t o t he refere nce treat me nt of ‘ E E
al o ne’ ( Peri o d 2 ).
C o h ort 2
Nat ural l o g e-tra nsf or me d AU C i nf (as data per mit), Cma x a n d A U C last of mi daz ola m 
a d mi nistere d al o ne or c oa d mi nistere d wit h se ma gl uti de i n C o h ort 2 will be a nalyz e d a n d 
re p orte d se parately usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or o me praz ole.  
T he test treat me nt will b e ‘ mi daz ola m a n d se ma gl uti de 2. 4 m g wee kl y’ ( Peri o d 3) w hic h will 
be re p orte d se paratel y i n c o m paris o n t o t he refere nce treat me nt of ‘ mi daz ola m al o ne’ 
( Peri o d 1).
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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. 2. Sc he m a
C o h ort 1 – P F -0 7 0 8 1 5 3 2 a n d Mi d az ol a m , O me pr az ole, a n d a n O C ( L E/ E E)
C o h ort 2 – S e m a gl uti de a n d Mi d az ol a m
N ote: f or C o h ort 2, partici pa nts will be disc har ge d fr o m t he st u d y site f oll o wi n g a d mi nistrati o n of t he first 0. 2 5 
m g se ma gl uti de i njecti o n o n Da y 1 of Peri o d 2 .  Peri o d 2 will be c o n d ucte d o ut-patie nt u ntil t he fi nal da y w he n 
partici pa nts will be rea d mitte d t o t he st u d y site t he da y pri or t o t he Peri o d 3 D DI assess me nt.  F or b ot h C o h orts 
1 a n d 2, partici pa nts will be rea d mitte d t o t he st u d y site f oll o wi n g a 2-wee k o ut -patie nt d urati o n wit h n o st u d y 
i nter ve nti o n at Peri o d 9 a n d Peri o d 4 , res pecti vel y. 
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 he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d i n t he S o A 
ta 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
C o h ort 1 : Sc he d ule of Acti vities
T a ble 1 .
C o h ort 1 - O ver all Sc he d ule of Acti vities Scree ni n g t o Peri o d 5
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble 
ma y be f o u n d i n A p pe n di x 9
Scree ni n g
Peri o d 1
(M D Z + 
O M P o nl y)
Peri o d 2
(O C o nl y )
Peri o d 3 
(P F -0 7 0 8 1 5 3 2 o nl y)
Peri o d 4 
( P F- 0 7 0 8 1 5 3 2 
+ M D Z + 
O M P)
Peri o d 5 
(P F -0 7 0 8 1 5 3 2 +
O C )
D a y i n St u d y Peri o d a
-2 8 t o - 2
- 1
1
1
2- 4
5
1
2- 7
8
9- 1 4
1 5
1 6 - 2 1
2 2
2 3 -2 7
2 8
1
1
2- 4
5
D a ys i n St u d y b
-2 8 t o - 2
- 1
1
2
3- 5
6
7
8- 1 3
1 4
1 5- 2 0
2 1
2 2 - 2 7
2 8
2 9 -3 3
3 4
3 5
3 6
3 7 -3 9
4 0
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 (after ≥1 0 h fast)
x
Me dical hist or y
x
Eli gi bilit y criteria
x
x
P h ysical e xa m c ( hei g ht at Scree n 
o nl y)
x
Re vie w c o ntrace pti o n use -
W O C B P O nl y ( Secti o n 5. 3. 4 )
x 
x
Re vie w dr u g, alc o h ol/t o bacc o use
x
x
C O VI D -1 9 pre -scree ni n gd
x
S A R S -C o V -2 testi n g d
x
Te m perat ure c hec k d
x
C -S S R S a n d P H Q -9
x
x
x
x
x
Re vie w pri or or c o nc o mita nt 
treat me nts 
x 
x
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

A E m o nit ori n g
x 
x
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

I n patie nt sta y at C R U
x
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

Sta n dar dize d meals/s nac ks e
x
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

B o d y wei g ht 
x
Ta ble 3
Ta ble 4
x
x
x
x
Ta ble 3
Ta ble 4
S u pi ne 1 2 -lea d E C G
x
Ta ble 5
Si n gle, s u pi ne vital si g ns 
assess me nt f
x
Mi daz ola m a d mi nistrati o n
O m e praz ole a d mi nistrati o n
O C a d mi nistrati o n
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n g
x 
x 
x 
x 
x 
x 
x
x
x
x 
x 
x
Bl o o d S a m pli n g f or: h
- C he mistr y
x 
x
x
x
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 1 .
C o h ort 1 - O ver all Sc he d ule of Acti vities Scree ni n g t o Peri o d 5
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble 
ma y be f o u n d i n A p pe n di x 9
Scree ni n g
Peri o d 1
(M D Z + 
O M P o nl y)
Peri o d 2
(O C o nl y )
Peri o d 3 
(P F -0 7 0 8 1 5 3 2 o nl y)
Peri o d 4 
( P F- 0 7 0 8 1 5 3 2 
+ M D Z + 
O M P)
Peri o d 5 
(P F -0 7 0 8 1 5 3 2 +
O C )
D a y i n St u d y Peri o d a
-2 8 t o - 2
- 1
1
1
2- 4
5
1
2- 7
8
9- 1 4
1 5
1 6 - 2 1
2 2
2 3 -2 7
2 8
1
1
2- 4
5
D a ys i n St u d y b
-2 8 t o - 2
- 1
1
2
3- 5
6
7
8- 1 3
1 4
1 5- 2 0
2 1
2 2 - 2 7
2 8
2 9 -3 3
3 4
3 5
3 6
3 7 -3 9
4 0
- Calcit o ni n, a m ylase, li pase
x 
x
x
x
- Free T 4, T S H, li pi d pa nel , t otal 
bile aci ds
x 
x
- He mat ol o g y / H b A 1c
x 
x
x
- F S H ,i HI V, H Bs A g, H C V A b, 
H C V R N A, C -pe pti de
x
- Ser u m pre g na nc y test i
x 
x
- M D Z a n d 1 -h y dr o x y -M D Z P K
x j
x j
- O M P & 5 -h y dr o x y -O M P P K
x j
x j
- O C ( L E a n d E E) P K
x k
x k
x k
x k
x k
- P F -0 7 0 8 1 5 3 2 P K
x l
x
- 4-h y dr o x yc h olester ol , 
c h olester ol, 
Uri ne S a m pli n g f or:
- Uri ne dr u g testn
x 
x
- Uri nal ysis (a n d micr osc o p y, as
a p pr o priate)
x
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 1 .
C o h ort 1 - O ver all Sc he d ule of Acti vities Scree ni n g t o Peri o d 5
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble 
ma y be f o u n d i n A p pe n di x 9
Scree ni n g
Peri o d 1
(M D Z + 
O M P o nl y)
Peri o d 2
(O C o nl y )
Peri o d 3 
(P F -0 7 0 8 1 5 3 2 o nl y)
Peri o d 4 
( P F- 0 7 0 8 1 5 3 2 
+ M D Z + 
O M P)
Peri o d 5 
(P F -0 7 0 8 1 5 3 2 +
O C )
D a y i n St u d y Peri o d a
-2 8 t o - 2
- 1
1
1
2- 4
5
1
2- 7
8
9- 1 4
1 5
1 6 - 2 1
2 2
2 3 -2 7
2 8
1
1
2- 4
5
D a ys i n St u d y b
-2 8 t o - 2
- 1
1
2
3- 5
6
7
8- 1 3
1 4
1 5- 2 0
2 1
2 2 - 2 7
2 8
2 9 -3 3
3 4
3 5
3 6
3 7 -3 9
4 0
a.
D a y  relati ve t o start of d osi n g Da y 1 of t hat Peri o d.
b.
D a y  relati ve t o first d ose of i n vesti gati o nal pr o d uct ( mi daz ola m/ o me praz ole) o n Da y 1 of Peri o d 1.
c.
C o m plete p h ysical e xa m at Scre e ni n g; ot her wise, brief e xa m if fi n di n gs d uri n g pre vi o us e xa m or ne w/ o pe n A Es, if a p pr o priate, at i n vesti gat or discreti o n. 
d.
Partici pa nts will be teste d f or S A R S -C O VI D -1 9 i nfecti o n b y P C R.  Test m ust be ne gati ve pri or t o a d missi o n o n Da y -1, Peri o d 1.  A s u bse q ue nt test will be 
d o ne acc or di n g t o l ocal pr oce d ure if partici pa nts de vel o p C O VI D -1 9 li ke s y m pt o ms.  Pri or t o S A R S -C o V -2 test, te m perat ure c hec k a n d C O VI D -1 9 pre -
scree ni n g f or C O VI D-1 9 relate d si g ns a n d s y m pt o ms will be d o ne. See als o Secti o n 8. 3. 5 ( C O VI D-1 9 S pecific Assess me nts). If partici pa nts test p ositi ve f or 
S A R S -C o V -2 i nfecti o n, t he y will be disc har ge d fr o m t he st u d y.
e.
M eals t o be pr o vi de d at a p pr o xi matel y 0 h, 4 h, a n d 1 0 h p ost A M d ose; pl us, s nac ks pr o vi de d acc or di n g t o Secti o n 5. 3. 1 .
f.
I ncl u des B P a n d P R pre d ose.
g.
D osi n g t o occ ur Q D wit h brea kfast as s pecifie d i n Secti o n 5. 3. 1 .
h.
C ollecti o n f o ll o wi n g fasti n g d urati o n s pecifie d i n Secti o n 5. 3. 1 .
i.
F S H f or fe male partici pa nts t o c o nfir m P M stat us o nl y.  Ser u m -h C G f or all W O C B P; test res ult s h o ul d c o nfir m n o pre g na nc y pri or t o d osi n g.
j.
F oll o w i n g mi daz ola m a n d o me praz ole d osi n g o n Da y 1 i n b ot h Peri o ds 1 a n d 4, mi daz ola m, o me praz ole, 1-O H -mi daz ola m, a n d 5 -h y dr o x y o me praz ole P K 
s h o ul d be o btai ne d at a p pr o xi matel y 2 4h p ost mi daz ola m a n d o me praz ole d ose. 
k.
F oll o w i n g O C d osi n g o n Da y 1 i n b ot h Peri o ds 2 a n d 5, L E a n d E E P K s h o ul d be o btai ne d at 2 4 h, 4 8 h, 7 2 h, 9 6 h a n d 1 2 0 h p ost O C d ose o n Da y 1 of t he 
sa me peri o d.
l.
T he P F -0 7 0 8 1 5 3 2 P K sa m ple s h o ul d be o btai ne d at 2 4 h o urs f oll o wi n g t he d ose i n P 3 D 2 8, w hic h is t he sa me as t he 0 h o ur P K sa m ple i n P 4 D 1 .
 
n.
Partici pa nts 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 2 .
C o h ort 1 - O ver all Sc he d ule of Acti vities Peri o d 6 t o E T
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble ma y be 
f o u n d i n A p pe n di x 9
Peri o d 6
(P F -0 7 0 8 1 5 3 2 o nl y)
Peri o d 7
( P F-
0 7 0 8 1 5 3 2 
+ M D Z + 
O M P)
Peri o d 8
(P F -0 7 0 8 1 5 3 2 +
O C )
Peri o d 9 
( M D Z o nl y)
F/ U
Visit
F/ U 
C o nt act 
Tele p h o ne
E T
D a y i n St u d y Peri o d a
1- 7
8- 1 4
1 5 -2 1 2 2 -2 8 2 9 -3 5 3 6 -4 2 4 3 -4 9 5 0 -5 6 5 7 -6 3
1
1
2- 5
6
- 1
1
2
7- 1 0
2 8 -3 5
-
D a ys i n St u d y b
4 1 -
4 7
4 8 -5 4 5 5 -6 1 6 2 -6 8 6 9 -7 5 7 6 -8 2 8 3 -8 9 9 0 -9 6 9 7 - 1 0 3
1 0 4
1 0 5
1 0 6 -
1 0 9
1 1 0
1 2 4
1 2 5
1 2 6
1 3 2-
1 3 5
1 5 3 - 1 6 0
-
I nf or me d c o nse nt an d de m o gra p h y
O ut patie nt visit (after ≥1 0 -h fast)
x
Me dical hist or y
x
Eli gi bilit y criteria
P h ysical e xa m ( hei g ht at Scree n o nl y)
X c
Re vie w c o ntrace pti o n use - W O C B P 
O nl y (Secti o n 5. 3. 4 )
x
x 
x
Re vie w dr u g, alc o h ol/t o bacc o use
x


x
C O VI D -1 9 pre -scree ni n gd
x
S A R S -C o V -2 testi n gd
x
Te m perat ure c hec k d
x
C -S S R S a n d P H Q -9 e
x
x
x
x
x
x
x
Re vie w pri or or c o nc o mita nt treat me nts
 
 
 
 
 
 
 
 
 
 
 

x 
x


x 
x
A E m o nit ori n g
 
 
 
 
 
 
 
 
 
 
 

x 
x


x 
x
I n patie nt sta y at Cli nical Researc h U nit
 
 
 
 
 
 
 
 
 
 
 

x f
x g

x f
Sta n dar dize d meals/s nac ks h
 
 
 
 
 
 
 
 
 
 
 
 

x


B o d y wei g ht i
x
x
x
x
x
x
x
x
x
Ta ble 5
Ta ble 3
Ta ble 4
x
Ta ble 3
x
x
S u pi ne 1 2 -lea d E C G
x
x
x
Si n gle, s u pi ne vital si g ns assess me nt j
x
x
x
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n k
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
O m e praz ole a d mi nistrati o n
Mi daz ola m a d mi nistrati o n
O C a d mi nistrati o n
Bl o o d S a m pli n g f or: l
- C he mistr ym
x 
x
x 
x 
x
x
x 
x
x
- Calcit o ni n, a m ylase, li pase m
x 
x
x 
x 
x
x
x 
x
x
- Free T 4, T S H, li pi d pa nel , t otal bile 
aci ds
x
x
x
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 2.
C o h ort 1 - O ver all Sc he d ule of Acti vities Peri o d 6 t o E T
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble ma y be 
f o u n d i n A p pe n di x 9
Peri o d 6
(P F -0 7 0 8 1 5 3 2 o nl y)
Peri o d 7
( P F-
0 7 0 8 1 5 3 2 
+ M D Z + 
O M P)
Peri o d 8
(P F -0 7 0 8 1 5 3 2 +
O C )
Peri o d 9 
( M D Z o nl y)
F/ U
Visit
F/ U 
C o nt act 
Tele p h o ne
E T
D a y i n St u d y Peri o d a
1- 7
8- 1 4
1 5 -2 1 2 2 -2 8 2 9 -3 5 3 6 -4 2 4 3 -4 9 5 0 -5 6 5 7 -6 3
1
1
2- 5
6
- 1
1
2
7- 1 0
2 8 -3 5
-
D a ys i n St u d y b
4 1 -
4 7
4 8 -5 4 5 5 -6 1 6 2 -6 8 6 9 -7 5 7 6 -8 2 8 3 -8 9 9 0 -9 6 9 7 - 1 0 3
1 0 4
1 0 5
1 0 6 -
1 0 9
1 1 0
1 2 4
1 2 5
1 2 6
1 3 2-
1 3 5
1 5 3 - 1 6 0
-
- He mat ol o g y / H b A 1cn
x
x
x
x 
x
x
- F S H, o HI V, H Bs A g, H C V R N A, 
H C V A b, C -pe pti de 
- Ser u m pre g na nc y test o
x
- O M P a n d 5 -h y dr o x y -O M P P K
x p
x
-
MD Z a n d 1- h y dr o x y -M D Z
P K
x p
x p
x
- O C ( L E/ E E) P K
x q
x q
x q
x
- P F -0 7 0 8 1 5 3 2 P K
x r
x
x
- 4 -β -h y dr o x yc h olester ol , c h olester ol, 
Uri ne S a m pli n g f or:
- Uri ne dr u g test s
- Uri nal ysis (a n d micr osc o p y, as 
a p pr o priate)
x
x
a.
D a y  relati ve t o start of d osi n g Da y 1 of t hat Peri o d.
b.
D a y  relati ve t o first d ose of i n vesti gati o nal pr o d uct ( mi daz ola m/ o me praz ole) o n Da y 1 of Peri o d 1.
c.
Brief e xa m if fi n di n gs d uri n g pre vi o us e xa m or ne w/ o pe n A Es, if a p pr o priate, at i n vesti gat or discreti o n.
d.
Partici pa nts will be teste d f or S A R S -C O VI D -1 9 i nfecti o n b y P C R.  Test m ust be ne gati ve pri or t o rea d missi o n o n Da y -1, Peri o d 9.  A s u bse q ue nt test w ill 
be d o ne acc or di n g t o l ocal pr oce d ure if partici pa nts de vel o p C O VI D -1 9 li ke s y m pt o ms.  Pri or t o S A R S -C o V -2 test, te m perat ure c hec k a n d C O VI D -1 9 
pre -scree ni n g f or C O VI D-1 9 relate d si g ns a n d s y m pt o ms will be d o ne. See als o Secti o n 8. 3. 5 ( C O VI D-1 9 S pecific Assess me nts). If partici pa nts test p ositi ve 
f or S A R S-C o V -2 i nfecti o n, t he y will be disc har ge d fr o m t he st u d y.
e.
C- S S R S a n d P H Q will be a d mi nistere d i n Peri o d 6 o n Da ys 1 4, 2 8, 4 2, 5 6, a n d 6 3.
f.
Disc har ge fr o m C R U.
g.
Rea d mit t o C R U.
h.
Meals t o be pr o vi de d at a p pr o xi matel y 0 h , 4h , a n d 1 0h p ost A M d ose.
i.
B o d y  wei g ht t o be o btai ne d o nce wee kl y i n Peri o d 6 o n Da ys 1, 8, 1 5, 2 2, 2 9, 3 6, 4 3, 5 0, a n d 5 7.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 2 .
C o h ort 1 - O ver all Sc he d ule of Acti vities Peri o d 6 t o E T
Visit I de ntifier
A b bre viati o ns use d i n t his ta ble ma y be 
f o u n d i n A p pe n di x 9
Peri o d 6
(P F -0 7 0 8 1 5 3 2 o nl y)
Peri o d 7
( P F-
0 7 0 8 1 5 3 2 
+ M D Z + 
O M P)
Peri o d 8
(P F -0 7 0 8 1 5 3 2 +
O C )
Peri o d 9 
( M D Z o nl y)
F/ U
Visit
F/ U 
C o nt act 
Tele p h o ne
E T
D a y i n St u d y Peri o d a
1- 7
8- 1 4
1 5 -2 1 2 2 -2 8 2 9 -3 5 3 6 -4 2 4 3 -4 9 5 0 -5 6 5 7 -6 3
1
1
2- 5
6
- 1
1
2
7- 1 0
2 8 -3 5
-
D a ys i n St u d y b
4 1 -
4 7
4 8 -5 4 5 5 -6 1 6 2 -6 8 6 9 -7 5 7 6 -8 2 8 3 -8 9 9 0 -9 6 9 7 - 1 0 3
1 0 4
1 0 5
1 0 6 -
1 0 9
1 1 0
1 2 4
1 2 5
1 2 6
1 3 2-
1 3 5
1 5 3 - 1 6 0
-
j.
I ncl u des B P a n d P R pred ose.
k.
D osi n g t o occ ur Q D wit h brea kfast.  N ote t hat t here is n o P F -0 7 0 8 1 5 3 2 a d mi nistrati o n o n Da y 1 1 0 or a n yti me t hereafter.
l.
C ollecti o n f oll o wi n g fasti n g d urati o n s pecifie d i n. Secti o n 5. 3. 1 . 
m.
T o be o btai ne d o n Da ys 1, 1 5, 2 9, 4 3, a n d 5 7 i n Peri o d 6.
n.
T o be o btai ne d o n Da ys 1 5 a n d 4 3 i n Peri o d 6.
o.
F S H f or fe male partici pa nts t o c o nfir m P M stat us o nl y.  Ser u m -h C G f or all W O C B P; test res ult s h o ul d c o nfir m n o pre g na nc y pri or t o d osi n g.
p.
F oll o w i n g mi daz ola m a n d o me praz ole d osi n g o n Da y 1 i n Peri o d 7, mi daz ola m, o me praz ole, 1-O H -mi daz ola m, a n d 5 -h y dr o x y o me praz ole P K s h o ul d be 
o btai ne d at a p pr o xi matel y 2 4 h p ost mi daz ola m a n d o me praz ole d oses.   F oll o w i n g t he mi daz ola m d ose o n Da y 1 i n Peri o d 9, mi daz ola m a n d 
1- O H -mi daz ola m P K s h o ul d be o btai ne d at a p pr o xi matel y 2 4 h p ost -d ose.
q.
F oll o w i n g O C d osi n g i n Peri o d 5, L E a n d E E P K s h o ul d be o btai ne d at 1 2 0h p ost d ose o n Da y 1 of t he sa me pe ri o d.  F oll o wi n g O C d osi n g i n Peri o d 8, L E 
a n d E E P K s h o ul d be o btai ne d at 2 4 h , 4 8h , 7 2h, 9 6 h , a n d 1 2 0h p ost O C d ose o n Da y 1 of t he sa me peri o d. 
r.
T he P F -0 7 0 8 1 5 3 2 P K sa m ple s h o ul d be o btai ne d at 2 4 h o urs f oll o wi n g t he d ose i n  P 6 D 6 3 , w hic h is t he sa me as t he 0 hr P K sa m ple i n P 7 D 1 .
s.
Partici pa nts 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 3.
Sc he d ule of Acti vities – D a y 1 of Peri o d 1 ( Mi d az ol a m + O me pr az ole O N L Y), Peri o d 4 ( Mi d az ol a m + O me pr az ole 
+ P F -0 7 0 8 1 5 3 2 8 0 m g Q D), Peri o d 7 ( Mi d az ol a m + O me pr az ole + P F- 0 7 0 8 1 5 3 2 2 6 0 m g Q D), a n d Peri o d 9 
( Mi d az ol a m O N L Y)
H o urs Rel ati ve t o D osi n g at 0 h
0
0. 5
1
2
3
4
6
8
1 0
1 4
B o d y Wei g ht
X
Mi daz ola m ad mi nistrati o n
X a
O m e praz ole a d mi nistrati o n ( Peri o ds 1, 4, a n d 7 o nly)
X a
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n ( Peri o ds 4 a n d 7 o nly)
X a
Bl o o d s a m pli n g f or: b
- C he mistr y ( Peri o d 9 o nly)
x
- Calcit o ni n, a m ylase, li pase ( Peri o d 9 o nly)
x
- Free T 4, T S H, li pi d pa nel , t otal bile aci ds ( Peri o d 9 o nly)
x
- He mat ol o g y / H b A 1c ( Peri o d 9 o nly)
x
- Mi daz ola m a n d 1 -h y dr o x y -M D Z P K
x
x
x
x
x
x
x
x
x
x
- O me praz ole a n d 5 -h y dr o x y -O M P P K ( Peri o ds 1, 4, a n d 7 o nly)
x
x
x
x
x
x
x
x
x
x
- 4 -β -h y dr o x yc h olester ol/c h olester ol, 
x
- P F -0 7 0 8 1 5 3 2 P K ( Peri o ds 4 a n d 7 o nly)d
x
Uri ne s a m pli n g f or:
- Uri nal ysis a n d micr osc o p y, as a p pr o priate (Peri o d 1 o nly )
x
a.
D osi n g t o occ ur wit h brea kfast as s pecifie d i n Secti o n 5. 3. 1 . 
b.
C ollecti o n f oll o wi n g fasti n g d urati o n acc or di n g t o d osi n g fre q ue nc y as s pecifie d i n Secti o n 5. 3. 1 .
d.
F or Peri o ds 4 a n d 7 o nl y, P F -0 7 0 8 1 5 3 2 P K sa m ple t o be dra w n at 0 h , a p pr o xi matel y 2 4h after t he P F -0 7 0 8 1 5 3 2 m or ni n g d ose o n t he pre vi o us da y 
( Peri o d 3 Da y 2 8 a n d Peri o d 6 Da y 6 3, res pecti vel y).
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI
C CI
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 4 .
Sc he d ule of Acti vities – D a y 1 of Peri o d 2 ( O C O N L Y), Peri o d 5 ( O C + P F- 0 7 0 8 1 5 3 2 8 0 m g Q D) a n d Peri o d 8 ( O C 
+ P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D)
H o urs Rel ati ve t o D osi n g at 0 h
0
0. 7 5
2
4
8
1 2
O C a d mi nistrati o n
X a
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n ( Peri o ds 5 a n d 8 o nly)
X a
Bl o o d s a m pli n g f or :b
- O C P K
x
x
x
x
x
x
- Mi daz ola m, 1 -h y dr o x y -M D Z, o me praz ole, 5 -h y dr o x y -O M P P K
X c
- P F -0 7 0 8 1 5 3 2 P K ( Peri o ds 5 a n d 8 o nly)
x
a.
D osi n g t o occ ur wit h brea kfast as s pecifie d i n Secti o n 5. 3. 1 . 
b.
C ollecti o n f oll o wi n g fasti n g d urati o n acc or di n g t o d osi n g fre q ue nc y as s pecifie d i n Secti o n 5. 3. 1 .
c.
M i daz ola m, 1-h y dr o x y -M D Z, o me praz ole, a n d 5 -h y dr o x y -O M P P K sa m ples t o be dra w n at 0 h , a p pr o xi matel y 2 4h after t he mi daz ola m/ o me praz ole m or ni n g 
d ose o n t he pre vi o us da y ( Da y 1 of Peri o d 1, Peri o d 4 , a n d Peri o d 7 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 5 .
Sc he d ule of Acti vities – D a y 2 8 of Peri o d 3 a n d D a y 6 3 of Peri o d 6 ( P F- 0 7 0 8 1 5 3 2 o nl y)
H o urs Rel ati ve t o D osi n g at 0 h
0
0. 5
1
2
4
6
8
1 0
1 4
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n 
X a
Bl o o d s a m pli n g f or: b
- P F -0 7 0 8 1 5 3 2 P K
x
x
x
x
x
x
x
x
x
Uri ne sa m pli n g f or:
- Uri nal ysis a n d micr osc o p y, as a p pr o priate 
x
a.
D osi n g t o occ ur wit h brea kfast as s pecifie d i n Secti o n 5. 3. 1 . 
b.
C ollecti o n f oll o wi n g fasti n g d urati o n acc or di n g t o d osi n g fre q ue nc y as s pecifie d i n Secti o n 5. 3. 1 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 6 .
C o h ort 2: Sc he d ule of Acti vities
Visit I de ntifier
A b bre viati o ns use d 
i n t his ta ble ma y be 
f o u n d i n A p pe n di x 9
Scree ni n g Peri o d 1
(M D Z
o nl y)
Peri o d 2 ( O ut -p atie nt : Se ma gl uti de o nl y )
Peri o d 3 
( Se m a gl uti de
+ M D Z)
Peri o d 4 
( MD Z O nl y)
F/ U
Visit
F/ U 
C o nt act 
Tele -
p h o ne
E T
D a y i n St u d y 
Peri o d a
-2 8 t o - 2 - 1
1
1-
7
8-
1 4
1 5 -
2 1
2 2 -
2 8
2 9 -
3 5
3 6 -
4 2
4 3 -
4 9
5 0 -
5 6
5 7 -
6 3
6 4 -
7 0
7 1 -
7 7
7 8 -
8 4
8 5 -
9 1
9 2 -
9 8
9 9 -
1 0 5
1 0 6 -
1 1 2
1 1 3-
1 1 9
1 2 0 -
1 2 6
1 2 7 -
1 3 3
1 3 4 -
1 4 0
1 4 1 -
1 4 6
1 4
7
1
2
- 1
1
2
7- 1 0 2 8 -3 5
Wee k i n St u d y 
Peri o d a
-
-
-
1
2
3
4
5
6
7
8
9
1 0 1 1
1 2 1 3 1 4 1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 1
-
-
-
-
-
-
-
-
D a ys i n St u d y b
-2 8 t o - 2 - 1
1
2-
8
9-
1 5
1 6 -
2 2
2 3 -
2 9
3 0 -
3 6
3 7 -
4 3
4 4 -
5 0
5 1 -
5 7
5 8 -
6 4
6 5 -
7 1
7 2 -
7 8
7 9 -
8 5
8 6 -
9 2
9 3 -
9 9
1 0 0-
1 0 6
1 0 7 -
1 1 3
1 1 4-
1 2 0
1 2 1 -
1 2 7
1 2 8 -
1 3 4
1 3 5 -
1 4 1
1 4 2 -
1 4 7
1 4
8
1 4 9
1 5 0 1 6 4
1 6 5
1 6 6 1 7 2-
1 7 5
1 9 3 -
2 0 0
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 
(after ≥1 0 h fast)
x
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Me dical hist or y
x
x
x
Eli gi bilit y criteria
x 
x
P h ysical e xa m c
( hei g ht at Scree n 
o nl y)
x
x
Re vie w 
c o ntrace pti o n use 
(Secti o n 5. 3. 4 )d
x
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x 
x
x
x 
x 
x
C O VI D - 1 9 
pre -scree ni n ge
x
x
x
S A R S -C o V -2 
testi n ge
x
x
x
x
Te m perat ure c hec k e
x
x
x
x
C- S S R S a n d P H Q - 9f
x 
x
x
x
x
x
x
x
Re vie w dr u g, 
alc o h ol/t o bacc o use g
x 
x 
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x 
x
x
 

Re vie w pri or or 
c o nc o mita nt 
treat me ntsg
x 
x 
x 
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x 
x
 

x
 

x 
x 
x
A E m o nit ori n g g
x 
x 
x 
x
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x 
x
 

x
 

x 
x 
x
I n patie nt sta y at 
C R U
x 
x
x h
x i
x 
x h x i

x h 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 6 .
C o h ort 2: Sc he d ule of Acti vities
Visit I de ntifier
A b bre viati o ns use d 
i n t his ta ble ma y be 
f o u n d i n A p pe n di x 9
Scree ni n g Peri o d 1
(M D Z
o nl y)
Peri o d 2 ( O ut -p atie nt : Se ma gl uti de o nl y )
Peri o d 3 
( Se m a gl uti de
+ M D Z)
Peri o d 4 
( MD Z O nl y)
F/ U
Visit
F/ U 
C o nt act 
Tele -
p h o ne
E T
D a y i n St u d y 
Peri o d a
-2 8 t o - 2 - 1
1
1-
7
8-
1 4
1 5 -
2 1
2 2 -
2 8
2 9 -
3 5
3 6 -
4 2
4 3 -
4 9
5 0 -
5 6
5 7 -
6 3
6 4 -
7 0
7 1 -
7 7
7 8 -
8 4
8 5 -
9 1
9 2 -
9 8
9 9 -
1 0 5
1 0 6 -
1 1 2
1 1 3-
1 1 9
1 2 0 -
1 2 6
1 2 7 -
1 3 3
1 3 4 -
1 4 0
1 4 1 -
1 4 6
1 4
7
1
2
- 1
1
2
7- 1 0 2 8 -3 5
Wee k i n St u d y 
Peri o d a
-
-
-
1
2
3
4
5
6
7
8
9
1 0 1 1
1 2 1 3 1 4 1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 1
-
-
-
-
-
-
-
-
D a ys i n St u d y b
-2 8 t o - 2 - 1
1
2-
8
9-
1 5
1 6 -
2 2
2 3 -
2 9
3 0 -
3 6
3 7 -
4 3
4 4 -
5 0
5 1 -
5 7
5 8 -
6 4
6 5 -
7 1
7 2 -
7 8
7 9 -
8 5
8 6 -
9 2
9 3 -
9 9
1 0 0-
1 0 6
1 0 7 -
1 1 3
1 1 4-
1 2 0
1 2 1 -
1 2 7
1 2 8 -
1 3 4
1 3 5 -
1 4 1
1 4 2 -
1 4 7
1 4
8
1 4 9
1 5 0 1 6 4
1 6 5
1 6 6 1 7 2-
1 7 5
1 9 3 -
2 0 0
Sta n dar dize d 
meals/s nac ks j
x

x
 

 
 

B o d y wei g ht k
x
Ta ble 7
x
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Ta ble 7
x
Ta ble 7
x 
x
S u pi ne 1 2 -lea d E C G
x
x
x
x
Si n gle, s u pi ne vital 
si g ns assess me ntl
x
x
x
x
Se ma gl uti de d osi n g m
x
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Mi daz ola m
d osi n g
Bl o o d S a m pli n g 
f or:n
- C he mistr yo
x
x
x
x
x
x
x
x 
x 
x
- Calcit o ni n, 
a m ylase, li pase o
x
x
x
x
x
x
x
x 
x
-
He mat ol o g y / H b A 1co
x
x
x
x
x
x
x
x 
x 
x
- Free T 4, T S H, li pi d 
pa nel, t otal bile 
aci ds
x
x
x 
x
- F S H p, HI V, 
H Bs A g, H C V A b, 
H C V R N A, C-
pe pti de
x
- Ser u m pre g na nc y 
testp
x 
x
x
x
x 
x
- Uri ne pre g na nc y 
testg
x 
x 
x 
x 
x 
x 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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 a ble 6 .
C o h ort 2: Sc he d ule of Acti vities
Visit I de ntifier
A b bre viati o ns use d 
i n t his ta ble ma y be 
f o u n d i n A p pe n di x 9
Scree ni n g Peri o d 1
(M D Z
o nl y)
Peri o d 2 ( O ut -p atie nt : Se ma gl uti de o nl y )
Peri o d 3 
( Se m a gl uti de
+ M D Z)
Peri o d 4 
( MD Z O nl y)
F/ U
Visit
F/ U 
C o nt act 
Tele -
p h o ne
E T
D a y i n St u d y 
Peri o d a
-2 8 t o - 2 - 1
1
1-
7
8-
1 4
1 5 -
2 1
2 2 -
2 8
2 9 -
3 5
3 6 -
4 2
4 3 -
4 9
5 0 -
5 6
5 7 -
6 3
6 4 -
7 0
7 1 -
7 7
7 8 -
8 4
8 5 -
9 1
9 2 -
9 8
9 9 -
1 0 5
1 0 6 -
1 1 2
1 1 3-
1 1 9
1 2 0 -
1 2 6
1 2 7 -
1 3 3
1 3 4 -
1 4 0
1 4 1 -
1 4 6
1 4
7
1
2
- 1
1
2
7- 1 0 2 8 -3 5
Wee k i n St u d y 
Peri o d a
-
-
-
1
2
3
4
5
6
7
8
9
1 0 1 1
1 2 1 3 1 4 1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 1
-
-
-
-
-
-
-
-
D a ys i n St u d y b
-2 8 t o - 2 - 1
1
2-
8
9-
1 5
1 6 -
2 2
2 3 -
2 9
3 0 -
3 6
3 7 -
4 3
4 4 -
5 0
5 1 -
5 7
5 8 -
6 4
6 5 -
7 1
7 2 -
7 8
7 9 -
8 5
8 6 -
9 2
9 3 -
9 9
1 0 0-
1 0 6
1 0 7 -
1 1 3
1 1 4-
1 2 0
1 2 1 -
1 2 7
1 2 8 -
1 3 4
1 3 5 -
1 4 1
1 4 2 -
1 4 7
1 4
8
1 4 9
1 5 0 1 6 4
1 6 5
1 6 6 1 7 2-
1 7 5
1 9 3 -
2 0 0
- M D Z, 1 -h y dr o x y -
M D Z P K
x q
x q
x q
x
- Se ma gl uti de P K r
x
x
x
x
x
- 4- β-
h y dr o x yc h olester ol , 
c h olester ol, 
Uri ne S a m pli n g 
f or:
- Uri ne dr u g test t
x 
x
x
x
- Uri nal ysis (a n d 
micr osc o p y, as 
a p pr o priate)
x
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 6 .
C o h ort 2: Sc he d ule of Acti vities
Visit I de ntifier
A b bre viati o ns use d 
i n t his ta ble ma y be 
f o u n d i n A p pe n di x 9
Scree ni n g Peri o d 1
(M D Z
o nl y)
Peri o d 2 ( O ut -p atie nt : Se ma gl uti de o nl y )
Peri o d 3 
( Se m a gl uti de
+ M D Z)
Peri o d 4 
( MD Z O nl y)
F/ U
Visit
F/ U 
C o nt act 
Tele -
p h o ne
E T
D a y i n St u d y 
Peri o d a
-2 8 t o - 2 - 1
1
1-
7
8-
1 4
1 5 -
2 1
2 2 -
2 8
2 9 -
3 5
3 6 -
4 2
4 3 -
4 9
5 0 -
5 6
5 7 -
6 3
6 4 -
7 0
7 1 -
7 7
7 8 -
8 4
8 5 -
9 1
9 2 -
9 8
9 9 -
1 0 5
1 0 6 -
1 1 2
1 1 3-
1 1 9
1 2 0 -
1 2 6
1 2 7 -
1 3 3
1 3 4 -
1 4 0
1 4 1 -
1 4 6
1 4
7
1
2
- 1
1
2
7- 1 0 2 8 -3 5
Wee k i n St u d y 
Peri o d a
-
-
-
1
2
3
4
5
6
7
8
9
1 0 1 1
1 2 1 3 1 4 1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 1
-
-
-
-
-
-
-
-
D a ys i n St u d y b
-2 8 t o - 2 - 1
1
2-
8
9-
1 5
1 6 -
2 2
2 3 -
2 9
3 0 -
3 6
3 7 -
4 3
4 4 -
5 0
5 1 -
5 7
5 8 -
6 4
6 5 -
7 1
7 2 -
7 8
7 9 -
8 5
8 6 -
9 2
9 3 -
9 9
1 0 0-
1 0 6
1 0 7 -
1 1 3
1 1 4-
1 2 0
1 2 1 -
1 2 7
1 2 8 -
1 3 4
1 3 5 -
1 4 1
1 4 2 -
1 4 7
1 4
8
1 4 9
1 5 0 1 6 4
1 6 5
1 6 6 1 7 2-
1 7 5
1 9 3 -
2 0 0
a.
D a y  or Wee k relati ve t o start of d osi n g Da y 1 of t hat Peri o d.
b.
D a y  relati ve t o first d ose of mi daz ola m o n Da y 1 of Peri o d 1. 
c.
C o m plete p h ysical e xa m at Scree ni n g, ot her wise, brief e xa m if fi n di n gs d uri n g pre vi o us e xa m or ne w/ o pe n A Es, if a p pr o priate, at i n vesti gat or discreti o n.
d.
F or W O C B P, c o ntrace pti ve use w ill be re viewe d a n d a uri ne pre g na nc y test c o n d ucte d at wee kl y o u t-patie nt visits.  If t he uri ne pre g na nc y test is p ositi ve or 
i nc o ncl usi ve, a ser u m pre g na nc y test will be c o n d ucte d.
e.
Partici pa nts will be teste d f or S A R S -C O VI D -1 9 i nfecti o n b y P C R pri or t o a d missi o n o n Da y -1 i n Peri o ds 1, 3 a n d 4.  A s u bse q ue nt test will be d o ne 
acc or di n g t o l ocal pr oce d ure if partici pa nts de vel o p C O VI D -1 9 li ke s y m pt o ms or si g ns.  Pri or t o S A R S -C o V -2 test, a te m perat ure c hec k a n d C O VI D -1 9 
pre -scree ni n g f or C O VI D-1 9 relate d si g ns a n d s y m pt o ms will be d o ne.  See als o Secti o n 8. 3. 5 ( C O VI D-1 9 S pecific Assess me nts ). If partici pa nts test 
p ositi ve f or S A R S -C o V -2 i nfecti o n, t he y will be disc har ge d fr o m t he st u d y.
f. 
C-S S R S a n d P H Q - 9 will be a d mi nistere d i n Peri o d 2 at t he Wee k 5, 9, 1 3, a n d 1 7 visits.
g.
T o be m o nit ore d at wee kl y o ut-patie nt visits i n Peri o d 2.
h.
Disc har ge fr o m C R U o n Da y 1 i n Peri o d 2 a n d o n Da ys 2 i n Peri o ds 3 a n d 4 .
i.
Rea d mit t o C R U.
j.
Meals t o be pr o vi de d at a p pr o xi matel y 0 h , 4h , a n d 1 0h p ost A M d ose.
k.
B o d y  wei g ht t o be o btai ne d o nce wee kl y i n Peri o d 2 w he n partici pa nts ret ur n t o t he C R U f or t heir wee kl y se ma gl uti de i njecti o n s.
l.
I ncl u des B P a n d P R.
m.
D osi n g t o occ ur w ee kl y, prefera bl y i n t he m or ni n g, as s pecifie d i n Secti o n 5. 3. 1 .
n.
C ollecti o n f oll o wi n g fasti n g d urati o n s pecifie d i n Secti o n 5. 3. 1 .
o.
T o be c ollecte d o n Da ys 2 2 , 50 , 7 8 , a n d 10 6 , a n d 13 4 of Peri o d 2.
p .
F S H f or f e male partici pa nts t o c o nfir m P M stat us o nl y.  Ser u m b- h C G f or all W O C B P; test res ult s h o ul d c o nfir m n o pre g na nc y pri or t o d osi n g.
q.
F oll o w i n g mi daz ola m d osi n g o n Da y 1 i n Peri o ds 1, 3, a n d 4, mi daz ola m a n d 1 -h y dr o x y mi daz ola m P K s h o ul d be o btai ne d at a p pr o xi matel y 2 4 h p ost d ose.
r.
Se m a gl uti de P K sa m ples t o be c ollecte d pri or t o t he first 0. 5, 1. 0, 1. 7, a n d 2. 4 m g se ma gl uti de d ose s at t he i n-patie nt visits at Wee ks 5, 9, 1 3, a n d 1 7, 
res pecti vel y, d uri n g Peri o d 2, a n d pri or t o d osi n g i n Peri o d 3, Da y 1.  
t.
Partici pa nts 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 v esti gat or.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F - 07 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , 0 7 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
T a ble 7.
Sc he d ule of Acti vities – D a y 1 of Peri o d 1 ( Mi d az ol a m O N L Y), Peri o d 3 ( Mi d az ol a m + Se m a gl uti de 2. 4 m g), a n d 
Peri o d 4 ( Mi d az ol a m O N L Y)
H o urs Rel ati ve t o D osi n g at 0 h
0
0. 5
1
2
3
4
6
8
1 0
1 4
B o d y wei g ht
x
Mi daz ola m
a d mi nistrati o n
x a
S e ma gl uti de a d mi nistrati o n ( Peri o d 3 o nly)
x a
Bl o o d s a m pli n g f or: b
- C he mistr y 
x
- Calcit o ni n, a m ylase, li pase 
x
- Free T 4, T S H, li pi d pa nel , t otal bile aci ds
x
- He mat ol o g y / H b A 1c
x
- Mi daz ola m a n d 1 -h y dr o x y -M D Z
P K
x
x
x
x
x
x
x
x
x
x
- S e ma gl uti de P K ( Peri o d 3 o nly )
x
- 4 -β -h y dr o x yc h olester ol/c h olester ol, 
x
a.
D osi n g t o occ ur wit h brea kfast as s pecifie d i n Secti o n 5. 3. 1 . 
b.
C ollecti o n f oll o wi n g fasti n g d urati o n acc or di n g t o d osi n g fre q ue nc y as s pecifie d i n Secti o n 5. 3. 1 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI
C CI
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. I N T R O D U C TI O N
G L P- 1 is a ne ur oe n d ocri ne h or m o ne t hat is pre d o mi na ntl y release d fr o m t he s mall i ntesti ne 
i n res p o nse t o f o o d i nta ke.1  G L P- 1 acti vati o n of t he G L P- 1 R sti m ulates i ns uli n release, 
i n hi bits gl uca g o n secreti o n i n a gl uc ose-de pe n de nt ma n ner, a n d dela y s gastric e m pt yi n g.2 ,3
I n a d diti o n, G LP- 1 has bee n s h o w n t o i ncrease satiet y  an d s u p press f o o d i nta ke. 4
P F -0 7 0 8 1 5 3 2 is a n orall y a d mi nistere d, p ote nt a n d selecti ve G L P -1 R a g o nist i n de vel o p me nt 
as a dj u nct t o diet a n d e xercise, t o i m pr o ve glyce mic c o ntr ol i n T 2 D M, a n d f or c hr o nic wei g ht 
ma na ge me nt i n a p o p ulati o n t hat is o ver wei g ht wit h c o - m or bi dities or w h o ha ve o besity.   
2. 1. St u d y R ati o n ale
T he p ur p ose of t his P hase 1, o pe n- la bel, fi xe d-se q ue nce st u dy is t o e val uate t he effect of 
2 d ose le vels of P F -0 7 0 8 1 5 3 2 a d mi nistere d t o stea d y state o n t he S D p har mac o ki netics of 
mi daz ola m , o me praz ole, a n d a n O C ( L E/ E E) (C o h ort 1 ), a n d t o e val uate t he effect of 
stea d y-state se ma gl uti de o n t he S D p har mac o ki netics of mi daz ola m ( C o h ort 2 ), i n ot her wise 
healt h y , o bese , a d ult fe male partici pa nt s. T he i nte nt of t his st u d y is t o ge nerate safety, 
t olera bilit y, a n d P K data f or f urt her cli nical de vel o p me nt .
2. 2. B ac k gr o u n d 
T 2 D M is esti mate d t o affect m ore t ha n 4 2 4 milli o n pe o ple w orl d wi de ,5 a n d t he pre vale nce of 
T 2 D M wit hi n t he U S is esti mate d t o ra n ge fr o m 1 2 t o 1 4 %.6 Patie nts wit h p o orl y  c o ntr olle d 
T 2 D M ha ve a n i ncrease d ris k of de vel o pi n g c o m plicati o ns ass ociate d wit h b ot h 
micr o vasc ular a n d macr o vasc ular disease, i ncl u di n g ne p hr o pat h y , ne ur o pat h y, reti n o pat hy, 
car di o vasc ular disease a n d str o ke; a n d are at 2 t o 4 ti mes i ncrease d ris k of m ortalit y t ha n 
a d ults w h o d o n ot ha ve dia betes. 7 W hile e xisti n g p har mac ol o gical o pti o ns f or t he tr eat me nt 
of dia betes ma y  pr o vi de satisfact or y glyc e mic c o ntr ol f or s o me patie nts, t here re mai ns a lar ge 
n u m ber of patie nts w h o d o n ot ac hie ve tar get gl yc ate d H b A 1c le vels, s u g gesti n g a nee d f or 
a d diti o nal t hera pe utic o pti o ns.
O besit y  is a c hr o nic disease t hat is ass ociate d wit h seri o us c o -m or bi dities, i ncl u di n g T 2 D M, 
d y sli pi de mia, h yperte nsi o n, at her oscler osis, o bstr ucti ve slee p a p nea a n d certai n ca ncers, 8 a n d 
is als o ass ociate d wit h i ncrease d all-ca use m ortalit y.9  T he gl o bal b ur de n of o besit y  is hi g h 
wit h m ore t ha n 6 0 0 milli o n a d ults esti mate d t o h a ve o besit y w orl d wi de.  I n a d diti o n, t he 
pre vale nce of o besit y  has d o u ble d i n m ore t ha n 7 0 c o u ntries si nce 1 9 8 0 a n d p oses a maj or 
p u blic healt h c halle n ge. 1 0 First li ne treat me nt f or o besit y is lifestyl e i nter ve nti o n i ncl u di n g 
diet, e xercise a n d be ha vi oral t hera p y.  W hile effecti ve i n ma n y patie nts, lifest yle i nter ve nti o n 
is ofte n n ot s ustai na ble, a n d ma n y patie nts re gai n wei g ht after i nitial wei g ht l oss.1 1
P har mac ot hera p y has bee n a p pr o ve d f or t he l o n g -ter m treat me nt of o besit y a n d ca n be a 
usef ul a dj u nct t o lifest yl e i nter ve nti o n t o a u g me nt a n d mai ntai n wei g ht l oss.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
Mar kete d i njecta ble G L P-1 R a g o nists ha ve de m o nstrate d r o b ust gl y ce mic efficac y, wei g ht 
l oss, a n d car di o vasc ular safety, wit h m ore t ha n o ne mar kete d a ge nt de m o nstrati n g 
car di o vasc ular be nefit. 1 2  Base d o n t he cli nical hist or y  of i njecta ble G L P- 1 R a g o nists, a n 
oral, s mall m olec ule G L P- 1 R a g o nist is e x pecte d t o i m pr o ve gl uc ose c o ntr ol a n d re d uce 
H b A 1c le vels i n patie nts wit h T 2 D M, w hile decreasi n g a p petite a n d b o d y wei g ht , res ulti n g i n 
wei g ht l oss i n patie nts wit h T 2 D M a n d o besit y , w hile a v oi di n g t he s u bc uta ne o us i njecti o n 
re q uire d by c urre ntl y a vaila ble pe pti dic G LP- 1 R a g o nists .
2. 2. 1. N o ncli nic al P h ar m ac ol o g y
Refer t o t he I B f or details o n t he n o ncli nical p har mac ol o g y of P F -0 7 0 8 1 5 3 2 .
2. 2. 2. N o ncli nic al P h ar m ac o ki netics a n d Met a b olis m
I n rats a n d m o n ke ys f oll o wi n g si n gle I V a n d oral d osi n g, P F-0 7 0 8 1 5 3 2 e x hi bite d l o w C L p
(1 3 a n d 0. 6 m L / mi n/ k g, res pecti vely) , wit h l o w t o m o derate stea d y-state Vss ( 0. 7 6 a n d 
0. 2 1 L/ k g, res pecti vel y), lea di n g t o a t ½ of 1. 6 h o urs i n rats a n d 8. 8 h o urs i n m o n ke y s.
Re nal 
e xcreti o n was ne gli gi ble i n b ot h s pecies, a n d b iliar y e xcreti o n was mi ni mal i n rats. T he 
s yste mic e x p os ure (assesse d b y A U C a n d Cma x ) of PF- 0 7 0 8 1 5 3 2 f oll o wi n g oral re peat d ose 
pi v otal t o xicit y  st u dies i n rats, ra b bits a n d m o n ke ys ge nerally i ncrease d i n a d ose -
pr o p orti o nal ma n ner. 
In vitr o, P F - 0 7 0 8 1 5 3 2 was a s u bstrate f or t he he patic u pta ke tra ns p orter, O A T P 1 B 3, b ut n ot 
f or O A T P 1 B 1. C oa d mi n istrati o n of a n O A T P i n hi bit or wit h P F-0 7 0 8 1 5 3 2 i n m o n ke y s 
res ulte d i n a n ota ble i ncrease i n t he plas ma A U C e x p os ure of P F-0 7 0 8 1 5 3 2 a n d 
c orres p o n di n g decrease i n C L , s u g gesti n g a p ote ntial r ole f or O A T P tra ns p ort i n t he 
u pta ke -li mite d C L i n m o n ke ys.
Preli m i nar y e val uati o n of t he i n vitr o meta b olis m of P F-0 7 0 8 1 5 3 2 s h o we d si milar meta b olic 
pr ofiles acr oss s pecies wit h n o e vi de nce of h u ma n s pecific meta b olites. P F -0 7 0 8 1 5 3 2 was 
e xte nsi vel y meta b olize d via o xi dati ve C Y P a n d c o nj u gati o n U G T pat h wa ys.
C Y P -me diate d 
meta b olis m acc o u nte d f or 6 7 % of t he he patic meta b olis m, wit h C Y P 3 A ( 3 1 %) bei n g t he 
pre d o mi na nt C Y P is of or m. T he c o ntri b uti o n of n o n - C Y P meta b olis m was esti mate d t o be 
3 3 % of t he he patic meta b olis m, w hic h was d ue t o gl uc ur o ni dati o n ( 2 4 %) a n d c he mical 
h y dr ol ys is ( 9 %). U G T 1 A 1 a n d U G T 1 A 3 were pri maril y  res p o nsi ble f or t he gl uc ur o ni dati o n 
of P F -0 7 0 8 1 5 3 2, wit h p ossi ble mi n or c o ntri b uti o ns b y  t he n o n-he patic U G T is of or ms, 
U G T 1 A 7 a n d U G T 1 A 8.
Usi n g a p h ys i ol o gically rele va nt static mec ha nistic m o del, P F - 0 70 8 1 5 3 2 was s h o w n t o ha ve 
t he p ote ntial t o be a re versi ble i n hi bitor of U G T 1 A 1 a n d a m o derate ti me-de pe n de nt i n hi bit or 
of C Y P 2 C 1 9 acti vit y  at a cli nical d ose of 2 6 0 m g .  
After e val uati n g t he a bilit y  t o i n d uce C Y P e nz ymes, P F - 0 7 0 8 1 5 3 2 elicite d a wea k i n d ucti o n
of C Y P 3 A 4 a n d C Y P 2 B 6 m R N A i n a si n gle l ot of he pat oc y tes, a n d di d n ot elicit a > 2 -f ol d
i n d ucti o n of C Y P 1 A 2 m R N A or e nz yme acti vit y . Alt h o u g h P F -0 7 0 8 1 5 3 2 de m o nstrate d
> 2 -f ol d C Y P 3 A 4 a n d C Y P 2 B 6 m R N A i n d ucti o n, t he res p o nses lac ke d c o nce ntrati o n
de pe n de n c y, t heref ore, P F- 0 7 0 8 1 5 3 2 was n ot a n i n vitr o i n d ucer of C Y Ps 3 A 4, 2 B 6, or 1 A 2.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
Refer t o t he I B f or m ore details o n t he n o ncli nical P K a n d meta b olis m of P F - 0 7 0 8 1 5 3 2.
2. 2. 3. N o ncli nic al S afet y
Refer t o t he I B f or m ore details o n t he n o ncli nical safet y of P F - 0 7 0 8 1 5 3 2.
2. 2. 4. Cli nic al O ver vie w a n d S afet y
As of iss ua nce of t his pr ot oc ol, t w o P hase 1 st u dies e val uati n g P F -0 7 0 8 1 5 3 2 ha ve bee n
c o m plete d. I n t otal, 8 8 partici pa nts ha ve bee n ra n d o mize d i ncl u di n g 2 2 healt h y a d ult
partici pa nts, 5 1 a d ult partici pa nts wit h T 2 D M, a n d 1 5 a d ult partici pa nts wit h o besit y . A t otal
of 7 4 u ni q ue partici pa nts ha ve bee n e x p ose d t o at least 1 d ose of P F- 0 7 0 8 1 5 3 2. T he s afet y
pr ofile of P F - 0 7 0 8 1 5 3 2 was assesse d i n t hese 2 c o m plete d cli nical st u dies a n d, t o date,
a d mi nistrati o n of P F - 0 7 0 8 1 5 3 2 at si n gle d oses u p t o 2 0 0 m g a n d m ulti ple d oses u p t o 
1 8 0 m g Q D has bee n c o nsi dere d safe, wit h t he maj orit y  of t he T E A Es bei n g mil d i n 
i nte nsit y.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
O ne P hase 1 st u d y, C 3 9 9 1 0 0 3, rece ntl y c o ncl u de d. T his i n patie nt st u d y  e nr olle d partici pa nts
wit h T 2 D M i na de q uately c o ntr olle d o n metf or mi n, a n d partici pa nts wit h o besit y , t o recei ve
P F -0 7 0 8 1 5 3 2 or place b o Q D f or 4 2 da ys. T he starti n g d ose f or t he first c o h ort of t his st u d y
was 2 0 m g Q D of P F - 0 7 0 8 1 5 3 2, wit h s u bse q ue nt d ose le vels deter mi ne d base d o n e mer gi n g
data; t he ma xi m u m d ose a d mi nistere d was 8 0 m g Q D. 
W hile fi nal cli nical data fr o m t his
st u d y are n ot yet a vaila ble, as of iss ua nce of t h is pr ot oc ol, t here ha ve bee n n o deat hs, S A Es
or A Es of se vere i nte nsit y  re p orte d.
Refer t o t he I B f or m ore details o n t he cli nical safet y  of P F- 0 7 0 8 1 5 3 2.
2. 2. 4. 1. Cli nic al P h ar m ac o ki netics
T he cli nical P K of P F -0 7 0 8 1 5 3 2 i n a d ult partici pa nts ha ve bee n e val uate d t o date i n 
2 c o m plete d st u dies ( C 3 9 9 1 0 0 1 a n d C 3 9 9 1 0 0 2).
T he res ults of t hese c o m plete d st u dies are 
s u m marize d i n t he P F-0 7 0 8 1 5 3 2 I B.  
I n St u dy C 3 9 9 1 0 0 1 f oll o wi n g a d mi nistrati o n of si n gle oral d oses of P F-0 7 0 8 1 5 3 2 u n der 
faste d c o n diti o ns t o healt h y  partici pa nts, P F -0 7 0 8 1 5 3 2 was a bs or be d relati vel y  ra pi dl y wit h a 
me dia n T ma x of 1. 0 0 t o 4. 0 2 h o urs (i n di vi d ual T ma x val ues ra n ge d bet wee n 0. 5 a n d 6 h o urs).
Base d o n t he i n di vi d ual plas ma c o nce ntrati o n -ti me pr ofiles, t he a bs or pti o n p hase e x hi bite d 
m ulti ple pea ks, e s peciall y at t he hi g her d ose le vels. Mea n t
½ ra n ge d fr o m 1 8. 0 3 t o 
2 0. 9 0 h o urs acr oss all d oses. Plas ma C ma x i ncrease d less t ha n pr o p orti o nall y acr oss t he e ntire 
i n vesti gate d d ose ra n ge (fr o m 1 0 m g t o 2 0 0 m g ), w hile plas ma A U Ci nf i ncrease d less t ha n 
pr o p or ti o nall y fr o m 1 0 m g t o 3 0 m g  a n d a p pr o xi matel y pr o p orti o nally fr o m 3 0 m g t o 
2 0 0 m g. I nter-partici pa nt varia bilit y  f or P F-0 7 0 8 1 5 3 2 e x p os ure was l o w t o m o derate a n d 
ra n ge d fr o m 9 % t o 3 6 % C V f or Cma x a n d 1 5 % t o 4 4 % C V f or A U Ci nf acr oss all d oses.
O verall, t he res ults i n dicate t hat P F -0 7 0 8 1 5 3 2 ma y  be a d mi nistere d wit h o ut re gar d t o f o o d.  
I n St u dy C 3 9 9 1 0 0 2 f oll o wi n g a d mi nistrati o n of P F - 0 7 0 8 1 5 3 2, Cma x was o bser ve d at 1 t o 
2 h o urs o n Da y  1, a n d 2 t o 8 h o urs f oll o wi n g t he last d ose o n Da y 2 8 or 4 2. Acr oss all d ose 
gr o u ps, t he mea n t ½ ra n ge d fr o m 2 0. 7 0 t o 2 6. 5 0 h o urs. P F -0 7 0 8 1 5 3 2 e x p os ure ge nerall y 
i ncrease d i n a n a p pr o xi matel y d ose pr o p orti o nal ma n ner acr oss t he d ose ra n ge st u die d, a n d 
acc u m ulati o n of less t ha n 2. 1- f ol d was o bser ve d. Uri nar y  rec o ver y of u nc han ge d 
P F -0 7 0 8 1 5 3 2 was l o w, wit h less t ha n 0. 2 % of t he d ose rec o vere d i n t he 2 4 -h o ur d osi n g 
i nter val f oll o wi n g last d ose a d mi nistrati o n. I nter-partici pa nt varia bilit y f or P F - 0 7 0 8 1 5 3 2 
e x p os ure ra n ge d fr o m 1 7 % t o 5 1 % C V f or Cma x a n d 1 5 % t o 6 2 % C V f or A U C ta u acr oss all 
d oses .  N o s u bsta ntial differe nces i n P F -0 7 0 8 1 5 3 2 e x p os ure ( C ma x a n d A U C ta u) were 
o bser ve d bet wee n partici pa nts wit h T 2 D M a n d o besit y  eit her after si n gle d ose ( Da y 1, 
1 0 m g) or m ulti ple d ose ( Da y  2 8, 1 2 0 m g a n d Da y 4 2, 1 8 0 m g) a d mi nistrati o n.
Refer t o t he I B f or m ore details o n t he cli nical P K of P F - 0 7 0 8 1 5 3 2.
2. 3. Be nefit/ Ris k Assess me nt
P F - 0 7 0 8 1 5 3 2 is n ot e x pecte d t o pr o vi de a ny l o n g-ter m cli nical be nefit t o t he healt h y a d ult  
fe male partici pa nts i n t his st u d y.  T his st u d y is desi g ne d pri maril y t o ge nerate safet y , 
t olera bilit y, a n d P K data f or f urt her cli nical de vel o p me nt.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es of P F -0 7 0 8 1 5 3 2 ma 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 t he site s o urce d mi daz ola m ( mi daz ola m h y dr oc hl ori de s yr u p), o me praz ole, 
a n d O C ( 0. 1 5 m g L E / 0. 0 3 m g E E ) pr o d ucts are t he c orres p o n di n g U S PI s.1 3 ,1 4 ,1 5 T he S R S D 
f or t he se ma gl uti de (prefille d, si n gle -use pe ns, d oses 0. 2 5 t o 2. 4 m g ) pr o d uct(s) are t he
c orres p o n di n g U S PI s.1 6 ,1 7
2. 3. 1. Ris k Assess me nt
P ote nti al Ris k of 
Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or Ris k
Miti g ati o n Str ate g y
St u d y I nter ve nti o n P F -0 7 0 8 1 5 3 2 a n d se m a gl uti de
T h yr oi d C -cell t u m ors
T he p ote ntial ris ks are base d o n pr o d uct 
la beli n g f or i njecta ble G L P-1 R a g o nists 
(ie, lira gl uti de, d ula gl uti de, se ma gl uti de, 
a n d e xe nati de) d ue t o d ose -de pe n de nt 
a n d treat me nt d urati o n -de pe n de nt 
t h yr oi d C-cell t u m ors i n n o ncli nical 
st u dies i n rats a n d mice at cli nicall y 
rele va nt e x p os ures. 
Of n ote, si milar t u m ors were n ot see n i n 
r o de nt st u dies wit h P F-0 7 0 8 1 5 3 2 , li kel y 
as P F-0 7 0 8 1 5 3 2 d oes n ot sti m ulate 
r o de nt G L P-1 rece pt ors .
P ote ntial partici pa nts wit h a 
pers o nal or fa mil y hist or y of 
me d ullar y t h yr oi d carci n o ma or 
M ulti ple E n d ocri ne Ne o plasia 
s y n dr o me t y pe 2 are e xcl u de d fr o m 
t he cli nical de vel o p me nt pr o gra m.  
T h yr oi d f u ncti o n tests are i ncl u de d 
i n t he cli nical trial pr ot oc ols t o 
m o nit or partici pa nts’ t h yr oi d 
f u ncti o n.  
Pa ncreatitis
T he p ote ntial ris ks are base d o n pr o d uct 
la beli n g f or i njecta ble G L P-1 R a g o nists 
(ie, lira gl uti de, e xe nati de, se ma gl uti de
a n d d ula gl uti de). 
O ne S A E of o bstr ucti ve p a ncreatitis has 
bee n o bser ve d i n t he P F -0 7 0 8 1 5 3 2
cli nical trial pr o gra m, w hic h was 
c o nsi dere d t o be treat me nt -related b y t he 
i n vesti gat or, b ut u nrelate d b y t he 
S p o ns or .
Per e xcl usi o n criteria, p ote ntial 
partici pa nts wit h ac ute pa ncreatitis 
or a hist or y of c hr o nic pa ncreatitis 
are n ot eli gi ble f or st u d y e ntr y.  
Ser u m a m ylase a n d li pase are 
m o nit ore d d uri n g cli nical st u dies.  
H y p o gl yce mia
Cli nical trials wit h i njecta ble G L P -1 R 
a g o nists ha ve n ot de m o nstrate d a n 
i ncrease d ris k f or h y p o gl yce mia.  B ut
w he n a d mi nistere d i n c o m bi nati o n wit h 
a nti -dia betic a ge nts t hat are k n o w n t o 
ha ve a n i ncrease d ris k of h y p o gl yce mia 
(s uc h as i ns uli n or s ulf o n yl ureas), a n 
i ncrease d ris k f or h y p o gl yce mia was 
o bser ve d.  
Partici pa nts wit h o besit y w h o d o n ot 
ha ve c o -e xisti n g T 2 D M w o ul d n ot be 
ta ki n g a nti-dia betic a ge nts a n d t heref ore 
w o ul d n ot be e x pecte d t o ha ve a n 
i ncrease d ris k f or h y p o gl yce mia.  
A l o w o verall fre q ue nc y of ge nerall y 
mil d h y p o gl yce mia has bee n re p orte d i n 
A nti -dia betic me dicati o ns ar e 
pr o hi bite d i n t his st u d y, a n d bl o o d 
gl uc ose is m o nit ore d as a part of t he 
la b assess me nts d uri n g t he st u d y.  
Partici pa nts are i nf or me d a b o ut t he 
si g ns a n d s y m pt o ms of 
h y p o gl yce mia a n d are m o nit ore d 
f or t hese s y m pt o ms d uri n g t he 
st u d y.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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 he P F-0 7 0 8 1 5 3 2 cli nical de vel o p me nt 
pr o gra m t o date.
I mpair m e nt i n re nal 
f u ncti o n
P ote ntial ris ks are base d o n pr o d uct 
la beli n g f or i njecta ble G L P-1 R a g o nists, 
a n d pre d o mi na ntl y occ ur i n patie nts wit h 
si g nifica nt na usea, v o miti n g, a n d 
de h y drati o n.
I n t he cli nical trial pr o gra m o nl y o ne 
mil d a d verse e ve nt ( Preferre d Ter m 
Bl o o d creati ni ne i ncrease d) has bee n 
o bser ve d.
Per e xcl usi o n criteria, p ote ntial 
partici pa nts wit h si g nifica nt re nal 
i mpair m e nt are n ot eli gi ble f or 
st u d y e ntr y.  
Re nal f u ncti o n is m o nit ore d b y la b 
assess me nts of ser u m B U N , 
creati ni ne a n d e G F R.
H y drati o n will be e nc o ura ge d, a n d 
re d uce d fl ui d i nta ke a n d e vi de nce 
of de h y drati o n , if detecte d , wi ll be
treate d b y cl ose cli nical f oll o w- u p.
Gastr oi ntesti nal a d verse 
reacti o ns
T he p ote ntial ris ks are base d o n pr o d uct 
la beli n g f or i njecta ble G L P-1 R a g o nists 
(ie, lira gl uti de, e xe nati de, se ma gl uti de
a n d d ula gl uti de).
G astr oi ntesti nal A Es , t he maj orit y of 
w hic h were mil d i n se verit y, ha ve bee n 
o bser ve d i n t he cli nical pr o gra m wit h 
P F -0 7 0 8 1 5 3 2 .  I n n o ncli nical st u dies 
wit h P F -0 7 0 8 1 5 3 2 , gastr oi ntesti nal 
a d verse effects were o bser ve d i n rats a n d 
m o n ke ys.
Partici pa nts are m o nit ore d d uri n g 
t he cli nical st u dies t o pre ve nt 
p ote ntial se q uelae of a n y se vere 
gastr oi ntesti nal reacti o ns, 
e g, de h y drati o n.  
H y drati o n will be e nc o ura ge d a n d 
co nc o mita nt me dicati o n f or na usea 
is per mitte d i n t he st u d y.  
P F -0 7 0 8 1 5 3 2 will be titrate d fr o m a
2 0 m g Q D d ose t o 8 0 m g Q D o ver 
2 8 da ys , t he n fr o m 10 0 m g Q D t o 
2 6 0 m g Q D o ver 6 3 da ys i n t he 
st u d y i n a n atte m pt t o mi ni mize 
gastr oi ntesti nal a d verse reacti o ns. 
Dia betic reti n o pat h y 
c o m plicati o ns
T he p ote ntial ris k is base d o n t he pr o d uct 
la beli n g f or t he i njecta ble G L P-1 R 
a g o nist se ma gl uti de a n d d ula gl uti de i n 
patie nts wit h T 2 D M. 
T here are n o n o ncli nical or cli nical data 
i n v ol vi n g P F -0 7 0 8 1 5 3 2 t o s u ggest a n 
i ncrease d ris k of dia betic reti n o pat h y 
c o m plicati o ns.
P ote ntial partici pa nts wit h dia betes 
mellit us are e xcl u de d fr o m t his 
cli nical st u d y.
S uici dal i deati o n a n d 
be ha vi or
T he p ote ntial ris k is base d o n t he pr o d uct 
la beli n g f or t he i njecta ble G L P-1 R
a g o nists lira gl uti de a n d se ma gl uti de f or 
o besit y base d o n l o n g -ter m st u dies.
S uici dal i deati o n has n ot bee n o bser ve d 
i n t he P F-0 7 0 8 1 5 3 2 cli nical st u dies t o 
date.
S uici dal i deati o n a n d be ha vi or, 
al o n g wit h s y m pt o ms of de pressi o n, 
will be m o nit ore d at s pecifie d
i nter vals d uri n g t he st u d y usi n g t he 
C- S S R S a n d P H Q -9 q uesti o n naires, 
wit h referral t o a M H P
f or f urt her 
e val uati o n if nee de d.
C ha n ges i n heart rate 
P ote ntial ris k is base d o n t he pr o d uct 
la beli n g f or t he i njecta ble G L P-1 R 
a g o nists, lira gl uti de a n d se ma gl uti de, f or 
T 2 D M a n d o besit y .
M o dest i ncreases i n H R ha ve bee n n ote d 
i n t he earl y cli nical st u dies wit h 
P F -0 7 0 8 1 5 3 2 , wit h m ost val ues 
r e mai ni n g wit hi n t he n or mal ra n ge .
H R is m o nit ore d d uri n g t he cli nical 
st u d y.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
Decli nes i n b o d y wei g ht
Decrease d a p petite a n d b o d y wei g ht l oss 
ha ve bee n re p orte d f or mar kete d 
G L P -1 R a g o nists, a n d decli nes i n b o d y 
wei g ht ha ve bee n n ote d at hi g her d oses 
of P F -0 7 0 8 1 5 3 2 .
Wei g ht is c ollecte d at m ulti ple 
ti me p oi nts a n d will be m o nit ore d 
t hr o u g h o ut t he trial.
Ac ute gall bla d der disease
P ote ntial ris k is base d o n t he pr o d uct 
la beli n g f or t he i njecta ble G L P-1 R 
a g o nists, se ma gl uti de a n d lira gl uti de , f or 
T 2 D M a n d o besit y .
Ac ute gall bla d der disease has n ot bee n 
o bser ve d i n t he P F -0 7 0 8 1 5 3 2 cli nical 
trial pr o gra m t o date.
Partici pa nts wit h s y m pt o matic 
gall bla d der disease are e xcl u de d 
fr o m t his cli nical st u d y. 
Partici pa nts are m o nit ore d f or A E s
a n d la b orat or y tests t hat ma y 
s u g gest de vel o p me nt of ac ute 
gall bla d der disease.
St u d y I nter ve nti o n: O m e pr az ole
Hea dac he, a b d o mi nal 
pai n, na usea, diarr hea, 
v o m iti n g, a n d flat ule nce
Ris k base d o n pr o d uct la beli n g.
A s i n gle oral d ose of 2 0 m g is 
a d mi nistere d i n t his st u d y a n d p oses 
mi ni mal ris k.  Partici pa nts will be 
m o nit ore d i n a n i n patie nt cli nical 
researc h u nit.
St u d y I nter ve nti o n: Mi d az ol a m
Res pirat or y de pressi o n
Ris k base d o n pr o d uct la beli n g.
A si n gle oral d ose of 2 m g is 
a d mi nistere d i n t he st u d y a n d p oses 
mi ni mal ris k.  Partici pa nts will be 
m o nit ore d i n a n i n patie nt cli nical 
researc h u nit.
St u d y I nter ve nti o n : O C (L E/ E E )
I ncrease d B P
Ris k base d o n pr o d uct la beli n g.
A si n gle d ose of 0. 1 5 m g L E / 0. 0 3 
m g E E is a d mi nistere d i n t his st u d y 
a n d p oses mi ni mal ris k.  
Partici pa nts will be m o nit ore d i n a n 
i n patie nt cli nical researc h u nit.
Ot her
Ris k of C O VI D -1 9 
e x p os ure d uri n g st u d y
D uri n g t he pa n de mic, st u d 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 d uri n g st u d y partici pati o n. T his 
c o ul d lea d t o i ncrease d healt h ris k f or 
t his partici pa nt a n d ot hers i n t he st u d y.
Partici pa nts u n der g o C O VI D -1 9 
s pecific assess me nts pri or t o 
a d missi o n t o st u d y site a n d 
acc or di n g t o t he S o A .
2. 3. 2. Be nefit Assess me nt
W hile P F - 0 7 0 8 1 5 3 2 is n ot e x pecte d t o pr o vi de a n y si g nifica nt l o n g-ter m cli nical be nefit t o 
t he healt h y o bese partici pa nts i n t his relati vel y s h ort-ter m st u d y, p ote ntial be nefits ma y 
i ncl u de wei g ht l oss, recei vi n g me dical e val uati o ns/ assess me nts ass ociate d wit h cli nical 
st u d y visits (e g, p h y sical e xa mi nati o ns, E C Gs, la bs), a n d c o ntri b uti n g t o t he pr ocess of 
de vel o pi n g a p ote ntial ne w t hera p y f o r T 2 D M a n d o besit y.
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es of P F -0 7 0 8 1 5 3 2 ma y  be f o u n d i n t he I B, w hic h is S R S D, f or t his st u d y.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
2. 3. 3. O ver all Be nefit /Ris k C o ncl usi o n
T he S p o ns or c o nsi ders t hat t he a vaila ble i nf or mati o n fr o m t he n o ncli nical st u dies a n d t he 
cli nical st u dies c o m plete d t o date wit h P F -0 7 0 8 1 5 3 2 c o m prises a be nefit -ris k pr ofile t hat 
s u p p orts t he c o nti n ue d cli nical i n vesti gati o n of t he c o m p o u n d as a p ote ntial o pti o n f or t he 
treat me nt of T 2 DM a n d o besit y .  C o nsi deri n g t he meas ures t o mi ni mize ris k t o st u d y
partici pa nts , t he p ote ntial ris ks i de ntifie d i n ass ociati o n wit h P F - 0 7 0 8 1 5 3 2 are j ustifie d b y 
t he a ntici pate d be nefits t hat ma y be aff or de d t o partici pa nts wit h o besit y .
3. O B J E C TI V E S A N D E N D P OI N T S
O bjecti ves
E n d p oi nts
C o h ort 1
Pri m ar y: 
Pri m ar y: 

T o e val uate t he effects of P F - 07 0 8 1 5 3 2 o n t he
p har mac o ki netics of mi daz ola m, o me praz ole, 
a n d a n oral c o ntrace pti ve ( O C; le v o n or gestrel 
[ L E]/et hi n yl estra di ol [ E E]) i n o bese a d ult 
fe male partici pa nt s.

Mi daz ola m plas ma p har m ac o ki netic para meters: 
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o ds 1, 4 a n d 7.

O m e praz ole plas ma p har mac o ki netic 
para meters: A U C i nf (if data per mit* ot her wise 
A U C last) i n Peri o ds 1, 4 a n d 7.

L E plas ma p har mac o ki netic para meters: A U C i nf
(if data per mit* o t her wise A U Clast) i n Peri o ds 2 , 
5 a n d 8 .

E E plas ma p har mac o ki netic para meters: A U C i nf
(if data per mit* o t her wise A U Clast) i n i n Peri o ds 
2 , 5 a n d 8 .
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 
P F - 07 0 8 1 5 3 2 a d mi nistere d se paratel y a n d i n 
c o m bi nati o n wit h mi daz ola m, o me praz ole, a n d 
a n O C ( L E/ E E) i n o bese a d ult fe male 
partici pa nts .

Assess me nt of T E A Es , cli nical la b orat or y 
a b n or malities, a n d b o d y wei g ht .

Assess me nt of me ntal healt h as deter mi ne d b y 
C- S S R S a n d P H Q - 9. 

T o e val uate t he p har mac o ki netics of S D 
mi daz ola m f oll o wi n g t he disc o nti n uati o n of 
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n i n o bese a d ult 
fe male partici pa nts .  

Mi daz ola m plas ma p har m ac o ki netic para meters: 
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o d 9.

T o e val uate t he effects of P F - 07 0 8 1 5 3 2 o n 
a d diti o nal p har mac o ki netic para meters of 
mi daz ola m , o me praz ole, a n d a n O C ( L E/ E E) i n 
o bese a d ult fe male partici pa nts.

A d diti o nal plas ma p har mac o ki netic para meters 
f or mi daz ola m a n d o me praz ole ( Peri o ds 1, 4 a n d 
7) , a n d L E a n d E E ( Peri o ds 2, 5 a n d 8): Cm a x a n d 
T ma x ; a n d C L/ F, Vz/ F, t½ , as data per mit.

T o e val uate t he effects of P F - 07 0 8 1 5 3 2 o n t he 
meta b olite/ pare nt rati os f or mi daz ola m a n d 
o m e praz ole i n o bese a d ult fe male partici pa nts.

M R A U C
i nf ( 1-h y dr o x y mi daz ola m 
A U C i nf/ mi daz ola m A U Ci nf).

M R A U C
i nf ( 5-h y dr o x y o m e praz ole
A U C i nf/o m e praz ole A U C i nf).
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

T o e val uate t he M D p har mac o ki netics of 
P F - 07 0 8 1 5 3 2 i n o bese a d ult fe male partici pa nts.

P F - 07 0 8 1 5 3 2 plas ma p har mac o ki netic 
para meters at Da ys 3 4 a n d 1 0 3: A U C 2 4, Cma x , 
T ma x .
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 0 8 1 5 3 2 o n t he 
p har mac o ki netics of 1 -h y dr o x y mi daz ola m i n 
o bese a d ult fe male partici pa nts.

1- h y dr o x y mi daz ola m plas ma p har mac o ki netic 
para meters: A U C last, Cma x , Tma x; a n d A U Ci nf a n d 
t½ as data per mit i n Peri o ds 1 , 4 a n d 7 .  

Meta b olite/ pare nt 
( 1-h y dr o x y mi daz ola m/ mi daz ola m) rati os f or 
A U C i nf (as data per mit), A U Clast, a n d Cma x will 
als o be calc ulate d.

T o e val uate t he effects of P F - 07 0 8 1 5 3 2 o n t he 
p har mac o ki netics of 5- h y dr o x y o me praz ole i n 
o bese a d ult fe male partici pa nts. 

5- h y dr o x y o me praz ole plas ma p har mac o ki netic 
para meters: A U C last, Cma x , Tma x; a n d A U Ci nf a n d 
t½ as data per mit i n Peri o ds 1, 4 a n d 7.  

Meta b olite/ pare nt ( 5- h y dr o x y o me praz ole
/o m e praz ole ) rati os f or A U Ci nf (as data per mit), 
A U C last, a n d Cma x will als o be calc ulate d. 

T o e val uate t he effects of P F - 07 0 8 1 5 3 2 o n 
bi o mar kers of C Y P 3 A i n d ucti o n. [ O pti o nal] .

M or ni n g pre d ose 
4 β -h y dr o x yc h olester ol/c h olester ol plas ma rati o 
o n Da y 1 i n Peri o ds 1, 4, a n d 7.  
C o h ort 2
Pri m ar y: 
Pri m ar y: 

T o e val uate t he effects of se ma gl uti de 
(s u bc uta ne o us se ma gl uti de) o n t he S D P K of 
mi daz ola m i n o bese a d ult fe male partici pa nts.

Mi daz ola m plas ma p har mac o ki netic para m eters: 
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o ds 1 a n d 3 .
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 
se ma gl uti de a d mi nistere d se paratel y a n d i n 
c o m bi nati o n wit h mi daz ola m i n o bese a d ult 
fe male partici pa nts.

Assess me nt of T E A Es , cli nical la b orat or y 
a b n or malities, a n d b o d y wei g ht .

Assess me nt of me ntal healt h as deter mi ne d b y 
C- S S R S a n d P H Q -9.

T o e val uate t he p har mac o ki netics of S D 
mi daz ola m f oll o wi n g t he disc o nti n uati o n of 
se ma gl uti de a d mi nistrati o n i n o bese a d ult 
fe male partici pa nts .

Mi daz ola m plas ma p har m ac o ki netic para meters: 
A U C i nf (if data per mit* ot her wise A U C last) i n 
Peri o d 4.

T o e val uate t he effects of se ma gl uti de o n 
a d diti o nal p har mac o ki netic para meters of 
mi daz ola m i n o bese a d ult fe male partici pa nts .

A d diti o nal plas m a p har m ac o ki netic para meters 
f or mi daz ola m (i n Peri o ds 1 a n d 3): Cma x , Tma x ,
a n d C L/ F, Vz/ F, t ½ as data per mit.

T o e val uate t he effects of se ma gl uti de o n t he 
meta b olite/ pare nt rati o f or mi daz ola m i n o bese 
a d ult fe male partici pa nts.

M R A U C
i nf ( 1-h y dr o x y mi daz ola m 
A U C i nf/ mi daz ola m A U Ci nf).
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 se ma gl uti de o n t he 
p har mac o ki netics of 1 -h y dr o x y mi daz ola m i n 
o bese a d ult fe male partici pa nts.

1- h y dr o x y mi daz ola m plas ma p har mac o ki netic 
para meters: A U C last, Cma x , Tma x; a n d A U Ci nf a n d 
t½ as data per mit i n Peri o ds 1 a n d 3 .  

Meta b olite/ pare nt 
( 1-h y dr o x y mi daz ola m/ mi daz ola m) rati os f or 
A U C i nf (as data per mit), A U Clast, a n d Cma x will 
als o be calc ulate d.

T o e val uate t he effects of se ma gl uti de o n 
bi o mar kers of C Y P 3 A i n d ucti o n. [ O pti o nal]

M or ni n g pre d ose 
4 β -h y dr o x yc h olester ol/c h olester ol plas ma rati o 
o n Da y 1 i n Peri o ds 1 a n d 3.  
* S h o ul d it be dee me d t hat t o o fe w A U C i nf esti mates (e g, less t ha n 1 2 f or a si n gle treat me nt) are o btai ne d 
fr o m t he e val ua ble partici pa nts, A U Clast ma y be selecte d as t he pri mar y e n d p oi nt f or C S R re p orti n g.  T his 
will be c o nsi dere d f or t he mi daz ola m , 1-h y dr o x y mi daz ola m, o me praz ole, 5 -h y dr o x y o me praz ole, L E, a n d E E
o bjecti ves se paratel y.
4. S T U D Y D E SI G N
4. 1. O ver all Desi g n
T his st u d y will be c o n d ucte d wit h 2 c o h orts .  C o h ort 1 will e val uate t he effect of 
2 stea d y-state d ose le vels of P F -0 7 0 8 1 5 3 2 o n t he S D p har mac o ki netics of mi daz ola m , 
o me praz ole, a n d a n O C ( L E/ E E). C o h ort 2 will e val uate t he effect of stea d y-state
se ma gl uti de o n t he S D p har mac o ki netics of mi daz ola m .  Titrati o n will be i m ple me nte d i n 
b ot h c o h orts i n or der t o e nha nce gastr oi ntesti nal t olera bilit y  si milarly t o t he a p pr oac h 
i m ple me nte d f or mar kete d G LP -1 R a g o nists.  Partici pa nts will partici pate i n eit her C o h ort 1 
or C o h ort 2 ( n ot b ot h), a n d C o h ort 1 a n d C o h ort 2 are preferre d t o be c o n d ucte d i n parallel, if 
p ossi ble.
All partici pa nts will pr o vi de i nf or me d c o nse nt a n d u n der g o Scree ni n g e val uati o ns t o 
deter mi ne t heir eli gi bilit y.  Scree ni n g will occ ur wit hi n 2 8 da y s of t he first d ose of st u d y 
i nter ve nti o n o n Da y  1 of Peri o d 1 f or b ot h C o h orts 1 a n d 2 .  Partici pa nts w h o disc o nti n ue 
fr o m t he st u d y bef ore c o m pleti n g all assess me nts 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.
P F -0 7 0 8 1 5 3 2 will be pr o vi de d as ta blets f or oral a d m i nistrati o n.  P F - 0 7 0 8 1 5 3 2 m ust be 
a d mi nistere d wit hi n a p pr o xi matel y 1 0 mi n utes of c o m pleti o n of t he m or ni n g meal.  
P F - 0 7 0 8 1 5 3 2 will be a d mi nistere d first a n d mi daz ola m a n d o me praz ole or t he O C will be 
a d mi nistere d wit hi n 5 mi n utes of P F -0 7 0 8 1 5 3 2 d uri n g t he D DI assess me nt peri o ds.
S e ma gl uti de will be pr o vi de d as pre- fille d, si n gle- d ose pe ns f or s u bc uta ne o us i njecti o n.  
Dr u g a d mi nistrati o n will f oll o w t he i nstr ucti o ns pr o vi de d i n t he a p pr o ve d Hi g hli g hts of 
Prescri bi n g I nf or mati o n as o utli ne d i n t he U S PI . 1 6 ,1 7  Se ma gl uti de m ust be a d mi nis tere d o nce 
wee kl y, prefera bl y i n t he m or ni n g, wit h o ut re gar d t o ti mi n g of t he brea kfast meal d uri n g 
o ut patie nt visits t o t he C R U f or d ose a d mi nistrati o n.  D uri n g t he D DI assess me nt i n patie nt 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
visit ( Peri o d 3), se ma gl uti de a n d mi daz ola m m ust be a d mi nistere d wit hi n a p pr o xi matel y  
1 0 mi n utes of c o m pleti o n of t he m or ni n g meal.  S e ma gl uti de will be a d mi nistere d first , a n d 
mi daz ola m will be a d mi nistere d wit hi n 5 mi n utes of se ma gl uti de.
4. 1. 1. C o h ort 1
C o h ort 1 is a n o pe n-la bel, 9 -peri o d, fi xe d-se q ue nce desi g n t o e val uate t he effect of 
2 stea d y-state d ose le vels of P F - 0 7 0 8 1 5 3 2 o n t he S D p har mac o ki netics of mi daz ola m a n d 
o me praz ole, a d mi nistere d si m ulta ne o usl y , a n d a n O C ( LE/ E E) i n ot her wise healt h y  o bese 
a d ult fe male partici pa nts wit h a B MI ≥3 0 k g/ m 2.  
A p pr o xi m atel y 1 6 partici pa nts will be e nr olle d i n C o h ort 1 .  
T he t otal d urati o n of partici pati o n fr o m t he Scree ni n g Visit t o t he F/U tele p h o ne c o ntact will 
be a p pr o xi matel y  2 7 wee ks; ie, 1 8 8 da y s, of w hic h 1 1 2 da y s will be i n-patie nt as f oll o ws: 
Peri o d 1 ( S D mi daz ola m a n d o me praz ole): 1 da y ; Peri o d 2 ( S D O C): 5 da ys; Peri o d 3 
(P F -0 7 0 8 1 5 3 2 titrate d t o 8 0 m g Q D) : 28 d a y s; Peri o d 4 ( 8 0 m g P F -0 7 0 8 1 5 3 2 + S D 
mi daz ola m a n d o me praz ole ): 1 da y; Peri o d 5 ( 8 0 m g P F -0 7 0 8 1 5 3 2 + S D O C ): 5 da y s; 
Peri o d 6 ( P F -0 7 0 8 1 5 3 2 titrate d t o 2 6 0 m g Q D) : 6 3 da y s; Peri o d 7 ( 2 6 0 m g P F - 0 7 0 8 1 5 3 2
+ S D mi daz ola m a n d o me praz ole ): 1 da y; Peri o d 8 ( 2 6 0 m g  P F -0 7 0 8 1 5 3 2 + S D O C ): 
6 da y s; Peri o d 9 (S D mi daz ola m o nl y ): 2 da ys.
T he F /U o ut- patie nt visit will occ ur 7 -1 0 da y s fr o m t he last d ose of st u d y i nter ve nti o n a n d a 
tele p h o ne F/ U c o ntact will occ ur 2 8 - 3 5 d a y s fr o m t he last d ose of st u d y i nter ve nti o n. 
4. 1. 2. C o h ort 2
C o h ort 2 is a n o pe n-la bel, 4 -peri o d, fi xe d-se q ue nce desi g n t o e val uate t he effect of 
stea d y-state se ma gl uti de o n t he S D P K of mi daz ola m i n o bese a d ult fe male partici pa nts wit h 
a B MI ≥3 0 k g/ m 2.
A p pr o xi matel y  1 6 partici pa nts will be e nr olle d i n C o h ort 2 .
T he t otal d urati o n of partici pati o n fr o m t he Scree ni n g Visit t o t he F/U tele p h o ne c o ntact will 
be a p pr o xi matel y  3 3 wee ks; i .e., 2 2 8 da y s, of w hic h 6 d a y s will be i n-patie nt as f oll o ws:
Peri o d 1 ( S D mi daz ola m): 1 da y ; Peri o d 2 (fi nal da y of se ma gl uti de treat me nt ( 2. 4 m g): 
1 da y ; Peri o d 3 ( 2. 4 m g se ma gl uti de o nce wee kl y + S D mi daz ola m) 2 da y s; Peri o d 4 
(S D mi daz ola m): 2 da y s.  Partici pa nts will als o be re q uire d t o ret ur n t o t he cli nic d uri n g 
o ut- patie nt visits , prefera bl y i n t he m or ni n g, t o recei ve t heir o nce wee kl y se ma gl uti de
i njecti o ns ( Peri o d 2).
T he o ut- patie nt F/ U visit will occ ur 7 -1 0 da y s fr o m t he last d ose of st u d y  i nter ve nti o n a n d a
tele p h o ne F/ U c o ntact will occ ur 2 8- 3 5 d a y s fr o m t he last d ose of st u d y i nter ve nti o n.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
4. 2. Scie ntific R ati o n ale f or St u d y Desi g n
T he p ur p ose of t his st u d y is t o c haracterize t he effect of P F - 0 7 0 8 1 5 3 2, a d mi nistere d at 
2 stea d y-state d ose le vels, o n t he P K of si n gle d oses of mi daz ola m ( 2 m g oral ) a n d
o me praz ole ( 2 0 m g oral ), a d mi nistere d si m ulta ne o usl y, a n d a n O C (L E 0. 1 5 m g /E E 0. 0 3 m g
oral ) i n ot her wise healt h y  o bese a d ult fe male partici pa nts i n C o h ort 1.  Mi daz ola m a n d 
o me praz ole will be a d mi nistere d si m ulta ne o usl y  t o all o w f or e val uati o n of 2 D DIs wit hi n o ne 
st u d y peri o d. Si m ulta ne o us a d mi nistrati o n of t hese 2 pr o be s u bstrates has bee n vali date d; 
ie, n o D DI a n d s h o w n t o be safe. 1 8 ,1 9 T he i m pact of stea dy- state s u bc uta ne o us se ma gl uti de
o n t he P K of si n gle-d ose mi daz ola m ( 2 m g oral ) will als o be assesse d i n ot her wise healt h y  
o bese a d ult fe male partici pa nts i n C o h ort 2. Ot her wise healt h y o bese a d ult fe males will be 
e nr olle d i n t his st u d y as t he y are o ne of t he tar get p o p ulati o ns f or P F-0 7 0 8 1 5 3 2.  
I n C o h ort 1, titrati o n of P F - 0 7 0 8 1 5 3 2 d oses will be utilize d t o ac hie ve 8 0 m g Q D a n d 
2 6 0 m g Q D .  T he D DI effect will be i nitiall y assesse d at t he P F -0 7 0 8 1 5 3 2 8 0 m g Q D d ose as 
t his is e x pecte d t o be a p ote ntial t hera pe utic d ose f or treat me nt of T 2 D M.  T he D DI effect 
will als o be assesse d at t he 2 6 0 m g Q D d ose as t h is is t he ma xi m u m d ose i n t he P hase 2 
st u d y f or b ot h T 2 D M a n d o besit y . P F -0 7 0 8 1 5 3 2 will be a d mi nistere d f or a d urati o n of 
7 da y s at eac h of t he 8 0 m g Q D a n d 2 6 0 m g Q D d osi n g re gi me ns pri or t o a d mi nistrati o n of 
t he S D mi daz ola m a n d o me praz ole, or O C treat me nts (Ta ble 8 ) t o e ns ure t hat cli nicall y 
rele va nt stea dy -state P F - 0 7 0 8 1 5 3 2 e x p os ures are ac hie ve d .
T itrati o n of se ma gl uti de d oses will be utilize d t o ac hie ve 2. 4 m g i n C o h ort 2, w hic h is t he 
ma xi m u m a p pr o ve d d ose f or wei g ht l oss .  T he D DI effect will be assesse d at t he 2. 4 m g d ose
f oll o wi n g wee kl y titrati o ns f or 4 wee ks eac h at t he 0. 2 5 m g, 0. 5 m g, 1. 0 m g, 1. 7 m g, a n d 
2. 4 m g d oses as i nstr ucte d i n t he U S PI .1 6 ,1 7 S e ma gl uti de will be a d mi nistere d f or o ne 
a d diti o nal wee k ( half-life a p pr o ximatel y  1 wee k) at t he 2. 4 m g d ose t o e ns ure t hat cli nicall y 
rele va nt stea dy- state e x p os ures are ac hie ve d pri or t o a d mi nistrati o n of S D mi daz ola m i n 
Peri o d 3 ( Ta ble 9 ).
A d diti o nall y , partici pa nts i n b ot h c o h orts will be disc har ge d fr o m t he cli nical site f or 2 wee ks 
f oll o wi n g t he fi nal P K sa m ple c ollecti o n of O C ( L E/ E E) i n Peri o d 8, Da y 2 ( C o h ort 1) or 
mi da z ola m i n Peri o d 3, Da y 2 ( C o h ort 2), a n d disc o nti n ue all P F-0 7 0 8 1 5 3 2 or se ma gl uti de 
d osi n g at t hat ti me.  F oll o wi n g t he 2 -wee k o ut- patie nt d urati o n, partici pa nts will ret ur n t o t he 
cli nical site f or a fi nal mi daz ola m assess me nt, wit h o ut eit her P F -0 7 0 8 1 5 3 2 or se ma gl uti de 
c oa d mi nistrati o n. 
4. 2. 1. C o h ort 1 
4. 2. 1. 1. Mi d az ol a m A d mi nistr ati o n
Preli mi nar y  4--h y dr o x yc h olester ol/c h olester ol (bi o mar ker f or C Y P 3 A acti vit y) res ults fr o m 
S t u d y C 39 9 1 0 0 3 wit h P F -0 7 0 8 1 5 3 2 s u g gest a p o te ntial pert ur bati o n of C Y P 3 A acti vit y.  
T heref ore , mi da z ola m will be use d as a “se nsiti ve s u bstrate” of C Y P 3 A i n t his st u d y  t o 
assess t he i m pact of P F -0 7 0 8 1 5 3 2 a d mi nistrati o n o n b ot h mi daz ola m a n d its 1- h y dr o x y  
meta b olite , w hic h is f or me d via C Y P 3 A. T o f urt her i n vesti gate t he mec ha nis m of t his 
i nteracti o n, plas ma 4--h y d r o xyc h olester ol/c h olester ol a n d  
 sa m ples, use d as e n d o ge n o us 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
pr o bes f or C Y P 3 A i n d ucti o n, will be c ollecte d i n t his st u d y .  If t here are n o o bser ve d c ha n ges 
i n mi daz ola m e x p os ures d uri n g c o nc o mita nt a d mi nistrati o n of eit her P F -0 7 0 8 1 5 3 2 or 
se ma gl uti de, neit her p las ma 4--h y dr o x yc h olester ol/c h olester ol n or
 sa m ples will be 
a nal yz e d. 
F oll o wi n g assess me nt of t he D DI bet wee n P F -0 7 0 8 1 5 3 2 a n d mi daz ola m , the a d mi nistrati o n 
of P F - 0 7 0 8 1 5 3 2 will be disc o nti n ue d f or a 2-wee k peri o d , after w hic h a n a d diti o nal si n gle 
d ose of mi daz ola m will be a d mi nistere d t o assess t he i m pact of disc o nti n uati o n of 
P F -0 7 0 8 1 5 3 2 a d mi nistrati o n o n mi daz ola m p har mac o ki netics. If i n d ucti o n of C Y P 3 A 
acti vit y is o bser ve d (as deter mi ne d b y mi daz ola m P K d uri n g c oa d mi nistrati o n of 
P F - 0 7 0 8 1 5 3 2), a 2 -wee k peri o d of ti me wit h o ut P F - 0 7 0 8 1 5 3 2 d osi n g is e x pecte d t o be 
s ufficie nt t o all o w C Y P 3 A acti vit y  t o ret ur n t o baseli ne.2 0
Mi daz ola m is ra pi dl y  a bs or be d after oral a d mi nistrati o n a n d is s u bject t o s u bsta ntial i ntesti nal 
a n d he patic first -pass meta b olis m. F o o d effect has n ot bee n teste d usi n g mi daz ola m H Cl 
s yr u p; b ut w he n a 1 5 m g oral ta blet of mi daz ola m was a d m i nistere d wit h f o o d t o a d ults, t he 
a bs or pti o n a n d dis p ositi o n of mi daz ola m was n ot affecte d. T he e xte nt of plas ma pr otei n 
bi n di n g of mi daz ola m is m o deratel y hi g h a n d c o nce ntrati o n i n de pe n de nt. I n a d ults a n d 
pe diatric patie nts ol der t ha n 1 y ear, mi daz ola m is a p pr o xi matel y 9 7 % b o u n d t o plas ma 
pr otei n, pri nci pall y al b u mi n. I n healt h y v ol u nteers, 1- h y dr o x y m i daz ola m is b o u n d t o t he 
e xte nt of 8 9 %. 1 3
Mi daz ola m is pri maril y  meta b olize d i n t he li ver a n d g ut b y h u ma n C Y P 3 A 4 t o its 
p har mac ol o gic acti ve meta b olite, 1- h y dr o x y mi daz ola m, f oll o we d b y  gl uc ur o ni dati o n of t he 
1- h y dr o x y l meta b olite whic h is prese nt i n u nc o nj u gate d a n d c o nj u gate d f or ms i n h u ma n 
plas ma. T he 1- h y dr o x y m i daz ola m gl uc ur o ni de is t he n e xcrete d i n uri ne.  Mi daz ola m is als o 
meta b olize d t o 2 ot her mi n or meta b olites: 4- h y dr o x y  meta b olite (a b o ut 3 % of t he d ose) a n d 
1, 4- di h y dr o x y m eta b olite (a b o ut 1 % of t he d ose) are e xcrete d i n s mall a m o u nts i n t he uri ne 
as c o nj u gates. 1 3
Si x si n gle-d ose p har mac o ki netic st u dies i n v ol vi n g heal t h y a d ults yiel de d p har mac o ki netic 
para meters f or mi daz ola m i n t he f oll o wi n g ra n ges: v ol u me of distri b uti o n, 1 t o 3. 1 L/ k g; 
eli mi nati o n half -life, 1. 8 t o 6. 4 h o urs ( mea n a p pr o xi matel y 3 h o urs); a n d t otal cleara nce, 
0. 2 5 t o 0. 5 4 L/ hr/ k g. I n a st u d y c o m parin g n or mal ( n = 2 0) a n d o bese patie nts ( n = 2 0) t he 
mea n half -life was greater i n t he o bese gr o u p ( 5. 9 h o urs vs. 2. 3 h o urs), w hic h was attri b ute d 
t o a n i ncrease of a p pr o xi matel y 5 0 % i n t he v ol u me of distri b uti o n c orrecte d f or t otal b o d y 
wei g ht. 1 3 ,2 1 ,2 2 Plas ma sa m ples f or mi daz ola m a n d 1-h y dr o x y -mi daz ola m will be c ollecte d i n 
t his st u d y f or u p t o 2 4 h o urs after d osi n g, w hic h is e x pecte d t o be a de q uate e ve n wit h t he 
l o n ger eli mi nati o n half -life i n o bese s u bjects. 
Si n gle oral d oses of mi daz ola m ra n gi n g fr o m 2 t o 7. 5 m g ha ve bee n safel y a d mi nistere d t o 
healt h y  partici pa nts i n pre vi o us i nter nal Pfizer dr u g-dr u g i nteracti o n st u dies ( A 5 3 5 1 0 1 2, 
B 3 2 9 1 0 2 3, B 7 4 5 1 0 2 2, C 1 0 6 1 0 1 6) .  
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
4. 2. 1. 2. O me pr az ole A d mi nistr ati o n
A d ults wit h T 2 D M a n d o besit y ofte n re q uire treat me nt f or G E R D , t heref ore, it is li kel y t hat 
P F - 0 7 0 8 1 5 3 2 will be c oa d mi nistere d wit h o me praz ole i n cli nical practice.  A d diti o nall y , 
P F - 0 7 0 8 1 5 3 2 was s h o w n t o be a m o derate i n vitr o ti me- de pe n de nt i n hi bit or of C Y P 2 C 1 9 at a 
cli nical d ose of 2 6 0 m g. T heref ore, o me praz ole will be use d as a “se nsiti ve s u bstrate” of 
C Y P 2 C 1 9 i n t his st u d y t o assess t he i m pact of P F- 0 7 0 8 1 5 3 2 a d mi nistrati o n o n t he P K of 
b ot h o me praz ole a n d its 5- h y dr o x y  meta b olite, w hic h is f or me d via C YP 2 C 1 9 . 
O me praz ole a bs or pt i o n is ra pi d, wit h pea k plas ma le vels occ urri n g wit hi n 0. 5 t o 3. 5 h o urs. 
Pea k plas ma c o nce ntrati o ns of o me praz ole a n d A U C are a p pr o xi matel y  d ose pr o p orti o nal u p 
t o 4 0 m g. A bs ol ute bi oa vaila bilit y  is a b o ut 3 0- 4 0 % at d oses of 2 0-4 0 m g, d ue i n lar ge part t o 
pres ys te mic meta b olis m. I n healt h y s u bjects t he plas ma half-life is 0. 5 t o 1 h o ur, a n d t he 
t otal b o d y cleara nce is 5 0 0-6 0 0 m L / mi n. Pr otei n bi n di n g is a p pr o xi matel y  9 5 %.1 4
O me praz ole is e xte nsi vel y  meta b olize d b y C Y P 4 5 0 , wit h C Y P 2 C 1 9 bei n g t he pri mar y 
pat h wa y res ulti n g i n f or mati o n of 5-h y dr o x y o me praz ole .  C Y P 3 A 4 is a mi n or meta b olic 
pat h wa y res ulti n g i n t he f or mati o n of t he o me praz ole s ul p h o ne . A p pr o xi matel y  2-3 % of 
Ca ucasia n , 2 % of Africa n A merica ns , a n d 11 – 2 3 % of Asia n p o p ulati o ns are C Y P 2 C 1 9 p o or 
meta b olizers ( P M), t heref ore, C Y P 3 A is t he pre d o mi na nt meta b olic r o ute i n t hese 
i n di vi d uals.2 3 I n p har mac o ki netic st u dies of si n gle 2 0 m g o me praz ole d oses, a n i ncrease i n 
A U C of a p pr o xi matel y  4-f ol d was n ote d i n Asia n s u bjects c o m pare d wit h Ca ucasia ns. 1 4
F oll o wi n g si n gle -d ose oral a d mi nistrati o n of a b uffere d s ol uti o n of o me praz ole, little if a n y  
u nc ha n ge d dr u g was e xcrete d i n uri ne. M ost of
t he d ose (a b o ut 7 7 %) was eli mi nate d i n uri ne 
as at least 6 meta b olites . T w o were i de ntifie d as h y dr o x y o m e praz ole a n d t he c orres p o n di n g 
car b o x yl ic aci d. T he re mai n der of t he d ose was rec o vera ble i n feces. T his i m plies a 
si g nifica nt biliar y e xcreti o n of t he meta b olites of o me praz ole. T hree meta b olites ha ve bee n 
i de ntifie d i n plas ma; t he s ulfi de a n d s ulf o ne deri vati ves of o me praz ole, a n d 
h y dr o x y o m e praz ole. T hese meta b olites ha ve ver y  little or n o a ntisecretor y  acti vit y.1 4
Beca use t he eli mi nati o n half-li ves of o me praz ole a n d its 5 -h y dr o x y  meta b olit e ra n ge fr o m 
0. 5 t o 1 h o ur f oll o wi n g si n gle d oses ,2 4 plas ma will be c ollecte d f or 2 4 h o urs after d osi n g f or 
deter mi nati o n of P K para meters .  
O me praz ole is ge nerall y well-t olerate d by healt h y i n di vi d uals f oll o wi n g si n gle, oral, d oses of
1 0 m g 2 5 a n d 2 0 m g .2 6 I n a d diti o n, t he safet y of o me praz ole f or t he treat me nt of gastric ulcer
disease has bee n esta blis he d at d oses as hi g h as 4 0 m g o nce dail y f or 4 t o 8 wee ks .  A d verse 
reacti o ns ha ve us ually bee n mil d a n d tra nsie n t.  F or m ore c o m plete i nf or mati o n, please refer
t o t he U SPI f or o me praz ole .1 4
4. 2. 1. 3. Or al C o ntr ace pti ve A d mi nistr ati o n
T he estr o ge ns a n d pr o gesti ns c o ntai ne d i n oral c o ntrace pti ves are s u bstrates f or C Y P 3 A 4/ 5
a n d ot her i n d uci ble meta b olic e nz y mes.  Beca use t he a ntici pate d tar get p o p ulati o n f or 
P F -0 7 0 8 1 5 3 2 will i ncl u de fe males of c hil d beari n g p ote ntial w h o ma y  use a n O C, a t hir d 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
o bjecti ve of t his st u d y  is t o esti mate t he effect of a d mi nistrati o n of 8 0 m g Q D a n d 26 0 m g
Q D P F -0 7 0 8 1 5 3 2 o n t he S D P K of a n O C c o ntai ni n g 0. 1 5 m g  LE a n d 0. 0 3 m g E E.  
T he mea n ( S D) half -li ves of L E a n d E E are 2 9. 8 ( 8. 3) a n d 1 5. 4 ( 3. 2) h o urs ,1 5 res pecti vel y; 
t heref ore, plas ma will be c ollecte d f or u p t o 1 2 0 h o urs after d osi n g f or deter mi nati o n of P K 
para meters.  T he effect of f o o d o n t he rate a n d t he e xte nt of L E a n d E E a bs or pti o n f oll o wi n g 
oral a d mi nistrati o n of L E a n d E E ta blets has n ot bee n e val uate d. 1 5
Oral c o ntrace pti ve use has bee n s h o w n t o ca use a n i ncrease i n B P t hat i s re versi ble w he n t he
oral c o ntrace ptive is disc o nti n ue d.  T he use of a n O C a ge nt c o ntai ni n g 3 0 µ g E E a n d 1 5 0 u g 
L E was ass ociate d wit h a s mall i ncrease i n b ot h syst olic a n d diast olic B P .2 7 Alt h o u g h t he 
ris k of i ncrease d B P is e x pecte d t o be s mall f oll o wi n g S D a d mi nistrati o n of t he O C i n t his 
st u d y, B P effects res ulti n g fr o m c oa d mi nistrati o n of P F-0 7 0 8 1 5 3 2 wit h t he O C will be 
m o nit ore d as descri be d bel o w .  F or m ore c o m plete i nf or mati o n, please refer t o t he U S PI f or 
t he O C.1 5
4. 2. 1. 4. P F -0 7 0 8 1 5 3 2 A d mi nistr ati o n
A de nse P K pr ofile will be c ollecte d f or P F- 0 7 0 8 1 5 3 2 after reac hi n g t he tar get d oses of 
P F - 0 7 0 8 1 5 3 2 f or eac h D DI assess me nt; ie, 80 m g i n Peri o d 3, Da y  2 8 a n d 26 0 m g i n 
Peri o d 6, Da y 6 3 , t o better u n dersta n d t he P K i n o bese fe male partici pa nts.
P F - 0 7 0 8 1 5 3 2 will be a d mi nistere d via 7- d a y ( 1-wee k) titrati o n i ncre me nts u p t o t he 
8 0 m g Q D re gi me n i n Peri o d 3 pri or t o t he a d mi nistrati o n of mi daz ola m a n d o me praz ole i n 
Peri o d 4, a n d t he O C i n Peri o d 5.  L i ke wise, P F -0 7 0 8 1 5 3 2 will be a d mi nistere d via 1- wee k
titrati o n i ncre me nts u p t o t he 26 0 m g Q D re gi me n i n Peri o d 6 pri or t o a d mi nistrati o n of 
mi daz ola m a n d o me praz ole i n Peri o d 7, a n d t he O C i n Peri o d 8 ( Secti o n 6. 1. 1 , Ta ble 8 ). T he 
P F - 0 7 0 8 1 5 3 2 d osi n g re gi me n is desi g ne d t o ac hie ve a n d mai ntai n P K stea d y -state f or 
a p pr o xi matel y 7 d a y s pri or t o assess me nt of t he i nteracti o n wit h t he 3 s u bstrates.   T his will 
e na ble a n y i nteracti o n t hat is prese nt t o be assesse d u n der c o n diti o ns t hat are e x pecte d t o 
i ncrease t he p ote ntial f or ma xi mal C Y P 3 A i n d ucti o n a n d/ or C Y P 2 C 1 9 i n hi biti o n at t he 
P F - 0 7 0 8 1 5 3 2 d oses bei n g st u die d s h o uld t his occ ur . Base d o n e mer gi n g data fr o m ot her 
cli nical st u dies t hat ma y bec o me a vaila ble d uri n g t he c o n d uct of t his st u d y, t he titrati o n rate, 
i ncre me ntal i ncreases i n d ose, a n d/ or t he P F -0 7 0 8 1 5 3 2 d oses at w hic h t he mi daz ola m a n d
o me praz ole, or O C P K i nteracti o ns are e val uate d ma y be a dj uste d.  
D osi n g of P F - 0 7 0 8 1 5 3 2 ( wit h or wit h o ut mi daz ola m , o me praz ole, or t he O C ) is pla n ne d t o 
occ ur i n t he fe d state wit h a sta n dar d brea kfast, as t his is t he a ntici pate d m o de of 
a d mi nistrati o n i n cli nical use.  
4. 2. 2. C o h o rt 2
4. 2. 2. 1. Se m a gl uti de a n d Mi d az ol a m A d mi nistr ati o n
O besit y  has l o n g bee n ass ociate d wit h a state of c hr o nic, l o w -le vel i nfla m mati o n,2 8 ,2 9 ,3 0 wit h
adi p ose tiss ue bei n g o ne of t he mai n s o urces of i nfla m mat or y  me diat ors, i ncl u di n g I L- 6.3 1
A di p ose tiss ue has bee n descri be d as a n acti ve e n d ocri ne or ga n t hat secretes si g nali n g 
m olec ules i n v ol ve d i n t he re g ulati o n of i ns uli n se nsiti vit y , f o o d i nta ke a n d i nfla m mati o n. T o 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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 hat e n d, decreases i n I L - 6 a n d ot her i nfla m mat or y me diat ors ha ve bee n o bser ve d f oll o wi n g 
wei g ht l oss i n o bese i n di vi d uals, w het her it be a res ult of cal oric deficit or bariatric 
s ur ger y.3 2 ,3 3 ,3 4
I nfla m mat or y c yt o ki nes, s uc h as I L- 6, I L- 1, a n d T N Fα ha ve bee n s h o w n t o i n hi bit C Y P 3 A 
acti vit y. I n dee d, I L-6 is t he tar get f or dr u gs s uc h as saril u ma b a n d t ociliz u ma b use d t o treat
R A, a disease k n o w n t o ha ve a hi g h i nfla m mat or y b ur de n.  T he e x p os ure of si m vastati n, a 
C Y P 3 A s u bstrate, was decrease d by 4 5 % a n d 5 7 % , res pecti vely, d uri n g a d mi nistrati o n of 
saril u ma b or t ociliz u ma b. T his o bser vati o n was li kel y  d ue t o t he atte n uati o n of t he i n hi bit or y 
i m pact of I L-6 o n C Y P 3 A acti vit y , t h us, res ulti n g i n a ret ur n t o baseli ne or a “ n ormalizati o n” 
of e nz y me acti vit y.3 5 ,3 6
Pri or p u blicati o ns ha ve de m o nstrate d l o wer cleara nce of C Y P 3 A s u bstrates, i ncl u di n g 
mi daz ola m, i n partici pa nts wit h o besit y .2 1 ,3 7 F urt h er m ore, a n u m ber of cli nical st u dies ha ve 
de m o nstrate d i ncrease d cleara nce of C Y P 3 A s u bstrates f oll o wi n g wei g ht l oss. 3 8 ,3 9 ,4 0  F or 
e xa m ple, one y ear after bariatric s ur ger y, sys te mic cleara nce of mi daz ola m was 1. 7 ti mes
hi g her [ 0. 6 5 ( 7 %) vs 0. 3 9 ( 1 1 %) L/ mi n, mea n ± R S E ( p< 0. 0 1), res pecti vel y] i n 1 8 m or bi dl y  
o bese i n di vi d uals w h o l ost a mea n of 4 4. 5 ± 1 0. 2 k g b o d y  wei g ht.4 1 T he a ut h ors s u g geste d 
t hat t he o bser ve d i ncrease i n mi daz ola m cleara nce was p ote ntiall y  d ue t o i ncrease d C Y P 3 A 
acti vit y f oll owi n g wei g ht l oss.
T o t hat e n d , i n vitr o C Y P e nz y me acti vit y  d o w n-re g ulati o n f or a n o vel G L P - 1 Ra/ gl uca g o n 
c o-a g o nist di d n ot tra nslate t o cli nical D DIs. 4 2 B ase d o n i n vitr o data a n d P B P K m o deli n g, a 
2. 4 -f ol d i ncrease i n mi daz ola m A U C a n d a 1. 6 -f ol d i ncrease i n mi daz ola m C ma x was 
e x pecte d, w hile i n t he cli nic n o c ha n ge was o bser ve d i n A U C a n d Cma x was decrease d b y 
2 1 %. S u bjects als o l ost a c o nsi dera ble a m o u nt of b o d y wei g ht ( ~ 1 0 %) o ver t he c o urse of t he 
st u d y. These data hi g hli g ht t he u ncertai nt y f or tra nslati o n of i n vitr o data t o cli nical D DI f or 
t his mec ha nis m, a n d pr o vi de a d diti o nal s u p p or t t hat t he i ncreases i n C Y P 3 A acti vit y 
o bser ve d cli nicall y  wit h t he G LP- 1 Ra/ gl uca g o n c o -a g o nist a n d t he a p pare nt i ncreased 
C Y P 3 A acti vit y  f oll o wi n g wei g ht l oss m a y  be mec ha nis m -relate d; ie, d ue t o wei g ht l oss
itself, alterati o ns i n i nfla m mat or y stat us, G L P -1 R p har mac ol o g y , etc.  
T he o bjecti ve of C o h ort 2 is t o test t he h yp ot hesis t hat decreases i n b o d y  wei g ht lesse n t he
infla m mat or y  b ur de n of o besit y, a n d t heref ore, atte n uate s o me of t he i n hi bit or y i m pact of 
o besit y o n C Y P 3 A acti vit y.  T his res ults i n “ n or malizati o n” of C Y P 3 A acti vit y, w hic h 
ma nifests as e nz y me i n d ucti o n as e vi de nce d b y t he af ore me nti o ne d decreases i n mi daz ola m 
e x p os ure .
O nce wee kl y se ma gl uti de a d mi nistrati o n u p t o t he ma xi m u m a p pr o ve d d ose of 2. 4 m g  is 
e x pecte d t o res ult i n c o nsi dera ble wei g ht l oss. As se ma gl uti de is a p e pti de i nte n de d f or 
s u bc uta ne o us i njecti o n, C Y P -me diate d D DIs are n ot e x pecte d ; in vitr o st u dies ha ve s h o w n 
ver y  l o w p ote ntial f or se ma gl uti de t o i n hi bit or i n d uce C Y P e nz ymes. 1 6 ,1 7 T heref ore , a n y
decrease o bser ve d f or mi daz ola m s y tste mic e xp os ure s i n C o h ort 2 w o ul d li kel y be 
mec ha nis m base d; ie, d ue t o wei g ht l oss, alterati o ns i n i nfla m mat or y  stat us, G LP- 1 Ra
p har mac ol o g y , etc.  Base d o n hist orical wei g ht l oss data f or P F - 0 7 0 8 1 5 3 2 i n t he 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
m ulti ple -asce n di n g d ose st u d y ( C 39 9 1 0 0 2), P F -0 7 0 8 1 5 3 2 is e x pecte d t o res ult i n wei g ht l oss 
i n t he c urre nt st u dy , t h us, all o wi n g f or a c o m paris o n of t he i m pact of wei g ht l oss o n 
mi daz ola m P K bet wee n C o h orts 1 a n d 2.  
F oll o wi n g assess me nt of t he D DI bet wee n se ma gl uti de a n d mi daz ola m, t he a d mi nistr ati o n of 
se ma gl uti de will be disc o nti n ue d f or a 2- wee k peri o d, after w hic h a n a d diti o nal si n gle d ose 
of mi daz ola m will be a d mi nistere d t o assess a n y i m pact of disc o nti n uati o n of se ma gl uti de 
a d mi nistrati o n o n mi daz ola m p har mac o ki netics.  If i n d ucti o n of C Y P3 A acti vit y is o bser ve d
(as deter mi ne d by mi daz ola m P K d uri n g c oa d mi nistrati o n of se ma gl uti de ), t he 
disc o nti n uati o n of se ma gl uti de is n ot e x pecte d t o ha ve a n i m pact o n s u bse q ue nt mi daz ola m 
P K , a n d w o ul d m ost li kel y be attri b ute d t o wei g ht l oss a n d t he atte n uati o n of circ ulati n g 
i nfla m mat or y mar kers t hat i m pact C Y P 3 A acti vit y. 
Mi daz ola m will be use d as a “se nsiti ve s u bstrate” of C Y P 3 A i n C o h ort 2 t o assess t he i m pact 
of m ulti ple - d ose se ma gl uti de a d mi nistrati o n o n t he P K of b ot h mi daz ola m a n d its 1-h y dr o x y  
meta b olite.  T o f urt her i n vesti gate t he mec ha nis m of t his i nteracti o n, plas ma 
4- -h y dr o x yc h olester ol/c h olester ol a n d 
 sa m ples, use d as e n d o ge n o us pr o bes f or C Y P 3 A 
i n d ucti o n, will be c ollecte d a n d a nal yze d if c ha n ges are o bser ve d i n mi daz ola m e x p os ure s. 
S e ma gl uti de will be a d mi nistere d as i nstr ucte d i n t he res pecti ve a p pr o ve d U S PIs; ie, o nce 
wee kl y s u bc uta ne o us i njecti o ns at t he 0. 2 5 m g, 0. 5 m g, 1. 0 m g , 1. 7 m g a n d 2. 4 m g d oses ,
eac h f or 4 wee ks. 1 6 ,1 7 O ne a d diti o nal 2. 4 m g d ose of se ma gl uti de will be a d mi nistere d t o 
e ns ure attai n me nt of P K stea d y -state (ter mi nal half-life is a p pr oxi matel y  1 wee k) pri or t o 
a d mi nistrati o n of t he sec o n d mi daz ola m d ose i n Peri o d 3 ( Secti o n 6. 1. 1 ). T his will e na ble 
a n y i nteracti o n t hat is prese nt t o be assesse d u n der c o n diti o ns t hat are e x pecte d t o i ncrease 
t he p ote ntial f or ma xi mal C Y P 3 A i n d ucti o n at t he 2. 4 m g se ma gl uti de d ose , s h o ul d t his 
occ ur . 
4. 2. 3. S afet y Assess me nts ( C o h orts 1 a n d 2)
Cli nical la b orat or y  tests, assess me nts of vital si g ns, b o d y wei g ht, 1 2- lea d E C Gs, p h ysical 
e xa mi nati o ns, a n d A E m o nit ori n g will pr o vi de data t o e val uate t he safet y a n d t olera bilit y of 
P F -0 7 0 8 1 5 3 2.  Vital si g ns a n d 1 2-lea d E C Gs will be m o nit ore d at t he S cree ni n g a n d st u d y 
disc har ge visits, a n d as necessar y at t he discreti o n of t he i n vesti gat or. B o d y  wei g ht will be 
meas ure d at ti me p oi nts i n t he S o A , as G LP- 1 R a g o nists ha ve bee n s h o w n t o decrease f o o d 
i nta ke a n d b o dy wei g ht.  C O VI D - 1 9 s pecific assess me nts ha ve bee n i nc or p orate d t o 
mi ni mize t he ris ks of C O VI D -1 9 relate d c o m plicati o ns t o partici pa nts a n d t he st u d y  site 
pers o n nel.
As part of t he cli nical safet y  la b orat or y tests, fasti n g bl o o d gl uc ose a n d H b A 1c will be use d 
t o assess c han ges i n gl yc e mic para meters i n t his st u d y  p o p ulati o n.  I n a d diti o n, calcit o ni n, 
a m ylase, a n d li pase will be assesse d, as t hese la b orat or y para meters ha ve bee n s h o w n t o 
i ncrease wit h mar kete d G LP- 1 R a g o nists. 1 6 ,1 7,4 3 ,4 4 ,4 5 ,4 6 T S H, free T 4, li pi ds, a n d T B A will
als o be assesse d, base d o n n o na d verse fi n di n gs i n t he n o ncli nical st u dies wit h P F -0 7 0 8 1 5 3 2 .  
Assess me nt of SI B b y  C-S S R S 4 7 a n d P H Q- 9 4 8 will als o be perf or me d base d o n t he p ote ntial 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
ris k relate d t o t he pr o d uct la beli n g f or t he i njecta ble G LP- 1 R a g o nist s lira gl uti de a n d 
se ma gl uti de i n l o n g-ter m st u dies of patie nts wit h B MI ≥3 0 k g/ m 2.1 6 ,1 7 ,4 4 ,4 5
W hile G L P- 1 R a g o nists t y picall y  are n ot ass ociate d wit h h yp o gl yce mia u nless 
c oa d mi nistere d wit h a nti-dia betic a ge nts t hat ca n ca use h y p o gl yce mia (s uc h as i ns uli n or 
s ulf o n yl ureas), bl o o d gl uc ose c o nce ntrati o ns will be m o nit ore d t hr o u g h o ut t he st u d y via 
la b orat or y assess me nts, a n d m o nit ori n g of sy m pt o matic H A Es will be perf o r me d.  I n 
a d diti o n, all partici pa nts will be i nstr ucte d re gar di n g t he s y m pt o ms ass ociate d wit h, a n d 
ma na ge me nt of, h y p o gl yce mia, w hic h will per mit t he m o nit ori n g of s y m pt o matic H A Es.
W O C B P
ma y  be e nr olle d gi ve n t he a vaila bilit y of e m br yo fetal de vel o p me nta l t o xicit y 
st u dies wit h P F - 0 7 0 8 1 5 3 2.  H o we ver, as mar kete d G LP -1 R a g o nists are liste d as 
c o ntrai n dicate d i n pre g na nc y, t he use of a hi g hly effecti ve met h o d of n o n h or m o nal 
c o ntrace pti o n is re q uire d a n d meas ures will be ta ke n t o li mit t he ris k of pre g na nc y  in t he 
W O C B P
p o p ulati o n e nr olle d (see S o A a n d A p pe n di x 4 ).
4. 2. 4. Di versit y of St u d y P o p ul ati o n  
N ot a p plica ble.
4. 2. 5. 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 li mite d f or P F - 0 7 0 8 1 5 3 2, 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 c o m plete d n o ncli nical e m br yo- fetal de vel o p me ntal 
st u dies.  H o we ver, t he use of a hi g hly effecti ve met h o d of n o n h or m o nal c o ntrace pti o n is 
re q uire d f or b ot h c o h orts i n t his st u d y (see A p pe n di x 4 ).  
4. 2. 6. C ollecti o n of Ret ai ne d Rese arc h S a m ples
 
4. 3. J ustific ati o n f or D ose
P F -0 7 0 8 1 5 3 2 :
T he D DI will be assesse d at 2 p har mac o ki netic stea d y-state P F - 0 7 0 8 1 5 3 2 d ose le vels, 
8 0 m g Q D a n d 26 0 m g Q D .  T he se d ose s re prese nt a p ote ntial t hera pe utic d ose f or T 2 D M,
a n d t he hi g hest d ose bei n g as sesse d i n t he P hase 2 st u d y ( C 3 9 9 1 0 0 4) f or T 2 D M a n d o besit y , 
res pecti vely. E x p os ure mar gi ns f or P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D are gi ve n i n Secti o n 2. 2. 3 . 
T he titrati o n t o P F - 0 7 0 8 1 5 3 2 80 m g Q D is pla n ne d t o occ ur o ver a n a p pr o xi matel y 2 8-d a y  
peri o d i n i ncre me nts of 2 0 m g Q D e ver y 7 d a y s, a n d fr o m 8 0 m g Q D t o 26 0 m g Q D o ver 
9 wee ks , i n i ncre me nts of 2 0 m g e ver y  7 da y s (Secti o n 6. 1. 1 , Ta ble 8 a n d Ta ble 9 ). T itrati o n 
i ncre me nts as s h ort as 1- 2 da y s ha ve bee n a d mi nistere d pre vi o usl y i n S t u d y C 39 9 1 0 0 2 a n d 
were s ufficie ntl y t olerate d.   Base d o n e mer gi n g data fr o m ot her cli nical st u dies t hat ma y 
bec o me a vaila ble d uri n g t he c o n d uct of t his st u d y , t he titrati o n rate, i ncre me ntal i ncreases i n 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
d ose, a n d/ or t he P F -0 7 0 8 1 5 3 2 d oses at w hic h mi daz ola m , o me praz ole or t he O C P K 
i nteracti o ns are e val uate d ma y be a dj uste d.  
Mi d az ol a m:
Mi daz ola m has bee n a d mi nistere d at d oses of 2 -1 5 m g t o assess C Y P 3 A 4/ 5 D DI s a n d wa s 
ge nerall y well t olerate d.  T he si n gle, oral 2 m g  d ose of mi daz ola m i n t his st u d y s h o ul d all o w 
f or a de q uate q ua ntificati o n of mi daz ola m a n d its 1-h y dr o x y meta b olite i n plas ma f or 2 4 h o urs 
a n d is e x pecte d t o be well- t olerate d.  A d diti o nall y , as mi daz ola m a n d o me praz ole are t o be 
a d mi nistere d si m ulta ne o usl y ( C o h ort 1 o nly) , mi daz ola m d oses greater t ha n 2 m g ha ve n ot 
bee n vali date d f or c oa d mi nistrati o n wit h o me praz ole. 1 8 ,1 9
O me pr az ole :
T he safet y data descri be d i n t he U S PI1 4 f or o me praz ole m o n ot hera py reflects e x p os ure t o 
P RI L O S E C Dela y e d-Release Ca ps ules i n 3 0 9 6 patie nts fr o m w orl d wi de cli nical trials 
( 4 6 5 patie nts fr o m U S st u dies a n d 2, 6 3 1 patie nts fr o m i nter nati o nal st u dies). I n dicati o ns 
cli nicall y st u die d i n U S trials i ncl u de d d u o de nal ulcer, resista nt ulcer, a n d 
Z olli n ger -Ellis o n s y n dr o me. T he m ost c o m m o n a d verse reacti o ns re p orte d (ie, wit h a n 
i nci de nce rate ≥2 %) fr o m P RI L O S E C -treate d patie nts e nr olle d i n t hese st u dies i ncl u de d 
hea dac he ( 6. 9 %), a b d o mi nal pai n ( 5. 2 %), na usea ( 4. 0 %), diarr hea ( 3. 7 %), v o miti n g 
( 3. 2 %), a n d flat ule nce ( 2. 7 %). 
T he d ose ra n ge a n d rec o m me n de d starti n g d oses f or o me praz ole i n cli nical practice is 2 0 t o 
6 0 m g o nce dail y f or u p t o 8 wee ks i n a d ults de pe n di n g o n t he c o n diti o n bei n g treate d. 1 4 I n
patie nts wit h Z olli n ger -Ellis o n s y n dr o me, d oses of u p t o 2 4 0 m g/ da y m a y  be re q uire d. 
Base d o n i n vitr o data, P F - 0 7 0 8 1 5 3 2 is a m o derate ti me-de pe n de nt i n hi bit or of C Y P 2 C 1 9
a n d c o ul d p ote ntiall y i ncrease o me praz ole e x p os ure 2. 2- t o 3. 4 -f ol d at a 2 6 0 m g d ose.  
T heref ore , a 2 0 m g si n gle d ose of o me praz ole was selecte d f or t his st u d y.  Gi ve n t h e 
esta blis he d safety a n d t olera bilit y f or o me praz ole wit h m ulti ple - d ose a d mi nistrati o n u p t o 
2 4 0 m g/ da y , a 2 0 m g si n gle d ose is e x pecte d t o be well t olerate d e ve n if s yste mic e x p os ures 
i ncrease u p t o 5-f ol d as a res ult of c oa d mi nistrati o n wit h P F - 0 7 0 8 1 5 3 2. A d diti o nall y , as 
mi daz ola m a n d o me praz ole are t o be a d mi nistere d si m ulta ne o usl y ( C o h ort 1 o nl y), 
o me praz ole d oses greater t ha n 2 0 m g ha ve n ot bee n vali date d f or c oa d mi nistrati o n wit h 
mi daz ola m.
1 8 ,1 9
L E/ E E :
T he O C selecte d f or t his st u d y  c o ntai ns a fi xe d d ose of 0. 1 5 m g L E a n d 0. 0 3 m g E E .  The 
a m o u nts of estr o ge n a n d pr o gesti n i n t his pre parati o n are c o m para ble t o t h ose f o u n d i n ma n y 
of t he c o m m o nl y  prescri b e d O Cs a n d ha ve bee n use d i n a n u m ber of p u blis he d O C D DI
st u dies.4 9 ,5 0
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
S e m a gl uti de:
S u bc uta ne o us s e ma gl uti de will be titrate d u p t o 2. 4 m g wee kl y as t his is t he ma xi m u m 
a p pr o ve d d ose f or wei g ht l oss a n d was s h o w n t o be safe a n d well -t olerate d i n cli nical 
trials.1 6 ,1 7
4. 4. E n d of St u d y Defi niti o n
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y  if he/s he has c o m plete d all p hases of 
t he st u d y, i ncl u di n g t he F/ U c o ntact visit, a p pr o xi matel y  2 8 t o 3 5 d a y s p ost last d ose of st u d y 
i nter ve nti 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 visit ( F/ U c o ntact) of t he last partici pa nt 
i n t he st u d y.
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
Partic i pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nly if all of t he f oll o wi n g criteria a p pl y:
A ge a n d Se x :
1.
Ot her wise h ealt h y fe male partici pa nts m ust be at least 1 8 y ears of a ge at t he ti me of 
si g ni n g t he I C D ( healt hy is defi ne d as n o cli nicall y rele va nt a b n or malities i de ntifie d 
b y  a detaile d me dical hist or y , p h ysical e xa mi nati o n, i ncl u di n g bl o o d press ure a n d 
p ulse rate meas ure me nt, sta n dar d 1 2 -lea d E C G a n d cli nical la b orat or y tests).

W o me n ca n be of c hil d -beari n g p ote ntial, b ut ca n n ot be pre g na nt, breastfee di n g, 
or pla n ni n g t o bec o me pre g na nt w hile partici pati n g i n t he st u d y a n d ma y n ot be 
ta ki n g eit her oral c o ntrace pti ves or n o n - oral h or m o nal c o ntrace pti ves. 

Refer t o A p pe n di x 4 f or re pr o d ucti ve criteria f or fe male partici pa nts
(Secti o n 1 0. 4. 2 ).
T y pe of P artici p a nt a n d Dise ase C h ar acteristics:
2.
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 other st u d y  pr oce d ures.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
Wei g ht:
3.
B MI : ≥3 0 . 0 k g/ m2 a n d n ot m ore t ha n 4 5. 4 k g/ m 2 at Scree ni n g
4.
Sta ble b o d y  wei g ht, defi ne d as < 5 k g c ha n ge ( per partici pa nt re p ort) f or 9 0 da y s 
bef ore Scree ni n g. 
I nf or me d C o nse nt:
5.
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.
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, 
p ul m o nar y , gastr oi ntesti nal, car di o vasc ular, he patic, ps yc hiatric, ne ur ol o gical, or 
aller gic disease (i nclu di n g dr u g aller gies, b ut e xcl u di n g u ntreate d, as y m pt o matic, 
seas o nal aller gies at t he ti me of d osi n g).
2.
A n y  c o n diti o n p ossi bl y affecti n g dr u g a bs or pti o n (e g, pri or bariatric s ur ger y, 
gastrect o m y, or a n y area of i ntesti nal resecti o n, acti ve i nfla m mat or y  b o wel disease or 
pa ncreatic i ns ufficie nc y ). 
3.
Ot her me dical or ps y c hiatric c o n diti o n i ncl u di n g rece nt ( wit hi n t he past year) or 
acti ve s uici dal i deati o n/ be ha vi or or la b orat or y  a b n or malit y t hat ma y i ncrease t he ris k 
of st u d y partici pati o n or, i n t he i n vesti gat o r’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.
4.
K n o w n i nt olera nce or h y perse nsiti vit y  t o G L P-1 R a g o nists.
5.
K n o w n h y perse nsiti vit y  t o mi daz ola m , o me praz ole, L E , E E , or se ma gl uti de.
6.
Dia g n osis of t y p e 1 or t y pe 2 dia betes mellit us or sec o n dar y f or ms of dia betes at 
scree ni n g.  N ote: w o me n wit h pri or dia g n oses of gestati o nal dia betes d uri n g 
pre g n a ncy o n ly are eli gi ble if t he y meet t he ot her eli gi bilit y criteria.
7.
Hist or y  of my o car dial i nfarcti o n, u nsta ble a n gi na, arterial re vasc ularizati o n, str o ke,
Ne w Y or k Ass ociati o n F u ncti o nal Class II- I V heart fail ure, or tra nsie nt isc he mic 
attac k wit hi n 6 m o nt hs of Scree ni n g.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
8.
A n y mali g na nc y  n ot c o nsi dere d c ure d (e xce pt basal cell carci n o ma a n d s q uam o us cell
carci n o ma of t he s ki n); a st u d y partici pa nt is c o nsi dere d c ure d if t here has bee n n o
e vi de nce of ca ncer rec urre nce i n t he pre vi o us 5 ye ars (fr o m Scree ni n g).
9.
Pers o nal or fa mil y hist or y of me d ullar y  t h yr oi d carci n o ma ( M T C) or m ulti ple
e n d ocri ne ne o plasia s y n dr o me t y pe 2 ( M E N 2), or st u d y  partici pa nts wit h s us pecte d
M T C per t he i n vesti gat or’s j u d g me nt.
1 0. Ac ute pa ncreatitis or hist or y  of c hr o nic pa ncreatitis. S y m pt o matic gall bla d der 
disease.
1 1. Me dical hist or y  or c haracteristics s u g gesti ve of ge netic or s yn dr o mic o besit y  or
o besit y  i n d uce d by ot her e n d ocri n ol o gical dis or ders (e g, C us hi n g S y n dr o me).
1 2. Hist or y  of maj or de pressi ve dis or der or hist or y of ot her se vere psyc hiatric dis or ders
(e g, sc hiz o p hre nia or bi p olar dis or der) wit hi n t he last 2 years fr o m scree ni n g.
1 3. K n o w n me dical hist or y  of acti ve li ver disease ( ot her t ha n n o n-alc o h olic he patic
steat osis), i ncl u di n g c hr o nic acti ve he patitis B or C, pri mar y biliar y cirr h osis,
alc o h olic li ver disease, pri mar y  scler osi n g c h ola n gitis, a ut oi m m u ne he patitis, o verla p
s yn dr o me, or pri or k n o w n dr u g -i n d uce d li ver i nj ur y.
1 4. Hist or y  of HI V i nfecti o n.
1 5. A n y  lifeti me hist or y of a s uici de atte m pt.
Pri or/ C o nc o mit a nt T her a p y:
1 6. 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 
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. 9 C o nc o mita nt T hera p y f or a d diti o nal details).
1 7. Use of a n y t he me dicati o ns t hat are m o derate or str o n g C Y P 3 A 4/ 5 a n d/or C Y P 2 C 1 9 
i n hi bit ors wit hi n 2 8 da ys or 5 half-li ves ( w hic he ver is l o n ger) or mo derate or str o n g 
C Y P 3 A a n d/ or C Y P 2 C 1 9 i n d ucers wit hi n 1 4 da ys 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. 9 f or a d diti o nal 
details). 
1 8. C urre nt use of a n y pr o hi bite d c o nc o mita nt me dicati o n(s) or t h ose u n willi n g/ u na ble t o 
use a per mitte d c o nc o mita nt me dicati o n(s ). Refer t o Secti o n 6. 9 C o nc o mita nt
T hera p y .
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce:
1 9. 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 half -li ves prece di n g t he first d ose of st u d y i nter ve nti o n
use d i n t his st u d y ( w hic he ver is l o n ger). 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
2 0. Pre vi o us a d mi nistrati o n wit h a G L P- 1 R a g o nist wit hi n 9 0 da y s prece di n g t he first 
d ose of st u d y  i nter ve nti on use d i n t his st u d y .  
2 1. K n o w n pri or partici pati o n i n a trial i n v ol vi n g P F - 0 7 0 8 1 5 3 2 u nless place b o treat me nt 
was recei ve d .
Di a g n ostic Assess me nts ( at Scree ni n g u nless i n dic ate d):
2 2. A P H Q - 9 sc ore ≥1 5 o btai ne d at Scree ni n g or Da y  -1 i n St u d y .
2 3. Res p o nse of “ y es” t o q uesti o n 4 or 5, or o n a n y s uici dal be ha vi oral q uesti o n o n t he 
C- S S R S at Scree ni n g or Da y  -1 i n St u d y .
2 4. A p ositi ve uri ne dr u g test. 
2 5. 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.  B P s h o ul d be meas ure d i n tri plicate 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 .  N ote: At 
S cree ni n g, t he partici pa nt’s ar m circ u mfere nce s h o ul d be meas ure d (e g, usi n g a 
fle xi ble a nt hr o p o metric ta pe) at t he mi d p oint of t he le n gt h of t he u p per ar m, a n d t he 
a p pr o priate c uff selecte d a n d use d t hr o u g h o ut t he st u d y .
2 6. Scree ni n g 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, Q Tc F i n ter 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 yocar 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 ya rr hyt h mias or tac h y arr h yt h mias).  
If Q Tc F 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 b y a p h ys icia n e x perie nce d i n rea di n g E C Gs bef ore e xcl u di n g partici pa nts.
2 7. 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 
S cree ni n g, as assesse d b y t he st u d y  s pecific la b orat or y a n d c o nfir me d by a si n gle 
re peat test, if dee me d necessar y:

H b A 1c ≥6. 5 %.

A S T or A L T le vel ≥1. 5 x U L N.

T otal bilir u bi n le vel ≥1. 5 x U L N; partici pa nts wit h a hist or y  of Gil bert's sy 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.

T S H > 1. 5 x U L N or < L L N.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

Ser u m calcit o ni n > U L N.

A m y lase or li pase > U L N.

Fasti n g bl o o d gl uc ose ≥1 2 6 m g/ d L. 

Fasti n g C -pe pti de < 0. 8 n g/ m L.

e G F R < 7 5 m L / mi n/ 1. 7 3 m2 as calc ulate d b y t he C hr o nic Ki d ne y  Disease 
E pi de mi ol o g y  C olla b orati o n (C K D -E PI ) e q uati o n.

P ositi ve testi n g f or HI V, H Bs A g , or H C V A b.  St u d y partici pa nts p ositi ve f or 
H C V A b are t o be e xcl u de d u nless k n o w n t o ha ve bee n treate d wit h a k n o w n 
c urati ve t hera p y a n d ne gati ve f or H C V R N A.  He patitis B vacci nati o n is all o we d.

A p ositi ve S A R S -C o V - 2 test.
Ot her E xcl usi o ns : at Scree ni n g u nless i n dic ate d
2 8. Partici pati o n i n a f or mal wei g ht re d ucti o n pr o gra m (e g, Wei g ht Watc hers) wit hi n 
9 0 da y s pri or t o Scree ni n g.
2 9. 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) o f wi ne).
3 0. C urre nt 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 per da y.
3 1. K n o w n or s us pecte d illicit dr u g use.
3 2. 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 ra n d o mizati o n ( Da y-1). 
3 3. 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 if He p l oc k is 
use d f or I V bl o o d dra w.
3 4. 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.
3 5. 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. 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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) f or at least 8 h o urs 
pri or t o a n y m or ni n g pre d ose P K e val uati o ns (s pecifie d ti mes i n Peri o ds 1 - 9 i n 
C o h ort 1 a n d Peri o ds 1- 4 i n C o h ort 2 ).  O n da y s wit h o ut P K e val uati o ns, partici pa nts 
m ust a bstai n fr o m all f o o d a n d dri n k (e xce pt water) f or at least 4 h o urs pri or t o a n y  
safety la b orat or y  e val uati o ns (at least 1 2 h o urs if li pi ds are t o be e val uate d). 

Water ma y  be c o ns u me d as desire d (a d li bit u m).

C o h ort 1 - Partici pa nts s h o ul d be gi n c o ns u m pti o n of a sta n dar d brea kfast ( m or ni n g)
a p pr o xi matel y 3 0 mi n utes pri or t o d osi n g.  T he brea kfast meal will be c o ns u me d o ver 
a p pr o xi matel y a 2 0-mi n ute peri o d, wit h t he st u d y  i nter ve nti o n (P F -0 7 0 8 1 5 3 2 ) 
a d mi nistere d wit hi n a p pr o xi matel y 1 0 mi n utes of c o m pleti o n of t he meal.  
Partici pa nts will be e nc o ura ge d t o c o ns u me t he e ntire meal.
P F - 0 7 0 8 1 5 3 2 will be a d mi nistere d first a n d t he si n gle d ose of mi daz ola m a n d
o me praz ole or t he O C will be a d mi nistere d wit hi n 5 mi n utes of P F -0 7 0 8 1 5 3 2 f or t he 
peri o ds i n w hic h mi daz ola m a n d o me praz ole or t he O C are c oa d mi nistere d wit h 
P F - 0 7 0 8 1 5 3 2. 
Mi daz ola m a n d o me praz ole,
or t he O C, w he n a d mi nistere d al o ne , will be gi ve n 
wit hi n a p pr o xi matel y  1 0 mi n utes of c o m pleti o n of t he m or ni n g meal. 
C o h ort 2 – Peri o d 1 : O n t he i n-patie nt D DI assess me nt da y , p artici pa nts s h o ul d be gi n 
c o ns u m pti o n of a sta n dar d brea kfast ( m or ni n g) a p pr o xi matel y  3 0 mi n utes pri or t o 
d osi n g.  T he brea kfast meal will be c o ns u me d o ver a n a p pr o xi mate 2 0 -mi n ute peri o d, 
wit h t he st u d y  i nter ve nti o n (se ma gl uti de) a d mi nistere d wit hi n a p pr o xi matel y 
1 0 mi n utes of c o m pleti o n of t he meal, f oll o we d wit hi n 5 mi n utes b y  t he si n gle d ose 
of mi daz ola m.   Partici pa nts will be e nc o ura ge d t o c o ns u me t he e ntire meal.
Peri o d 2 : O n o ut-patie nt da y s, partici pa nts ma y c o ns u me meals at a n y ti me.  
Peri o d 3 : O n t he i n-patie nt D DI assess me nt da y , partici pa nts s h o ul d be gi n 
c o ns u m pti o n of a sta n dar d brea kfast ( m or ni n g) a p pr o xi matel y  3 0 mi n utes pri or t o 
d osi n g.  T he brea kfast meal will be c o ns u me d o ver a n a p pr o xi mate 2 0 -mi n ute peri o d , 
wit h t he st u d y  i nter ve nti o n (se ma gl uti de) a d mi nistere d wit hi n a p pr o xi matel y 
1 0 mi n utes of c o m pleti o n of t he meal, f oll o we d wit hi n 5 mi n utes b y  t he si n gle d ose 
of mi daz ola m. Partici pa nts will be e nc o ura ge d t o c o ns u me t he e ntire meal.

N o ncaffei nate d dri n ks (e xce pt re d wi ne, gra pefr uit or gra pefr uit- relate d citr us fr uit 
j uices [ e g, Se ville ora n ges, p o mel os]) ma y be c o ns u me d wit h meals a n d t he e ve ni n g 
s nac k.  
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

L u nc h will be pr o vi de d a p pr o xi matel y  4 h o urs after d osi n g wit h st u d y  i nter ve nti o n 
(P F - 0 7 0 8 1 5 3 2 or se ma gl uti de).  T his a p plies t o mi daz ola m , o me praz ole a n d t he O C
als o.

Di n ner will be pr o vi de d a p pr o xi matel y  1 0 h o urs after d osi n g wit h st u d y i nter ve nti o n. 
T his a p plies t o mi daz ola m, o me praz ole a n d t he O C als o.

A n e ve ni n g s nac k ma y  be per mitte d.

C o h ort 1: 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 a n d j uices (e g, Se ville ora n ges, p o mel os) fr o m 7 da ys pri or t o 
Peri o d 1 Da y 1 u ntil c ollecti o n of t he fi nal P K bl o o d sa m ple i n Peri o d 9, Da y 2 .
Partici p a nts are als o e x pecte d t o refrai n fr o m c o ns u mi n g t hese pr o d ucts d uri n g t he 
2 -wee k o ut -patie nt p orti o n of t he st u d y f oll o wi n g t he O C D DI assess me nt i n 
Peri o d 8 ; ie, bet wee n Peri o d 8, Da y 6 a n d Peri o d 9, Da y  1.

C o h ort 2: 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 a n d j uices (e g, Se ville ora n ges, p o mel os) fr o m 7 da ys pri or t o 
a d missi o n t o t he cli nical site o n Da y  1 of Peri o d s 1 a n d 3 a n d d uri n g all i n-patie nt 
sta ys. Partici pa nts are als o e x pecte d t o refrai n fr o m c o ns u mi n g t hese pr o d ucts d uri n g 
t he 2- wee k o ut -patie nt p orti o n of t he st u d y f oll o wi n g t he mi daz ola m D DI assess me nt 
i n Peri o d 3; ie, bet wee n Peri o d 3 , Da y 2 a n d Peri o d 4 , Da y 1.

W hile partici pa nts are c o nfi ne d, t heir t otal dail y  n utriti o nal co m p ositi o n s h o ul d be 
a p pr o xi matel y 5 5 % car b o h ydrate, 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.
5. 3. 2. C affei ne, Alc o h ol, a n d T o b acc o

T o bacc o or nic oti ne use ma y  be all o we d acc or di n g t o C R U practices.  T o bacc o or 
nic oti ne use will n ot be per mitte d d uri n g fre q ue nt sa m pli n g pr oce d ures a n d will n ot 
be per mitte d wit hi n 2 h o urs pri or t o a n y vital si g n or E C G assess me nts.  T o bacc o or 
nic oti ne use will als o n ot be per mitte d 2 h o urs bef ore a n d 2 h o urs f ol l o wi n g a ny d ose 
of st u d y  i nter ve nti o n.  

Caffei ne c o ntai ni n g pr o d ucts will be per mitte d d uri n g t he st u d y wit h t he f oll o wi n g 
restricti o ns: caffei ne c o ntai ni n g pr o d ucts ma y n ot be c o ns u me d wit hi n 1 h o ur pri or t o 
meas uri n g vital si g ns a n d E C Gs.

Partici pa nts w ill a bstai n fr o m alc o h ol f or 2 4 h o urs pri or 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 i n C o h ort 1, 
Peri o d 9 , D a y 2 .  Partici pa nts will a bstai n fr o m alc o h ol f or 2 4 h o urs pri or 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 mi daz ola m P K sa m ple i n C o h ort 2 ; Peri o d 2 Da y  1, Peri o d 3 Da y 2, a n d 
Peri o d 4 D a y 2.  Partici pa nts 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.  
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 oll ecti 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 P K sa m pli n g da ys, partici pa nts will be 
re q uire d t o refrai n fr o m l yi n g d o w n f or 4 h o urs after d osi n g i n t he m or ni n g o n da ys of 
p ost -d ose P K sa m ple c ollecti o ns (e xce pt if re q uire d f or B P, p ulse rate, a n d E C G 
meas ure m e nts).
5. 3. 4. C o ntr ace pti o n
W O C B P
O nl y  - 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 n o n h or m o nal 
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 
n o n h or m o nal c o ntrace pti o n met h o ds (see A p pe n di x 4 ) a n d will c o nfir m t hat t he partici pa nt 
has bee n i nstr ucte d i n its c o nsiste nt a n d c orrect use.  At ti me p oi nts i n dicate d i n t he 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 n o n h or m o nal c o ntrace pti o n c o nsiste ntl y a n d c orrectly a n d d oc u me nt t he 
c o n versati o n a n d t he partici pa nt’s affir mati o n i n t he partici pa nt’s c hart ( partici pa nts nee d t o 
affir m t heir c o nsiste nt a n d c orrect use of at least 1 of t he selecte d me t h o ds of n o n h or m o nal 
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.  
I n a d diti o n, t he i n vesti gat or or desi g nee will i nstr uct t he partici pa nt t o call i m me diatel y if t he 
selecte d n o n h or m o nal c o ntrace pti o n met h o d is disc o nti n ue d or if pre g na nc y  is k n o w n or 
s us pecte d i n t he partici pa nt or part ner .
5. 4. 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 d ose 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 t o t he cli nical data base.
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 wit hi n t he 2 8 -d a y  scree ni n g 
wi n d o w ma y  be re-scree ne d. I n t his sit uati o n, all scree ni n g pr oce d ures m ust be re peate d, a n d 
t he partici pa nt assi g ne d a ne w 8-di git S SI D n u m ber.  T his criteri o n w o ul d als o a p pl y  t o 
partici pa nts w h o scree ne d f or t his st u d y  m ore t ha n 2 8 da y s pri or t o d osi n g.
6. S T U D Y I N T E R V E N TI O N ( 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 define 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 0 8 1 5 3 2, mi daz ola m, 
o me praz ole , O C a n d se ma gl uti de.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
6. 1. St u d y I nter ve nti o n(s) A d mi nistere d
2 0 m g, 6 0 m g, a n d 1 0 0 m g P F - 0 7 0 8 1 5 3 2 oral ta blets will be s u p plie d b y Pfizer 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, as necessar y, f or u nit d osi n g.
C o m merciall y  a vaila ble s u bc uta ne o us se ma gl uti de ( We g o v y)  will be s u p plie d b y  Pfizer t o 
t he C R U.
C o m merciall y  a vaila ble mi daz ola m oral s yr u p ( 2 m g/ m L) will be s u p plie d b y t he C R U. 
C o m merciall y  a vaila ble oral o me praz ole 2 0 m g  ta blets will be s u p plie d b y t he C R U.
C o m merciall y  a vaila ble oral O C ta blets ( L E 0. 1 5 m g/ E E 0. 0 3 m g ) will be s u p plie d b y t he 
C R U. 
6. 1. 1. A d mi nistr ati o n
C o h ort 1 - Partici pa nts will recei ve P F -0 7 0 8 1 5 3 2 , mi daz ola m a n d o me praz ole, or t he O C as 
a p plica ble per t he S o A at a p pr o xi matel y 0 8 0 0 h o urs (± 2 h o urs).  Details o n meals a n d dietar y  
re q uire me nts a n d acti vit y restricti o ns o n d osi n g da ys are gi ve n i n Secti o n 5. 3 .  
F oll o wi n g a n o ver ni g ht fast of at least 1 0 h o urs, partici pa nts will recei ve st u d y  i nter ve nti o n
wit h t he brea kfast meal at a p pr o xi matel y 0 8 0 0 h o urs ( ± 2 h o urs). I n vesti gat or site pers o n nel 
will a d mi nister P F - 0 7 0 8 1 5 3 2, mi daz ola m a n d o me praz ole, or t he O C d uri n g eac h peri o d (as 
a p plica ble per S o A ) 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 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.   T he st u d y  i nter ve nti o n will be a d mi nistere d 
acc or di n g t o t he I P ma n ual.  
P F - 0 7 0 8 1 5 3 2 m ust be a d mi nistere d wit hi n a p pr o xi matel y  1 0 mi n utes of c o m pleti o n of t he 
m or ni n g meal.  P F -0 7 0 8 1 5 3 2 will be a d mi nistere d first a n d mi daz ola m a n d o me praz ole or 
t he O C will be a d mi nistere d wit hi n 5 mi n utes of P F -0 7 0 8 1 5 3 2 d uri n g t he D DI assess me nt 
peri o ds .
W he n mi daz ola m a n d o me praz ole or t he O C are a d mi nistere d al o ne, t he y m ust be 
a d mi nistere d wit hi n a p pr o xi matel y 1 0 mi n utes of t he c o m pleti o n of t he m or ni n g meal.  
A d mi nistrati o n of st u d y  i nter ve nti o n will occ ur acc or di n g t o t he f oll o wi n g D osi n g Peri o ds 
a n d D osi n g Da ys, als o liste d i n t he S o A a n d Ta ble 8 .
M o dificati o n of d osi n g of P F - 0 7 0 8 1 5 3 2 m a y be per mitte d u p o n S p o ns or a p pr o val o nl y. See
Secti o n 6. 6 . 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
T a ble 8 .  
C o h ort 1 D osi n g
St u d y Peri o d
D a ys i n St u d y
Dr u g a n d D os a ge
Peri o d 1, Da y 1
1
S D Mi daz ola m
( 2 m g) + S D O me praz ole ( 2 0 m g)
Peri o d 2, Da ys 1 -5
2 -6
S D O C (L E 0. 1 5 m g/ E E 0. 0 3 m g)
Peri o d 3, Da ys 1 -7
7 -1 3
P F -0 7 0 8 1 5 3 2 2 0 m g Q D
Peri o d 3, Da ys 8 -1 4
1 4 -2 0
P F -0 7 0 8 1 5 3 2 4 0 m g Q D
Peri o d 3, Da ys 1 5 -2 1
2 1 -2 7
P F -0 7 0 8 1 5 3 2 6 0 m g Q D
Peri o d 3, Da ys 2 2 -2 8
2 8 -3 4
P F -0 7 0 8 1 5 3 2 8 0 m g Q D
Peri o d 4, Da y 1
3 5
P F -0 7 0 8 1 5 3 2 8 0 m g Q D + S D Mi daz ola m ( 2 m g) + S D 
O m e praz ole ( 2 0 m g)
Peri o d 5, Da ys 1 -5
3 6 -4 0
P F -0 7 0 8 1 5 3 2 8 0 m g Q D + S D O C ( L E 0. 1 5 m g/ E E 0. 0 3 m g)
Peri o d 6, Da ys 1 -7
4 1 -4 7
P F -0 7 0 8 1 5 3 2 1 0 0 m g Q D
Peri o d 6, Da ys 8 -1 4
4 8 -5 4
P F -0 7 0 8 1 5 3 2 1 2 0 m g Q D
Peri o d 6, Da ys 1 5 -2 1
5 5 -6 1
P F -0 7 0 8 1 5 3 2 1 4 0 m g Q D
Peri o d 6, Da ys 2 2 -2 8
6 2 -6 8
P F -0 7 0 8 1 5 3 2 1 6 0 m g Q D
Peri o d 6, Da ys 2 9 -3 5
6 9 -7 5
P F -0 7 0 8 1 5 3 2 1 8 0 m g Q D
Peri o d 6, Da ys 3 6 -4 2
7 6 -8 2
P F -0 7 0 8 1 5 3 2 2 0 0 m g Q D
Peri o d 6, Da ys 4 3 -4 9
8 3 -8 9
P F -0 7 0 8 1 5 3 2 2 2 0 m g Q D
Peri o d 6, Da ys 5 0 -5 6
9 0 -9 6
P F -0 7 0 8 1 5 3 2 2 4 0 m g Q D
Peri o d 6, Wee k 5 7 -6 3
9 7 -1 0 3
P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D
Peri o d 7, Da y 1
1 0 4
P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D + S D Mi daz ola m ( 2 m g) + S D 
O m e praz ole ( 2 0 m g)
Peri o d 8, Da ys 1 - 6
1 0 5 -1 1 0 *
P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D + S D O C ( L E 0. 1 5 m g/ E E 0. 0 3 m g)
O ut -patie nt
1 1 1 -1 2 4
N o d osi n g
Peri o d 9, Da ys 1 - 2
1 2 5 -1 2 6
S D Mi daz ola m ( 2 m g) o nl y
* T here is n o P F -0 7 0 8 1 5 3 2 a d mi nistrati o n o n Da y 1 1 0 or t hereafter .
C o h ort 2 – Partici pa nts will recei ve se ma gl uti de or mi daz ola m as a p plica ble per t he S o A at 
a p pr o xi matel y 0 8 0 0 h o urs (± 2 h o urs).  Details o n meals a n d dietar y  re q uire me nts a n d acti vit y 
restricti o ns o n d osi n g da ys are gi ve n i n Secti o n 5. 3 .  
F oll o wi n g a n o ver ni g ht fast of at least 1 0 h o urs , 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). I n vesti gat or site pers o n nel will a d mi nister (as 
a p plica ble per S o A ) se ma gl uti de as a s u bc uta ne o us i njecti o n d uri n g eac h peri o d .  Mi daz ola m 
will be a d mi nistere 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 . T he st u d y i nter ve nti o n will be a d mi nistere d acc or di n g t o t he I P ma n ual.
Se ma gl uti de m ust be a d mi nistere d o nce wee kl y, prefera bl y i n t he m or ni n g, wit h o ut re gar d t o 
ti mi n g of t he brea kfast meal d uri n g o ut patie nt visits t o t he C R U f or d ose a d mi nistrati o n.  
D uri n g t he D DI assess me nt i n patie nt visit ( Peri o d 3), se ma gl uti de a n d mi da z ola m m ust be 
a d mi nistere d wit hi n a p pr o xi matel y 1 0 mi n utes of c o m pleti o n of t he m or ni n g meal.  
Se ma gl uti de will be a d mi nistere d first, a n d mi daz ola m will be a d mi nistere d wit hi n 5 mi n utes 
of se ma gl uti de.
W he n mi daz ola m is a d mi nistere d al o ne, it m ust be a d mi nistere d wit hi n a p pr o xi matel y  
1 0 mi n utes of t he c o m pleti o n of t he m or ni n g meal.  
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
A d mi nistrati o n of st u d y  i nter ve nti o n will occ ur acc or di n g t o t he f oll o wi n g D osi n g Peri o ds 
a n d D osi n g Da ys, als o liste d i n t he S o A a n d Ta ble 9 .
M o dificati o n of se ma gl uti de d osi n g m a y  be per mitte d u p o n S p o ns or a p pr o val o nl y . See
Secti o n 6. 6 . 
T a ble 9 .  
C o h ort 2 D osi n g
St u d y Peri o d
D a ys i n St u d y
Dr u g a n d D os a ge
Peri o d 1, Da y 1
1
S D Mi daz ola m
( 2 m g)
Peri o d 2 , Wee ks
1 -4
2 -2 9
S e ma gl uti de 0. 2 5 m g o nce wee kl y
Peri o d 2, Wee ks 5 -8
3 0 -5 7
S e ma gl uti de 0. 5 m g o nce wee kl y
Peri o d 2, Wee ks 9 -1 2
5 8 -8 5
S e ma gl uti de 1. 0 m g o nce wee kl y
Peri o d 2, Wee ks 1 3 -1 6
8 6 -1 1 3
S e ma gl uti de 1. 7 m g o nce wee kl y
Peri o d 2, Wee ks 1 7 -2 1
1 1 4 -1 4 8
S e ma gl uti de 2. 4 m g o nce wee kl y
Peri o d 3 , Da ys 1 -2
1 4 9 -1 5 0 *
S e ma gl uti de 2. 4 m g o nce wee kl y + S D Mi daz ola m ( 2 m g)
O ut -patie nt
1 5 1 -1 6 4
N o d osi n g
Peri o d 4, Da ys 1 -2
1 6 5 -1 6 6
S D Mi daz ola m ( 2 m g) o nl y
* T here is n o se ma gl uti de a d mi nistrati o n o n Da y 1 5 0 or t hereafter .
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 i nter ve nti o n a n d o nl y 
a ut h orize d site staff ma y  s u p pl y or a d mi nister st u d y i nter ve nti o n. All st u d y 
i nter ve nti o ns m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d 
( ma n ual or a uto 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 bl e u p o n re q uest. Data f or n o n w or ki n g da ys m ust 
i n dicate t he mi ni m u m a n d ma xi m u m te m perat ures si nce pre vi o usly 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 ud y  i nter ve nti o n m ust be q uara nti ne d a n d n ot use d u ntil Pfizer pr o vi des per missi o n 
t o use t he st u d y i nter ve nti o n. S pecific details re gar di n g t he defi niti o n of a n e xc ursi o n 
a n d i nf or mati o n t he site s h o ul d re p ort f or eac h e xc ursi o n will be pr o vi de d t o t he si te 
i n t he I P ma n ual.
4.
A n y  st ora ge c o n diti o ns state d i n t he S R S D will be s u perse de d b y t he st ora ge 
c o n diti o ns state d o n t he la bel.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 n stit uti o n ( w here a p plica ble) 
is res p o nsi ble f or st u dy i nter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d 
mai nte na nce (ie, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds) , s uc h as t he 
I P A L or s p o ns or-a p pr o ve d e q ui vale nt . All st u d y  i nter ve nti o ns will be acc o u nte d f or 
usi n g a st u d y i nter ve nti o n acc o u nta bilit y f or m/rec or d.
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 IP m a n ual. All destr ucti o n m ust be a de q uatel y  
d oc u me nte d. If destructi o n is a ut h orize d t o ta ke place at t he i n vesti gat or site, t he 
i n vesti gat or m ust e ns ure t hat t he materials are destr o ye d i n c o m plia nce wit h 
a p plica ble e n vir o n me ntal re g ulati o ns, i nstit uti o nal p olic y , a n d a n y s pecial 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, t he s p o ns or m ust be n otifie d w it hi n 1 b usi ness 
da y  of disc o ver y as descri be d i n t he IP m a 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 healthcare pr o vi der, 
partici pa nt i n acc or da nce wit h t his pr ot oc ol.  L ocal 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.
Ta blets will be dis pe ns e 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 ys icia 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. 
T he c o m merciall y  a vaila ble pr o d ucts mi daz ola m , o me praz ole, a n d t he O C pr o vi de d b y t he 
C R U, a n d se ma gl uti de ( Oze m pic or We g o v y) pr o vi de d b y  t he Pfizer , will be pre pare d as per 
t he la bel a n d i n acc or da nce wit h t he p r ot oc ol by 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 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).  T he ta blets
( o me praz ole, O C a n d P F-0 7 0 8 1 5 3 2), s yr u p ( mi daz ola m) , or si n gle -d ose prefille d pe ns 
(se ma gl uti de) 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.
6. 3. Assi g n me nt t o St u d y I nter ve nti o n
T his is a n o n -ra n d o mize d, o pe n-la bel 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
T he i n vesti gat or will assi g n partici pa nt n u m bers t o t he partici pa nts as t he y  are scree ne d f or 
t he st u d y.  T he first f o ur di gits of t he S SI D will reflect t he s p o ns or-assi g ne d site n u m ber a n d 
t he re mai ni n g f o ur di gits will reflect eac h partici pa nt’s u ni q ue n u m ber assi g ne d i n 
c hr o n ol o gical or der as i nf or me d c o nse nt is o btai ne d.  I n a d diti o n, o n Da y  1 of Peri o d 1, eac h 
partici pa nt w h o is d ose d wit h t he i n vesti gati o nal pr o d uct will be assi g ne d a se parate, disti nct 
n u m ber (as pr o vi de d t o t he site b y  t he S p o ns or at t he start of t he st u d y) t o e na ble e xec uti o n of 
S p o ns ors’sta n dar d pr ocesses f or a nal y sis of all P K-relate d sa m ples. 
I n C o h ort 1 ( Peri o ds 3 t o 8) partici pa nts will recei ve t he P F - 0 7 0 8 1 5 3 2 d oses as descri be d i n
Ta ble 1 0 .  I n C o h ort 2 ( Peri o ds 2 a n d 3) partici pa nts will recei ve t he se ma gl uti de d oses as 
descri be d i n Ta ble 1 1 .  
T a ble 1 0 . P F -0 7 0 8 1 5 3 2 D osi n g Re gi me ns i n C o h ort 1
Peri o d & P F -
0 7 0 8 1 5 3 2 D ose ( d ose d 
o nce d ail y)
N u m ber of P F -0 7 0 8 1 5 3 2 T a blets
T ot al N u m ber of 
T a blets
2 0 m g
6 0 m g
1 0 0 m g
Peri o d 3: 2 0 m g
1
-
-
1
Peri o d 3: 4 0 m g
2
-
-
2
Peri o d 3: 6 0 m g
-
1
-
1
Peri o d 3: 8 0 m g
1
1
-
2
Peri o d 4 : 8 0 m g
1
1
-
2
Peri o d 5 : 8 0 m g
1
1
-
2
Peri o d 6 : 10 0 m g
-
-
1
1
Peri o d 6: 1 2 0 m g
1
-
1
2
Peri o d 6: 1 4 0 m g
2
-
1
3
Peri o d 6: 1 6 0 m g
-
1
1
2
Peri o d 6: 1 8 0 m g
1
1
1
3
Peri o d 6: 2 0 0 m g
-
-
2
2
Peri o d 6: 2 2 0 m g
1
-
2
3
Peri o d 6: 2 4 0 m g
2
-
2
4
Peri o d 6: 2 6 0 m g
-
1
2
3
Peri o d 7: 2 6 0 m g
-
1
2
3
Peri o d 8: 2 6 0 m g
-
1
2
3
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
T a ble 1 1 . Se m a gl uti de D osi n g Re gi me ns i n C o h ort 2
Peri o d
Wee kl y D ose
D ose per I njecti o n ( pre -fille d, 
dis p os a ble, si n gle -d ose pe ns)
T ot al Stre n gt h per T ot al 
V ol u me
Peri o d 2 : Wee ks 1 - 4
0. 2 5 m g
0. 2 5 m g
0. 2 5 m g / 0. 5 m L
Peri o d 2 : Wee ks 5 - 8
0. 5 m g
0. 5 m g
0. 5 m g / 0. 5 m L
Peri o d 2 : Wee ks 9 -1 2
1. 0 m g
1. 0 m g
1. 0 m g / 0. 5 m L
Peri o d 2 : Wee ks 1 3 -1 6
1. 7 m g
1. 7 m g
1. 7 m g / 0. 7 5 m L
Peri o d 2 : Wee ks 1 7 -2 1
2. 4 m g
2. 4 m g
2 . 4 m g / 0. 7 5 m L
Peri o d 3 : Da y 1
2. 4 m g
2. 4 m g
2 . 4 m g / 0. 7 5 m L
St u d y  i nter ve nti o n will be dis pe nse d at t he st u d y visits as s u m marize d i n t he S o A . Ret ur ne d 
st u d y i nter ve nti o n m ust n ot be re dis pe nse d t o t he partici pa nts.
6. 4. Bli n di n g
N ot a p plica ble as t his is a n o n -ra n d o mize d, o pe n-la bel st u d y. 
6. 5. 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 u d 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 an 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 partici 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 sta ff 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 dy site pers o n nel will e x a mi ne e ac h p artici p a nt’s m o ut h t o e ns ure t h at t he st u dy 
i nterve nti o n (e xce pt se m a gl uti de) w as i n geste d ; t his is vit ally i m p ort a nt t o e ns ure d osi n g 
c o m pli a nce i n lig ht of t he p ote nti al g astr oi ntesti n al A Es .
A d diti o n ally, if v o miti n g occ urs 
f oll o wi n g or al d osi n g a n d u p t o 4 h o urs p ost -d ose (t wice t he me di a n Tm a x of P F - 0 7 0 8 1 5 3 2), 
site pers o n nel will e x a mi ne t he e mesis f or evi de nce of dr u g pr o d uct. A d diti o nall y , f or 
C o h ort 2, eac h wee kl y i njecti o n of se ma gl uti de will be d oc u me nte d b y st u d y site staff .
6. 6. D ose M o dific ati o n
If partici pa nts are n ot a ble t o t olerate titrati o n t o hi g her d oses of P F -0 7 0 8 1 5 3 2
(e g, ≥22 0 m g Q D ) or se ma gl uti de t he d ose ma y be te m p orarily d o w n -titrate d, titrati o n t o t he 
ne xt d ose le vel ma y  be dela ye d te m p oraril y, or titrati o n t o a ma xi m u m t olerate d d ose ma y  be 
per mitte d, wit h S p o ns or a p pr o val o nl y.
6. 7. 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 vi 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 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
6. 8. Tre at me nt of O ver d ose
F or t his st u d y , a n y d ose of P F- 0 7 0 8 1 5 3 2 greater t ha n 1. 6 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. A si n gle d ose of 1. 6 g is pr ojecte d t o res ult i n e x p os ure t hat will 
e xcee d t hat o bser ve d at t he N O A E L i n t he pi v otal 9 -m o nt h t o xic ol o g y  st u d y i n m o n ke ys, 
after acc o u nti n g f or s pecies differe nces i n plas ma pr otei n bi n di n g. 
F or t his st u d y , o ver d ose f or mi daz ola m ,1 3 o me praz ole, 1 4 t he O C1 5 or se ma gl uti de 1 6 ,1 7 will be 
as per t he U S PI la bel.
T here is n o s pecific treat me nt f or a n o ver d ose f or P F - 0 7 0 8 1 5 3 2.  Treat me nt of o ver d ose 
s h o ul d c o nsist of ge neral s u p p orti ve meas ures.
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d:
1.
C o ntact t he me dical m o nit or wit hi n 2 4 h o urs.
2.
Cl osel y  m o nit or t he partici pa nt f or a ny A Es/ S A Es a n d la b orat or y  a b n or malities f or at 
least 5 half-li ves (a p pr o xi matel y 5 da ys) after t he o ver d ose of st u d y i nter ve nti o n, a n d 
as me dicall y a p pr o priate u ntil t he ne xt sc he d ule d f oll o w - u p.
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 ve r 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 1 da y 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).  
Decis i 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 as nee de d base d o n t he cli nical e val uati o n of t he 
partici pa nt.
6. 9. C o nc o mit a nt T her a p y
St u d y  partici pa nts will a bstai n fr o m all c o nc o mita nt treat me nts, e xce pt f or t he treat me nt of 
A Es , as descri be d i n t he E xcl usi o n Criteria secti o ns of t his pr ot oc ol.
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
(e g, St. J o h n’s w ort) 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 dy i nter ve nti o n.  S yste mic t hera p y wit h a n y me dicati o ns t hat are m o derate 
or str o n g C Y P 3 A 4/ 5 a n d/ or C Y P 2 C 1 9 i n hi bit ors or m o derate or str o n g C Y P 3 A 4/ 5 a n d/ or 
C Y P 2 C 1 9 i n d ucers wit hi n 1 4 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 mi daz ola m a n d o me praz ole are pr o hi bite d .
Use of a G LP- 1 R a g o nist is pr o hi bite d wit hi n 9 0 da ys 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
H or m o nal c o ntrace pti ves (i ncl u di n g oral a n d n o n-oral) are n ot all o we d t o be use d i n 
partici pa nts w h o are W O C B P (see A p pe n di x 4 ).
Fe males usi n g h or m o nal c o ntrace pti ves or ta ki n g h or m o ne re place me nt t hera p y ma 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 d a y s 
pri or t o t he fir st d ose of st u d y treat me nt a n d re mai n off h or m o nal t hera py f or t he d urati o n of 
t he st u d y.  De p o-Pr o vera ® m ust be disc o nti n ue d at least 6 m o nt hs pri or t o t he first d ose of 
st u d y treat me nt.
S y ste mic t hera p y wit h i n hi bit ors of O A T P tra ns p orters wit hi n 1 4 d a 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 are pr o hi bite d .
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 .
A nti- e metics (e g, pr oc hl or perazi ne, pr o met hazi ne, o n da nsetr o n) ma y  be a d mi nistere d at t he 
i n vesti gat or’s discreti o n wit h n otificati o n t o t he s p o ns or a n d e ntr y i n t he C R F ( See 
Secti o n 6. 9. 1. 1 ).
Sites are e nc o ura ge d t o c o ntact t he s p o ns or s h o ul d t here be q uesti o ns as t o w het her a 
me dicati o n is per mitte d or pr o hi bite d.
All 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 nt as liste d i n t he S o A .
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.
6. 9. 1. 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 0 8 1 5 3 2; sta n dar d me dic al 
s u p p orti ve care m ust be pr o vi de d t o ma na ge t he A Es, i ncl u di n g a d mi nistrati o n of 
car b o h y drates t o treat H A E s (see Secti o n 8. 3. 6 ).
6. 9. 1. 1.
M a n a ge me nt of N a use a a n d V o miti n g
Na usea a n d v o miti n g ha ve bee n re p orte d wit h a d mi nistrati o n of G L P- 1 R a g o nists a n d als o 
wit h a d mi nistrati o n of P F - 0 7 0 8 1 5 3 2 (see Secti o n 2. 2. 4 ).  St u d y partici pa nts c o m plai ni n g of 
na usea ma y  be ma na ge d c o nser vativel y wit h be d rest a n d/ or fl ui d ma na ge me nt at t he 
discreti o n of t he i n vesti gat or.  If na usea a n d v o miti n g are n ot a me na ble t o c o nser vati ve 
ma na ge me nt, a nti -e metics (e g, pr oc hl or perazi ne, pr o met hazi ne, o n da nsetr o n) ma y  be 
a d mi nistere d at t he in vesti gat or’s discreti o n wit h n otificati o n t o t he s p o ns or a n d e ntr y  i n t he 
C R F .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 
( defi niti ve disc o nti n uati 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:

Criteria f or a p ote ntial H y ’s la w case are met (see A p pe n di x 6 ).

I nte nt t o bec o me pre g na nt or pre g na nc y c o nfir me d b y ser u m -h C G testi n g.  

Safet y  or t olera bility c o ncer n arises, i n partic ular if n ot res p o nsi ve t o s y m pt o matic 
ma na ge me nt, d osi n g wit h st u d y  i nter ve nti o n ma y be st o p pe d i n a n i n di vi d ual 
partici pa nt at i n vesti gat or discreti o n.  

Base d o n me ntal healt h assess me nt as o utli ne d i n Secti o n 8. 3. 8 , s h o ul d be 
disc o nti n ue d fr o m d osi n g at i n vesti gat or discreti o n.

If t he criteria f or per ma ne nt disc o nti n uati o n are met, t he site s h o ul d n otif y t he s p o ns or 
Me dical M o nit or or s p o ns or Cli nicia n.

P ositi ve S A R S -C o V - 2 Test .
N ote t hat disc o nti n uati o n of st u d y  i nter ve nti o n d oes n ot re prese nt wit h dra wal fr o m t he st u d y.  
If st u d y i nter ve nti o n is per ma ne nt l y disc o nti n ue d, t he partici pa nt will re mai n i n t he st u d y t o 
be e val uate d f or a n E T visit.   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 a n d f oll o w-u p f or a n y  f urt her e val uati o ns t hat nee d t o 
be c o m plete d.
I n t he e ve nt of disc o nti n uati o n of st u d y i nter ve nti o n, it m ust be d oc u me nte d o n t he 
a p pr o priate C R F/i n t he me dical rec or ds w het her t he partici pa nt is disc o nti n ui n g f urt her 
recei pt of st u dy i nter ve nti o n or als o fr o m st u d y  pr oce d ures, p osttreat me nt st u d y f oll o w- u p, 
a n d/ or f ut ure c ollecti o n of a d diti o nal i nf or mati o n.
A d diti o nall y , 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 or a ny p orti o n of t he st u d y (e g, C o h ort 2) at a n y ti me f or a n y reas o n (e g, i na bilit y t o 
sec ure i n vesti gati o nal pr o d uct s u p plies) at t he s ole discreti o n of t he s po ns or. ( A p pe n di x 1 , 
Secti o n 1 0. 1. 9 ).
7. 2. P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al
fr o m t he St u d y
A partici pa nt ma y wit h dra w fr o m t he st u d y  at a ny ti me at his/ her o w n re q uest.  Reas o ns f or 
disc o nti n 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 her st u d y pr oce d ures.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

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.

Safet y  or be ha vi oral reas o ns at t he discreti o n of t he i n vesti gat or, i ncl u di n g reas o ns 
relate d t o me ntal healt h assess me nts.
At t he ti me of disc o nti n uati o n fr o m t he st u d y, if p ossi ble, a n early 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 wn 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.  
If a partici pa nt wit h dra ws fr o m t he st u d y, he/s he ma y re q uest destr ucti o n of a n y re mai ni n g 
sa m ples ta ke n a n d n ot teste d, a n d t he i n vesti gat or m ust d oc u me nt a n y s uc h re q uests i n t he 
site 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 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 be f ore s uc h wit h dra wal of c o nse nt.
Lac k of c o m pleti o n of all or a n y of t he wit h dra wal/ E T pr oce d ures will n ot be vie we d as 
pr ot oc ol de viati o ns s o l o n g as t he partici pa nt’s safet y  was preserve d.
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 nl y 
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 o n. 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 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 
wit h dra wal is o nl y  fr o m f urt her recei pt of st u d y i nter ve nti o n or als o fr o m st u d y  pr oce d ures 
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 meas ure d, p u blicl y 
a vaila ble i nf or mati o n s h o ul d be use d t o deter mi ne vital stat us o nl y  as a p pr o priatel y directe d 
i n acc or da nce wit h l ocal la w.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
7. 3. L ost t o F ol l o w- up 
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o atte n d a re q uire d st u d y visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as 
s o o n as p ossi ble.
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 vesti gat or or desi g nee m ust 
ma ke e ver y  eff ort t o re gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne 
calls a n d, if necessar y, a certifie d letter t o t he partici pa nt’s last k n o w n maili n g 
a d dress or l ocal e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d;

S h o ul d t he partici pa nt c o nti n ue t o be u nre ac 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
8. 1. A d mi nistr ati ve Pr oce d ures
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.
Safet y  iss ues s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne w het her t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y  
i nter ve nti o n.
A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A , is esse ntial 
a n d re q uire d f or st u d y c o n d uct.
All scree ni n g e val u ati 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat pr ot oc ol re q uire d tests a n d pr oce d ures are 
c o m plete d as descri be d.  H o we ver, it is a ntici pate d t hat fr o m ti me t o ti me t here ma y  be 
circ u msta nces o utsi de t he c o ntr ol of t he i n vesti gat or t hat ma y  ma ke it u nfeasi ble t o perf or m 
t he test.  In t hese cases, t he i n vesti gat or m ust ta ke all ste ps necessar y t o e ns ure t he safety a n d 
well bei n g of t he partici pa nt.  W he n a pr ot oc ol re q uire d test ca n n ot be perf 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.
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 partici pa nts i n t his st u d y  is a p pr o xi matel y
8 8 0 m L  i n C o h ort 1 a n d 4 0 0 m L  i n C o h ort 2 .  The t otal bl o o d v ol u me ta ke n d oe s n ot e xcee d 
5 5 0 m L  i n a ny gi ve n 5 6- da y c o nsec uti ve peri o d of ti me f or eit her C o h ort 1 or 2.  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 n y peri o d of 5 6 c o nsec uti ve da ys.
T o pre pare f or st u dy 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.
8. 2. Effic ac y Assess me nts
N ot a p plica ble.
8. 3. 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. 3. 1. P h ysic al E x a mi n ati o ns
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 ye s, 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 n d car di o vasc ular sys te ms, a n d partici pa nt -re p orte d sy m pt o ms.
C o m plete p h y sical e xa m will be d o ne at ti me p oi nts s pecifie d i n t he S o A ot her wise, brief 
e xa m if fi n di n gs d uri n g pre vi o us e xa m or ne w/ o pe n A Es, if a p pr o priate, at i n vesti gat or 
discreti o n.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 .  Hei g ht will be 
meas ure d at scree ni n g o nl y .  Wei g ht will be rec or de d usi n g a cali brate d scale ( wit h t he sa me 
scale use d if p ossi ble, f or t he d urati o n of t he st u d y) re p orti n g wei g ht i n eit her p o u n ds (l b) or 
k il o gra ms ( k g), a n d acc urac y t o t he nearest 0. 2 l b ( or 0. 1 k g); ie, t he de vice 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).  T he scale m ust 
be place d o n a sta ble, flat s urface.  
Wei g ht meas ure me nt 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:

I n t he m or ni n g i n a fasti n g state.

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.

After r e m o val of p oc ket c o nte nts. 

W hile re mai ni n g still d uri n g t he meas ure 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 xa mi nati o n fi n di n gs t hat are i de ntifie d d uri n g t he acti ve c ollecti o n peri o d a n d meet t he 
defi niti o n of a n A E or S A E ( A p pe n di x 3 ) m ust be re p orte d acc or di n g t o t he pr ocesses i n 
Secti o n 8. 4. 1 t o 8. 4. 3 .
8. 3. 2. Vit al Si g ns
Vital si g ns (s ys t olic B P, diast olic B P a n d P R ) will occ ur as s pecifie d i n t he S o A .  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 xi matel y 5 mi n utes of s u pi ne rest.  T he sa me ar m ( prefera bly 
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 nts 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.  W he n tri plicate meas ure me nts are o btai ne d, t he y s h o ul d be 
c ollecte d a p pr o xi matel y 2 mi n utes a part. 
At S cree ni n g, t he partici pa nt’s ar m circ u mfere nce s h o ul d be meas ure d (e g, usi n g a fle xi ble 
a nt hr o p o metric ta pe) at t he mi d p oi nt of t he le n gt h of t he u p per ar m a n d t he a p pr o priate c uff 
selecte d a n d use d t hr o u g h o ut t he st u d y.  T 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 me.  
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 R is acce pta ble; b ut 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 R 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. 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
A d diti o nal 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 R will be per mitte d, 
as necessar y, t o e ns ure a p pr o priate c ollecti o n of safety data.
A n y  u nt o war d vital si g 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 ) m ust be re p orte d acc or di n g t o t he 
pr ocesses i n Secti o n 8. 4. 1 t o 8. 4. 3 .
8. 3. 2. 1. Te m per at ure
B o d y te m perat ure will be meas ure d at t he ti me p oi nts liste d i n t he S o A .  Te m perat ure will be 
meas ure d orall y . N o eati n g, dri n ki n g, or s m o ki n g is all o we d f or 1 5 mi n utes pri or t o t he 
meas ure me nt.
8. 3. 3. Electr oc ar di o gr a ms
Sta n dar d 1 2 -lea d EC Gs utilizi n g li m b lea ds ( wit h a 1 0 sec o n d r hyt h m stri p) s h o ul d be 
c ollecte d at ti mes s pecifie d i n t he S o A secti o n of t his pr ot oc ol usi n g a n E C G mac hi ne t hat 
aut o maticall y  calc ulates t he H R a n d meas ures P R, Q T, a n d Q Tc F i nter vals a n d Q R S 
c o m ple x .  Alter nati ve lea d place me nt met h o d ol o g y usi n g t ors o lea ds ( e g, Mas o n L i kar) is n ot 
rec o m me n de d gi ve n t he p ote ntial ris k of discre pa ncies wit h E C Gs ac q uire d usi n g sta n dar d 
li m b lea d place me nt. All sc he d ule d 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 1 0 mi n utes i n a s u pi ne p ositi o n. 
T o e ns ure safety 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 scree ni n g meas ure me nts.  A d diti o nal E C G m o nit ori n g will occ ur if 
a) a p ost d ose Q Tc F i nter val is i ncrease d b y ≥6 0 msec fr o m t he scree ni n g a n d is > 4 5 0 msec ; 
or b) a n a bs ol ute Q Tc F val ue is ≥5 0 0 msec 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 2 a d diti o nal E C Gs will be c ollecte d a p pr o xi matel y  2 t o 4 mi n utes 
a part t o c o nfir m t he ori gi nal meas ure me nt.   If t he Q TcF val ues fr o m t hese re peate d E C Gs 
re mai n a b o ve t he t hres h ol d val ue, t he n a si n gle E C G m ust be re peate d at least h o urly u ntil 
Q Tc F 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 
meas ure me nt.
If a) a p ost d ose Q Tc F i nter val re mai ns ≥3 0 msec fr o m the scree ni n g a n d is > 4 5 0 msec; or 
b) a n a bs ol ute Q Tc F val ue is ≥5 0 0 msec f or a n y 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 i nter vals d o n ot ret ur n t o less t ha n t he criteri o n 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 
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 F 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 val ues are i n t he 
acce pta ble ra n ge.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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. 3. 4. 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 ureme 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 [2 8 -3 5 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 
DI LI.
See A p pe n di x 7 f or i nstr ucti o ns f or la b orat or y testi n g t o m o nit or ki d ne y f u ncti o n a n d 
re p orti n g la b orat or y test a b n or malities.
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. 3. 4. 1. Alter n ati ve F acilities f or Cli nic al S afet y L a b or a t or y Assess me nt
If a l ocal la b orat or y is use d, q ualifie d st u d y site pers o n nel m ust or der, recei ve, a n d re vie w 
res ults. Site staff m ust c ollect t he l ocal la b orat or y refere nce ra n ges a n d certificati o ns/
accre ditati o ns f or fili n g at t he site.   La b orat or y test res ults are t o be pr o vi de d t o t he site staff 
as s o o n as p ossi ble.   T he l ocal la b orat or y  re p orts s h o ul d be file d i n t he partici pa nt’s s o urce
d oc u me nts/ me dical rec or ds. Rele va nt data fr o m t he l ocal la b orat or y  re p ort s h o ul d 
be  rec or de d o n t he C R F.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. 3. 5. C O VI D - 1 9 Specific A ssess me nts
C o h ort 1: Partici pa nts will be teste d f or S A R S -C o V - 2 i nfecti o n by P C R pri or t o bei n g 
a d mitte d t o t he cli nic f or c o nfi ne me nt i n Peri o ds 1 a n d 9.  A s u bse q ue nt test will als o be d o ne
acc or di n g t o l ocal pr oce d ure, if partici pa nts de v el o p s ym pt o ms s u g gesti ve of C O VI D - 1 9. If 
partic i pa nts test p ositi ve f or S A R S -C o V -2 i nfecti o n, t he y  will be disc har ge d fr o m t he st u d y. 
C o h ort 2: Partici pa nts will be teste d f or S A R S -C o V - 2 i nfecti o n by P C R pri or t o bei n g 
a d mitte d t o t he cli nic f or c o nfi ne m e nt i n Peri o ds 1, 3 a n d 4.  A s u bse q ue nt test will als o be 
d o ne acc or di n g t o l ocal pr oce d ure, if partici pa nts de vel o p s ym pt o ms s u g gesti ve of 
C O VI D - 1 9.  If partici pa nts test p ositi ve f or S A R S-C o V -2 i nfecti o n, t he y  will be disc har ge d 
fr o m t he st u d y.
A d diti o nal testi n g ma y  be re q uire d b y l ocal re g ulati o ns or b y t he Pri nci pal I n vesti gat or.
Res ults m ust be ne gati ve f or a d missi o n t o t he C R U . 
8. 3. 6. M a n a ge me nt of H y p o gl yce mi a
W hile h y p o gl yc e mia is n ot e x pecte d i n t he st u d y partici pa nts, fasti n g bl o o d gl uc ose will be 
meas ure d as part of la b orat or y  assess me nt per t he S o A .  In a d diti o n, as a preca uti o n, 
partici pa nts will be m o nit ore d f or t he si g ns a n d s y m pt o ms ass ociate d wit h h y p o gl yc e mia. 
A n y  e pis o de of h yp o gl yc e mia m ust be ca pt ure d o n t he H A E C R F wit h s pecific details 
ca pt ure d o n t he H A E F or m C R F.  F or t he defi niti o n of a h y p o gl yce mic e pis o de a n d se verit y 
cate g orizati o n see Secti o n 8. 3. 6. 1 bel o w.
F or me dical ma na ge me nt of h y p o gl yc e mia, t he i n vesti gat or ma y a d mi nister oral 
car b o h y drate, gl uca g o n, or I V gl uc ose acc or di n g t o his or her me dical j u d g me nt.  
8. 3. 6. 1. Defi niti o n a n d Se verit y of C ate g oriz ati o n of H y p o gl yce mic A d verse E ve n t 
( H A E)
T he i n vesti gat or m ust assess t he gl uc ose val ues re p orte d b y t he ce ntral/l ocal la b orat or y, as 
well as a n y si g ns or s ym pt o ms re p orte d by t he st u d y  partici pa nt.
H A E is defi ne d as o ne of t he f oll o wi n g: 5 1
a.
As y m pt o matic h y p o gl yc e mia: A n e ve nt n ot acc o m pa nie d b y  ty pical s y m pt o ms of 
H A E b ut a gl uc ose val ue of < 7 0 m g/ d L  ( 3. 9 m m ol/ L) usi n g eit her gl uc o meter 
(fi n gerstic k bl o o d gl uc ose) at t he st u dy s ite or s p o ns or-i de ntifie d ce ntral/l ocal 
la b orat or y ( bl o o d gl uc ose).
b.
D oc u me nte d s y m pt o matic h y p o gl yc e mia: A n e ve nt d uri n g w hic h t y pical s y m pt o ms 
of H A E are acc o m pa nie d wit h a gl uc ose val ue of < 7 0 m g/ d L ( 3. 9 m m ol/ L), usi n g 
gl uc o meter at t he st u d y s ite or s p ons or i de ntifie d ce ntral/l ocal la b orat or y , a n d t he 
cli nical pict ure i ncl u des pr o m pt res ol uti o n wit h f o o d i nta ke, s u bc uta ne o us gl uca g o n, 
or I V gl uc ose.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
c.
Pr o ba ble s y m pt o matic h y p o gl yc e mia: A n e ve nt d uri n g w hic h s ym pt o ms of H A E are 
n ot acc o m pa nie d b y a gl uc ose deter mi nati o n b ut was pres u ma bl y ca use d b y a gl uc ose 
c o nce ntrati o n of < 7 0 m g/ d L ( 3. 9 m m ol/ L), a n d t he cli nical pict ure i ncl u des pr o m pt 
res ol uti o n wit h f o o d i nta ke, s u bc uta ne o us gl uca g o n, or I V gl uc ose.
Eac h e pis o de of H A E m ust be cate g orize d wit h res pect t o se verit y.  I n or der t o c haracterize 
t he e ve nt as se vere, all 3 criteria bel o w m ust be met:
1.
T he partici pa nt was u na ble t o treat hi m/ herself.  Ne ur ol o gic i m pair me nt, a n d n ot t he 
a ge of t he partici pa nt, is t he e x pla nati o n f or w h y t he partici pa nt c o ul d n ot t reat 
hi m/ herself a n d re q uire d t he assista nce of a n ot her pers o n.
2.
T he partici pa nt e x hi bite d at least 1 of t he f oll o wi n g ne ur ol o gical s y m pt o ms:

Me m or y  l oss.

C o nf usi o n.

U nc o ntr olle d be ha vi or.

Irrati o nal be ha vi or.

U n us ual diffic ult y  i n a wa ke ni n g.

S us pecte d seiz ure.

Seiz ure.

L oss of c o nsci o us ness.
3.
Eit her :

If bl o o d gl uc ose was meas ure d a n d was ≤5 4 m g/ d L ( 2. 7 m m ol/ L) usi n g 
gl uc o meter ( or ce ntral /l ocal la b orat or y); or

If bl o o d gl uc ose was n ot meas ure d, t he cli nical ma nifestati o ns were re verse d b y 
oral car b o h y drates, s u bc uta ne o us gl uca g o n, or I V gl uc ose.
E ve nts t hat d o n ot meet all t he criteria a b o ve f or se vere H A E are c haracterize d as mil d or 
m o derate i n se verit y .
8. 3. 6. 2. Gl uc o meter M o nit ori n g of Gl uc ose
M o nit ori n g of F S B G usi n g gl uc o meter meas ure me nts is n ot re q uire d per pr ot oc ol b ut ma y  be 
o btai ne d if t he i n vesti gat or or partici pa nt n otes s y m pt o ms of h y p o gl y ce mia.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
If o btai ne d, F S B G rea di n gs will be mai ntai ne d at t he C R U i n s o urce d oc u me nts, a n d o nl y t he 
gl uc ose res ults fr o m t he la b orat or y  will be re p orte d i n t he st u d y data base.
If a n F S B G res ult is ≤7 0 m g/ d L, a sec o n d F S B G s h o ul d be o btai ne d t o c o nfir m t he gl uc ose 
val ue, i n a d diti o n t o a ve n o us sa m ple t hat will be se nt t o t he cli nical la b orat or y  f or 
c o nfir mati o n.  If t he val ue fr o m t his sec o n d F S B G is als o ≤7 0 m g/ d L , t he sec o n d val ue will 
be rec or de d as a h y p o gl yce mic A E.  F S B G will c o nti n ue t o be m o nit ore d u ntil t he gl uc ose 
val ue ret ur ns t o > 7 0 m g/ d L .  Sa m ples ma y be ta ke n m ore fre q ue ntly if dee me d necessar y  b y 
t he i n vesti gat or.  
8. 3. 7. Pre g n a nc y Testi n g 
A ser u m pre g na nc y  test is re q uire d at scree ni n g. Pre g na nc y  tests ma y be uri ne or ser u m tests 
b ut m ust ha ve a se nsiti vit y  of at least 2 5 mI U/ m L.
Pre g na nc y  tests will be perf or me d i n 
W O C B P at t he ti mes liste d i n t he S o A .  F oll o wi n g a ne gati ve pre g na nc y  test res ult at 
scree ni n g, a p pr o priate n o n h or m o nal c o ntrace pti o n m ust be c o m me nce d, a n d a sec o n d 
ne gati ve pre g na nc y  test res ult will be re q uire d at t he baseli ne visit pri or t he partici pa nt’s 
recei vi n g t he st u dy i nter ve nti o n/st u d y  treat me nt. Pre g na nc y  tests will als o be d o ne w he ne ver 
1 me nstr ual c y cle is misse d d uri n g t he acti ve treat me nt peri o d ( or w he n p ote ntial pre g na nc y  
is ot her wise s us pecte d) a n d at t he e n d of t he st u dy. Pre g na nc y  tests ma y als o be re peate d if 
re q ueste d by I RBs/ E Cs or if re q uire d b y  l ocal re g ulati o ns. If a uri ne test ca n n ot be c o nfir me d 
as ne gati ve (e g, a n a m bi g u o us res ult), a ser u m pre g na nc y  test is re q uire d. I n s uc h cases, t he 
partici pa nt m ust be e xcl u de d if t he ser u m pre g na nc y  res ult is p ositi ve.
8. 3. 8. 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. 3. 8. 1. C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)
T he C -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. 4 3  T he “ baseli ne/ scree ni n g” versi o n of t he C -S S R S will be a d mi nistere d at 
Scree ni n g a n d Da y  -1 i n st u d y .  Partici pa nts w h o res p o n d “ y es” t o Q uesti o n 4 or 
5 (i n dicati n g s uici dal i deati o n), or t o a n y s uici dal be ha vi oral q uesti o n o n t he C -S S R S at 
scree ni n g or Da y- 1 will n ot be per mitte d i n t he st u d y (see Secti o n 5. 2 ).  T he “si nc e last visit ” 
versi o n of t he C -S S R S will be a d mi nistere d a t t he ti me p oi nts s pecifie d i n t he S o A .  T he 
C- S S R S will be a d mi nistere d b y st u d y site staff w h o ha ve c o m plete d trai ni n g i n its 
a d mi nistrati o n .
8. 3. 8. 1. 1. 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 g ui da nce d oc u me nt 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 her 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 xercises ma y be c o n d ucte d, a n d writte n a n d si g ne d d oc u me ntati o n will be pr o vi de d b y t he 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
site f or eac h rater’s certificati o n.  In ret ur n, eac h site will be pr o vi de d wit h writte n a n d si g ne d 
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 d y  assess me nts.  
Recertificati o n ma 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 on d uct of t he st u d y.
8. 3. 8. 2. P atie nt He alt h Q uesti o n n aire -9 ( P H Q - 9)
T he P H Q -9 is a 9 ite m self -re p ort scale f or t he assess me nt of de pressi ve sy m pt o ms. 4 8 T he 
P H Q -9 will be c o m plete d b y  partici pa nts a n d re vie we d by site staff at t he pre -defi ne d ti me 
p oi nts o utli ne d i n t he S o A .  A P H Q-9 sc ore of ≥1 5 at Scree ni n g or Da y  -1 i n dicates cli nicall y 
si g nifica nt de pressi o n a n d ser ves as a n e xcl usi o n criteri o n f or t his st u d y (see Secti o n 5. 2 ).
8. 3. 8. 3. Referr al t o a Me nt al H e alt h P r ofessi o n al
A partici pa nt s h o ul d be referre d t o a M H P f or t he f oll o wi n g reas o ns:

Res p o nse of “ y es” t o q uesti o n 4 or 5 , or o n a n y s uici dal be ha vi oral q uesti o n o n t he 
C- S S R S .

A sc ore of ≥1 5 o n t he P H Q - 9.

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 re q uire d.
A cli nicall y q ualifie d M H P is a n M H P wit h a p pr o priate trai ni n g i n t he assess me nt of s uici de 
ris k, acc or di n g t o l ocal cli nical practice sta n dar ds a n d re g ulati o ns, w h o w o ul d n or mall y  
e val uate t he ris k f or s uici dal i deati o n a n d be ha vi or i n a patie nt.
Partici pa nts w h o ha ve rec urre nt s uici dal i deati o n or be ha vi or d uri n g t he st u d y  s h o ul d be 
disc o nti n ue d fr o m t he st u d y  a n d treate d a p pr o priatel y. If a st u d y partici pa nt e n d orses a 4 or 
5 o n t he i deati o n s u bscale or a n y be ha vi oral ite m of t he C -S S R S o n 2 or m ore occasi o ns a n d 
is c o nfir me d t o ha ve acti ve s uici dal i deati o n or be ha vi or o n b ot h occasi o ns b y a ris k
assess me nt c o n d ucte d b y a q ualifie d M H P, t h e n 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 treate d a p pr o priately.
Partici pa nts w h o meet criteria f or referral t o a M H P b ut
ref use e val uati o n a n d/ or treat me nt by 
a M H P, m ust be assesse d b y  t he i n vesti gat or t o deter mi ne if t he partici pa nt s h o ul d be 
disc o nti n ue d fr o m d osi n g or fr o m t he st u d y. 
8. 4. 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 ults, etc.).
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble t o p urs ue 
a n d o btai n a de q uate i nf or mati o n b ot h t o deter mi ne t he o utc o me a n d t o assess w het her t he 
e ve nt meets t he criteria f or classificati o n as a n S A E or ca use d t he partici pa nt t o disc o nti n ue 
t he st u d y i nter ve nti o n (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. 4. 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 ormati o n i n a n e x pe dite d fas hi o n.
8. 4. 1. Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
T he ti me peri o d f or acti vel y  eliciti n g a n d c ollecti n g A Es a n d S A Es (“acti ve c ollecti o n 
peri o d”) f or eac h partici pa nt be gi ns fr o m t he ti me t he partici pa nt pr o vi d es 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 oll o w - u p b y  t he i n vesti gat or c o nti n ues t hr o u g h o ut a n d after t he acti ve c ollecti o n peri o d a n d 
u ntil t he A E or S A E or its se q uelae res ol ve or sta bilize t o a le vel acce pta bl e t o t he 
i n vesti gat or.
W he n a cli nicall y  i m p orta nt A E re mai ns o n g oi n g at t he e n d of t he acti ve c ollecti o n peri o d, 
f oll o w-u p b y  t he i n vesti gat or c o nti n ues 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 a n d Pfizer c o nc urs wit h t hat assess me nt.
F or partici pa nts w h o are scree n fail ures, t he acti ve c ollecti o n peri o d e n ds w he n scree n fail ure 
stat us is deter mi ne d.
If t he partici pa nt wit h dra ws fr o m t he st u d y a n d als o wit h dra ws c o nse nt f or t he c ollecti o n of 
f ut ure i nf or mati o n, t he acti ve c ollecti o n peri o d e n ds w he n c o nse nt is wit h dra w n.
If a partici pa nt 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 b e 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 n y  ti me after a partici pa nt has c o m plete d t he st u d y, a n d he/s he 
c o nsi ders t he e ve nt t o be reas o na bl y relate d t o t he st u d y  i nter ve nti o n, t he i n vesti gat or m ust 
pr o m ptl y  re p ort t he S A E t o Pfizer usi n g t he C T S A E Re p ort F or m.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
8. 4. 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. 4. 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.
8. 4. 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. 4. 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.
As par t of o n g oi n g safety re vie ws c o n d ucte d b y t he s p o ns or, a n y n o nseri o us A E t hat is 
deter mi ne d b y t he s p o ns or t o be seri o us will be re p orte d b y t he s p o ns or as a n S A E. T o assist 
i n t he deter mi nati o n of case seri o us ness, f urt her i nf or mati o n ma y be re q ueste d fr o m t he 
i n vesti gat or t o pr o vi de clarit y a n d u n dersta n di n g of t he e ve nt i n t he c o nte xt of t he cli nical 
st u d y.
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 Sect i o n 5. 4 .
8. 4. 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 mitt i 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. 4. 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 m ati 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 n y i nf or mati o n rele va nt t o t he e ve nt, s uc h as c o nc o mita nt me dicati o ns 
a 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. 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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. 4. 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 hical res p o n si bilities t o war d t he safety 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.
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. 4. 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 mily me m bers, a n d ot hers w h o ma y be e x p ose d. 
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 
breastfee 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. 4. 5. 1. E x p os ure D uri n g Pre g n a nc y
A n E D P occ urs if: 

A fe male partici pa nt is f o u n d t o be pre g na nt w hile recei vi n g or after disc o nti n ui n g 
st u d y i nter ve nti o n.

A fe male is f o u n d t o be pre g na nt w hile bei n g e x p ose d or ha vi n g bee n e x p ose d t o 
st u d y i nter ve nti o n d ue t o e n vir o n me ntal e x p os ure. Bel o w are e xa m ples of 
e n vir o n me ntal E 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 v i 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 antici pate d date of deli ver y  (see bel o w f or i nf or mati o n relate d t o 
ter mi nati o n of pre g na nc y). 

If E D P occ urs i n a partici pa nt or a partici pa nt’s part ner, t he i n vesti gat or m ust re p ort 
t his i nf or mati o n t o Pfizer Safet y o n t he C T S A E Re p ort F or m a n d a n E D P 
S u p ple me ntal F or m, re gar dless of w het her a n S A E has occ urre d. Details of t he 
pre g na nc y  will be c ollecte d after t he start of st u d y i nter ve nti o n a n d u ntil 2 8 da y s after 
t he last d ose.

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 stu 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 an 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 Su 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 in 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 AEs. 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). I n 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 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
t he partici pa nt was gi ve n t he Pre g na nt Part ner Release of I nf or mati o n F or m t o pr o vi de t o his 
part ner.
8. 4. 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 m ber or healt hcare pr o vi der w h o re p orts t hat s he is 
breastfee di n g after ha vi n g bee n e x p ose d t o t he st u d y  i nter ve nti o n b y i n gesti o n.  
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 vi r o n me ntal e x p os ure, t he e x p os ure i nf or mati o n d oes 
n ot pertai n t o t he partici pa nt e nr olle d i n t he st u d y, s o t he i nf or mati o n is n ot rec or de d o n a 
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 u re d uri n g breastfee di n g re p ort is n ot create d w he n a Pfizer dr u g s 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. B ut if t he i nfa nt e x perie nces a n S A E ass ociate d wit h s uc h a dr u g, t he S A E is 
re p orte d t o get her wit h t he e x p os ure d uri n g breastfee di n g.
8. 4. 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; b ut 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. 4. 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. 4. 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. 4. 8. A d verse E ve nts of S peci al I nterest
N ot a p plica ble.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
8. 4. 8. 1. L ac k of Effic ac y
N ot a p plica ble.
8. 4. 9. Me dic al De vice Deficie ncies
N ot a p plica ble.
8. 4. 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 u res 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 err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o 
or d o n ot i n v ol ve t he st u d y partici pa nt .
S uc h me dicati o n err ors occ urri n g t o a st u d y partici pa nt are t o be ca pt ure d o n t he me dicati o n 
err or pa ge of t he C R F, w hic h is a s pecific versi o n of t he A E pa ge.
I n t he e ve nt of a me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d wit hi n 2 4 h o urs .
W het her or n ot t he me dicati o n err or is acc o m pa nie d b y  a n A E, as deter mi ne d b y t he 
i n vesti gat or, t he me dicati o n err or is rec or de d o n t he me dicati o n err or pa ge of t he C R F a n d, if 
a p plica ble, a n y ass ociate d A E(s), seri o us a n d n o nseri o us, are rec or de d o n t he A E pa ge of t he 
C R F. 
Me dicati o n err ors s h o ul d be re p orte d t o Pfizer Safet y wit hi n 2 4
h o urs o n a C T S A E Re p ort 
F or m o nl y w he n ass oci ate d wit h a n S A E.
8. 5. P h ar m ac o ki netics 
Bl o o d sa m ples will be c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of mi daz ola m, 
1 -h y dr o x y mi daz ola m, o me praz ole, 5 -h y dr o x y o m e praz ole, L E, E E , P F -0 7 0 8 1 5 3 2 , a n d 
se ma gl uti de as s pecifie d i n t he S o A .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 remai 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 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, if 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, if 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.
Sa m ples c ollecte d f or a nal yses of st u d y i nter ve nti o n 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 o n of t he bi oa nal y tical met h o d, or f or ot her i nter nal 
e x pl orat or y p ur p oses.
Sa m ples c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of st u d y  i nter ve nti o n will be 
a nal yz e d usi n g a va li date d a nalyt ical met h o d i n c o m plia nce wit h a p plica ble S O Ps.  P ote ntial 
meta b olites ma y  be a nalyze d wit h eit her vali date d or e x pl orat or y met h o ds.
Ge netic a nal ys es will n ot be perf or me d o n t hese 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.
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 
inte grit y h as bee n c o m pr o mise d. A n y  de viati o n fr o m t he s pecifie d sa m ple ha n dli n g 
pr oce d ure res ulti n g i n c o m pr o mise d sa m ple i nte grit y, will be c o nsi dere d a pr ot oc ol 
de viati o n.
A n y  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 assess 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 I R 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 safet y m o nit o ri n g sc he me or 
a me n d me nt of t he I C D.
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 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. 5. 1. P K of Mi d az ol a m a n d 1- h y dr o x y mi d az ol a m
Sa m ples will be use d t o e val uate t he P K of mi daz ola m a n d 1 -h y dr o x y mi daz ola m.  F or 
C o h ort 1, b l o o d sa m ples of a p pr o xi matel y 4 m L, t o pr o vi de 2 ali q u ots of plas ma v ol u me of 
a p pr o xi matel y 0. 8 m L  eac h, will be c ollecte d i nt o a p pr o priatel y la bele d t u bes c o ntai ni n g 
K 2E D T A f or meas ure me nt of plas ma c o nce ntrati o ns of mi daz ola m a n d 1 -h y dr o x y mi daz ola m 
as s pecifie d i n t he S o A .  F or C o h ort 2, bl o o d sa m ples of a p pr o xi matel y  5 m L, t o pr o vi de
2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  0. 8 m L  eac h will be c ollecte d i nt o 
a p pr o priatel y la bele d t u bes c o ntai ni n g K 2E D T A f or meas ure me nt of plas ma c o nce ntrati o ns 
of mi daz ola m a n d 1- h y dr o x y mi daz ola m as s pecifie d i n t he S o A . 
8. 5. 2. P K of O me pr az ole a n d 5 -h y dr o x y o me pr az ole
Sa m ples will be use d t o e val uate t he P K of o me praz ole a n d 5 -h y dr o x y o me praz ole .  Bl o o d 
sa m ples of a p pr o xi matel y 2 m L , t o pr o vi de 2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  
0. 4 m L  eac h, will be c ollecte d i nt o a p pr o priately la bele d t u bes c o n tai ni n g K2E D T A f or 
meas ure me nt of plas ma c o nce ntrati o ns of o me praz ole a n d 5 -h y dr o x y o me praz ole as s pecifie d 
i n t he S o A .  
8. 5. 3. P K of Le v o n or gestrel
Sa m ples will be use d t o e val uate t he P K of L E .  Bl o o d sa m ples of a p pr o xi matel y 6 m L , t o 
pr o vi de 2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  1. 2 m L  eac h, will be c ollecte d i nt o 
a p pr o priatel y la bele d t u bes c o ntai ni n g K 2E D T A f or meas ure me nt of plas ma c o nce ntrati o ns 
of L E as s pecifie d i n t he S o A .  
8. 5. 4. P K of Et hi n yl Estr a di ol
Sa m ples will be use d t o e val uate t he P K of E E .  Bl o o d sa m ples of a p pr o xi matel y 6 m L, t o 
pr o vi de 2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  1. 2 m L  eac h, will be c ollecte d i nt o 
a p pr o priatel y la bele d t u bes c o ntai ni n g K 2E D T A f or meas ure me nt of plas ma c o nc e ntrati o ns 
of E E as s pecifie d i n t he S o A .  
8. 5. 5. P K of P F - 0 7 0 8 1 5 3 2
Sa m ples will be use d t o e val uate t he P K of P F -0 7 0 8 1 5 3 2 .  Bl o o d sa m ples of a p pr o xi matel y 
2 m L , t o pr o vi de 2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  0. 3 m L  eac h, will be
c ollecte d i nt o a p pr o priatel y  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 P F -0 7 0 8 1 5 3 2 as s pecifie d i n t he S o A .  
8. 5. 6. P K of S e m a gl uti de
Sa m ples will be use d t o e val uate t he P K of se ma gl uti de.  Bl o o d sa m ples of a p pr o xi matel y  6
m L , t o pr o vi de 2 ali q u ots of plas ma v ol u me of a p pr o xi matel y  1. 2 m L  eac h, will be c ollecte d 
i nt o a p pr o priately la bele d t u bes c o ntai ni n g K 2E D T A f or meas ure me nt of plas ma 
c o nce ntrati o ns of se ma gl uti de as s pecifie d i n t he S o A .  
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. 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 .
See 
f or i nf 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 orat or y ma n ual.
8. 7. Bi o m ar kers
T he f oll o wi n g sa m ples f or bi o mar ker researc h are re q uire d a n d will be c ollecte d fr o m all 
partici pa nts i n t his st u d y  as s pecifie d i n t he S o A .
8. 7. 1. S pecifie d Pr otei n Rese arc h
8. 7. 2. 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.
8. 7. 3. 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. 4. Ret ai ne d Rese arc h S a m ples f or Bi o m ar kers
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI
C CI
C CI
C CI
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. 7. 5. Pl as m a f or A n al ysis of 4 -h y dr o x yc h olester ol/c h olester ol
Bl o o d sa m ples of a p pr o xi matel y  4 m L, t o pr o vi de 2 ali q u ots of plas ma v ol u me of 
a p pr o xi matel y 0. 8 m L  eac h, will be c ollecte d i nt o a p pr o priatel y la bele d t u bes c o ntai ni n g 
K 2E D T A f or t he a nalys is of 4-h y dr o x yc h olester ol a n d c h olester ol at ti mes s pecifie d i n t he 
S o A .  Instr 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 b e pr o vi de d i n 
t he la b orat or y ma n ual.
Sa m ples c ollecte d f or a nal y ses of 4-h y dr o x yc h olester ol/c h olester ol plas ma c o nce ntrati o n 
ma y  als o be use d t o e val uate safet y as pects or efficac y 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.
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 an 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 dif y w hat is o utli ne d i n t he pr ot oc ol w here a p pr o priate; ho 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 will be perf or me d i n t his st u d y .
9. 2. A n al ysis Sets
F or p ur p ose s of a nal ysis, t he f oll o wi n g a nal ys is sets are defi ne d:
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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. 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 dy, 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 n r olle d, u nless 
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 . 
Safet y
All partici pa nts ra n d o ml y  assi g ne d t o st u d y i nterve 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.
P K C o nce ntrati o n Set
T he P K c o nce ntrati o n p o p ulati o n is defi ne d as all partici pa nts 
w h o recei ve d at least 1 d ose of mi daz ola m , o me praz ole, a n 
oral c o ntrace pti ve , an d/ or P F - 0 7 0 8 1 5 3 2 a n d i n w h o m at least 
1 plas ma c o nce ntrati o n val ue is re p orte d.
P K Para meter Set
T he P K para meter a nal ys is p o p ulati o n is defi ne d as all 
partici pa nts w h o recei ve d at least 1 d ose of mi daz ola m,
o me praz ole, a n oral c o ntrace pti ve, a n d/ or P F -0 7 0 8 1 5 3 2 a n d 
ha ve at least 1 of t he P K para meters of i nterest calc ulate d. 
S h o ul d v o miti n g occ ur after c oa d mi nistrati o n of mi daz ola m, 
o me praz ole, or t he oral c o ntrace pti ve wit h P F -0 7 0 8 1 5 3 2 , t he 
res ulti n g P K para meters fr o m t hat partici pa nt fr o m t he 
c orres p o n di n g p eri o d ma y be e xcl u de d, w here f urt her details 
will be pr o vi de d i n t he S A P .
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
9. 3. 1. 1. Deri v ati o n of P h ar m ac o ki netic P ar a meters
T he plas ma P K para meters f or mi daz ola m, 1 -h y dr o x y mi daz ola m, o me praz ole, 
5 -h y dr o x y o me praz ole, L E a n d E E f oll o wi n g S D a d mi nistrati o n (eit her al o ne or d uri n g
c oa d mi nistrati o n wit h P F - 0 7 0 8 1 5 3 2 or se ma gl uti de [ mi daz ola m o nl y]) will be deri ve d fr o m 
t he c o nce ntrati o n-ti me pr ofiles as detailed i n Ta ble 1 2 bel o w .  T he plas ma P K para meters f or 
P F - 0 7 0 8 1 5 3 2 f oll o wi n g M D
a d mi nistrati o n will be deri ve d fr o m t he c o nce ntrati o n- ti me 
pr ofiles as detaile d i n Ta ble 1 3 bel o w. 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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. I n t he case t hat 
act ual P K sa m pli n g ti mes are n ot a vaila ble, n o mi nal P K sa m pli n g t i me will be use d i n t he 
deri vati o n of P K para meters.
T a ble 1 2 . Pl as m a P K P ar a meters f or Mi d az ol a m, 1 -O H -Mi d az ol a m, O me pr az ole, 
5 -O H -O me pr az ole, L e v o n or gestrel a n d E t hi n yl Estr a di ol
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 nf*
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 Clast* 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.
t1/ 2*
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 p pare nt oral cleara nce.
D ose/ A U C i nf.
V z/ F *
A p pare nt v ol u me of distri b uti o n.
D ose / (A U C i nf • kel). 
M R 
Mi daz ola m meta b olite/ pare nt 
rati o.
1- h y dr o x y mi daz ola m/ mi daz ola m
f or A U Ci nf, A U Clast, a n d Cma x
(a dj uste d t o acc o u nt f or differe nces 
i n m olec ular wei g ht).
M R
O m e praz ole meta b olite/ pare nt 
rati o.
5- h y dr o x y o m e praz ole/ o me praz ole 
f or A U Ci nf, A U Clast, a n d Cma x
(a dj uste d t o acc o u nt f or differe nces 
i n m olec ular wei g ht).
* as data per mit; C L/ F a n d V z/ F will n ot be calc ulate d f or 1-O H -mi daz ola m or 5 -O H -o m e praz ole
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
T a ble 1 3 .
Pl as m a P K P ar a meters f or P F - 0 7 0 8 1 5 3 2
P a r a m eter
Defi niti o n
M e t h o d of Deter m i n ati o n
A U C 2 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 2 4 h o urs.
A U C t (area u n der t he plas ma 
c o nce ntrati o n-ti me pr ofile w here 
t = 0 t o 2 4 h o urs) .
C ma x
Ma xi m u m plas ma c o nce ntrati o n 
o bser ve d fr o m ti me zer o t o 
2 4 h o urs .
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 .
A s i n gle tr o u g h c o nce ntrati o n sa m ple will be o btai ne d f or se ma gl uti de at 0 h o n Wee ks 5, 9, 1 3, a n d 1 7
d uri n g Peri o d 2 a n d pri or t o d osi n g i n Peri o d 3, Da y 1.  
9. 3. 2. St atistic al Met h o ds f or P h ar m ac o ki netic D at a
T he P K data f or mi daz ola m, 1 -h y dr o x y mi daz ola m , o me praz ole, 5 -h y dr o x y o me praz ole, L E, 
E E , a n d P F - 0 7 0 8 1 5 3 2 will be a nal yz e d a n d re p orte d se paratel y.
Plas ma c o nce ntrati o ns will be liste d a n d s u m marize d descri pti vel y b y P K sa m pli n g ti me a n d 
treat me nt ( d osi n g al o ne vs. c oa d mi nistrati o n or d ose b y  C o h ort of st u d y , as a p plica ble).
I n di vi d ual partici pa nt 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. F or s u m mar y statistics a n d me dia n pl ots b y sa m pli n g ti me, t he n o mi nal P K
sa m pli n g ti me will be use d .  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 f or plas ma sa m ples will be use d . 
Me dia n pr ofiles will be prese nte d o n bot h li near-li near 
a n d l o g-li near scales.
C o h ort 1
Nat ural l o g e-tra nsf or me d A U C i nf (as data per mit), A U Clast a n d C ma x of o me praz ole
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c oa d mi nistere d wit h P F - 0 7 0 8 1 5 3 2 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 % CI s will be o btai ne d fr o m t he m o dels.  T he a dj uste d mea n di ffere nces a n d 9 0 % CI s f or 
t he differe nces will be e x p o ne ntiate d t o pr 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 % CI s f or t he rati os.  T he 2 test treat me nts will be 
‘o me praz ole a n d P F -0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 4) a n d ‘ o me praz ole a n d P F - 0 7 0 8 1 5 3 2
2 6 0 m g Q D’ ( Peri o d 7), w hic h will be re p orte d se paratel y i n c o m paris o n t o t he refere nce 
treat me nt of ‘o me praz ole wit h o ut P F - 0 7 0 8 1 5 3 2’ ( Peri o d 1).  
Nat ural l o g e-tra nsf or me d A U Ci nf (as data per mit) of t he 5- h y r o xy o me praz ole/ o me pra z ole
rati os ( M R) a d mi nistere d wit h o ut P F- 0 7 0 8 1 5 3 2 or c oa d mi nistere d wit h P F - 0 7 0 8 1 5 3 2 will be 
a nal yz e 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 % CIs will be o btai ne d fr o m t he m o dels.  T he a dj uste d mea n differe nces 
a n d 9 0 % CIs f or t he differe nces will be e x p o ne ntiate d t o pr 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 % CI s f or t he rati os.  T he 2 test treat me nts 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
will be ‘ o me praz ole a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 4) a n d ‘ o me praz ole a n d 
P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 7), w hic h will be re p orte d se parately i n c o m paris o n t o t he 
refere nce treat me nt of ‘ o me praz ole wit h o ut P F - 0 7 0 8 1 5 3 2’ ( Peri o d 1).
Nat ural l o g etra nsf or me d A U Ci nf (as data per mit), Cma x a n d A U C last of mi daz ola m 
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c oa d mi nistere d wit h P F - 0 7 0 8 1 5 3 2 i n C o h ort 1 will be 
a nal yz e d a n d re p orte d se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or
o me praz ole .  T he 2 test treat me nts will be ‘ mi daz ola m a n d P F - 0 7 0 8 1 5 3 2 80 m g Q D’ 
( Peri o d 4 ) a n d ‘ mi daz ola m a n d P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 7 ), w hic h will be re p orte d 
se paratel y i n c o m paris o n t o t he refere nce treat me nt of ‘ mi daz ola m wit h o ut P F - 0 7 0 8 1 5 3 2’ 
( Peri o d 1 ).
Nat ural l o g etra nsf or me d A U Ci nf (as data per mit), Cma x a n d A U C last of mi daz ola m 
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c oa d mi nistere d wit h P F - 0 7 0 8 1 5 3 2 i n C o h ort 1 will be 
a nal yz e d a n d re p orte d se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or 
o me praz ole.  T he test treat me nt will be ‘ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of 
P F - 0 7 0 8 1 5 3 2’ ( Peri o d 9), w hic h will be re p orte d se paratel y i n c o m paris o n t o t he 2 refere nce 
treat me nts of ‘ mi daz ola m wit h o ut P F -0 7 0 8 1 5 3 2’ ( Peri o d 1) a n d ‘ mi daz ola m a n d 
P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 7).
Nat ural l o g etra nsf or me d A U Ci nf (as data per mit) of t he 1-h y r o xy m i daz ola m/ mi daz ola m rati os 
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c oa d mi nistere d wit h P F -0 7 0 8 1 5 3 2 i n C o h ort 1 will be 
a nal yz e d a n d re p orte d se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or 
o me praz ole.  T he 2 test treat me nts will be ‘ mi daz ola m a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D’ 
( Peri o d 4) a n d ‘ mi d az ola m a n d P F- 0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 7), w hic h will be re p orte d 
se paratel y i n c o m paris o n t o t he refere nce treat me nt of ‘ mi daz ola m wit h o ut P F-0 7 0 8 1 5 3 2’ 
( Peri o d 1).
Nat ural l o g etra nsf or me d A U Ci nf (as data per mit), Cma x a n d A U C last of L E a n d E E 
a d mi nistere d al o ne or c oa d mi nistere d wit h P F-0 7 0 8 1 5 3 2 will be a nal yz e d a n d re p orte d 
se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or o me praz ole.  F or L E, 
t he 2 test treat me nts will be ‘ L E a n d P F- 0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 5) a n d ‘ L E a n d 
P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 8), w hic h will be re p orte d se paratel y i n c o m paris o n t o t he 
refere nce treat me nt of ‘ L E al o ne’ ( Peri o d 2 ).  Si milarl y f or E E, t he 2 test treat me nts will be 
‘ E E a n d P F- 0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 5) a n d ‘ E E a n d P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D’ 
( Peri o d 8), w hic h will be re p orte d se paratel y i n c o m paris o n t o t he refere nce treat me nt of ‘ E E 
al o ne’ ( Peri o d 2 ).
C o h ort 2
Nat ural l o g e-tra nsf or me d A U Ci nf (as data per mit), Cma x a n d A U C last of mi daz ola m 
a d mi nistere d al o ne or c oa d mi nistere d wit h se ma gl uti de will be a nal y ze d a n d re p orte d 
se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or o me praz ole.  T he test 
treat me nt will be ‘ mi daz ola m a n d se ma gl uti de 2. 4 m g w ee kl y’ ( Peri o d 3) w hic h will be 
re p orte d se paratel y i n c o m paris o n t o t he refere nce treat me nt of ‘ mi daz ola m al o ne’ ( Peri o d 1).
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
Nat ural l o g etra nsf or me d A U Ci nf (as data per mit), Cma x a n d A U C last of mi daz ola m 
a d mi nistere d wit h o ut se ma gl uti de or c oa d mi nistere d wit h se ma gl uti de will be a nal yz e d a n d 
re p orte d se parately usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or o me praz ole.  
T he test treat me nt will be ‘ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of se ma gl uti de’
( Peri o d 4 ), w hic h will be re p orte d se paratel y i n c o m paris o n t o t he 2 refere nce treat me nts of 
‘ mi daz ola m wit h o ut se ma gl uti de’ ( Peri o d 1) a n d ‘ mi daz ola m a n d se ma gl uti de 2. 4 m g 
wee kl y ’ ( Peri o d 3).
Nat ural l o g etra nsf or me d A U Ci nf (as data per mit) of t he 1-h y r o xy m i daz ola m/ mi daz ola m rati os 
a d mi nistere d al o ne or c oa d mi nistere d wit h se ma gl uti de will be a nal y ze d a n d re p orte d 
se paratel y usi n g t he sa me mi xe d effect m o del as descri be d a b o ve f or o me praz ole.  T he test 
treat me nt will be ‘ mi daz ola m a n d se ma gl uti de 2. 4 m g wee kly’ ( Peri o d 3) w hic h w ill be 
re p orte d se parately i n c o m paris o n t o t he refere nce treat me nt of ‘ mi daz ola m al o ne’ ( Peri o d 2 ).
If less t ha n 1 2 partici pa nts ha ve P K para meters relate d t o c oa d mi nistrati o n wit h 
P F - 0 7 0 8 1 5 3 2 2 60 m g Q D, t he a b o ve mi xe d effect m o dels ma y  a d diti o nall y/alter nati vely 
i ncl u de P K para meters fr o m t he ma xi m u m t olerate d d ose of P F - 0 7 0 8 1 5 3 2 (if a p plica ble), 
w here f urt her details will be i ncl u de d i n t he S A P.
T he a b o ve a n d ot her P K para meters f or mi daz ola m, 1 -h y dr o x y m i daz ola m, o me praz ole, 
5- h y dr o x y o me praz ole , L E a n d E E , a n d P K para meters f or P F - 0 7 0 8 1 5 3 2, will be se parately 
s u m marize d descri pti vel y by treat me nt.
If e val uate d, the plas ma 4 -h y dr o x y c h olester ol, c h olester ol a n d 
data will be s u m marize d 
descri pti vel y b y peri o d ( D a y 1 i n Peri o ds 1, 4, 7 a n d 9 i n C o h ort 1 a n d Da y 1 i n Peri o ds 1 , 3 
a n d 4 i n C o h ort 2). T he p las ma rati os of 4 -h y dr o x y c h olester ol/c h olester ol will als o be 
s u m marize d descri pti vel y b y  peri o d.  Perce nt c ha n ge f or t he 4 -h y dr o x y c h olester ol/
c h olester ol rati o s fr o m baseli ne ( Da y 1 Peri o d 1 i n C o h orts 1 a n d 2) will be re p orte d, a n d 
f urt her details will be i ncl u de d i n t he S A P.
9. 3. 3. S afet y A n al yses
All safet y a nal ys es will be perf or me d o n t he safet y p o p ulati o n.
A E s, b o d y  wei g ht 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 nt s. Partici pa nts ma y  
u n der g o c ollecti o n of E C Gs, B P, a n d P R at t he discreti o n of t he i n vesti gat or.  A n y cli nical 
la b orat or y, E C G, B P, a n d P R 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 vel y, w here a p pr o priate.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
Me dica l hist or y a n d p h ysical 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 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.  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 y sical 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. 3. 1. Electr oc ar di o gr a m A n al yses
N ot a p plica ble.
9. 3. 4. Ot her A n al yse (s)
Tertiar y / E x pl orat or y a nal yses n ot i ncl u de d i n t he p har mac o ki netic or safety a nal ys es o utli ne d 
a b o ve will be d oc u me nte d i n t he S A P. 
9. 4. I nteri m A n al yses
N o f or mal i nteri m a nalys is will be c o n d ucte d f or t his st u d y.  As t his is a n o pe n-la bel st u dy, 
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 st u d y f or t he p ur p ose of 
safety assess me nt, facilitati n g P K m o deli n g, a n d/ or s u p p orti n g cli nical de vel o p me nt.
9. 5. S a m ple Size Deter mi n ati o n
A p pr o xi matel y  1 2 e val ua ble partici pa nts will c o m plete eac h c o h ort of t he st u d y .
A sa m ple size of 1 2 partici pa nts will pr o vi de 9 0 % CI s f or t he differe nce bet wee n treat me nts 
of ± 0. 2 4 9 1, ± 0. 2 4 8 a n d ± 0. 1 1 6 1 o n t he nat ural l o g scale f or A U Ci nf i n t he assess me nt of 
mi daz ola m, o me praz ole a n d L E or E E, res pecti vel y , wit h 8 0 % c o vera ge pr o ba bilit y. T he 
wi dt h of 9 0 % CI s f or differe nt esti mate d effects is prese nte d i n Ta ble 1 4 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
T a ble 1 4 . 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 a n d P ar a meters of I nterest
Refere nce
Esti m ate d Effect
( Test/ Refere nce)
A U C i nf
Pr o b a ble
9 0 % CI
Pr o b a ble
CI Wi dt h
Mi daz ola m
5 0 %
3 9 % - 6 4 %
2 5 %
7 5 %
5 8 % - 9 6 %
3 8 %
1 0 0 %
7 8 % - 1 2 8 %
5 0 %
1 2 5 %
9 7 % - 1 6 0 %
6 3 %
1 5 0 %
1 1 7 % - 1 9 2 %
7 5 %
2 0 0 %
1 5 6 % - 2 5 7 %
1 0 1 %
O m e praz ole
5 0 %
3 9 % - 6 4 %
2 5 %
7 5 %
5 8 % - 9 6 %
3 8 %
1 0 0 %
7 8 % - 1 2 8 %
5 0 %
1 2 5 %
9 7 % - 1 6 0 %
6 3 %
1 5 0 %
1 1 7 % - 1 9 2 %
7 5 %
2 0 0 %
1 5 6 % - 2 5 6 %
1 0 0 %
L E or E E
5 0 %
4 5 % - 5 6 %
1 1 %
7 5 %
6 7 % - 8 4 %
1 7 %
1 0 0 %
8 9 % -1 1 2 %
2 3 %
1 2 5 %
1 1 1 % - 1 4 0 %
2 9 %
1 5 0 %
1 3 4 % - 1 6 8 %
3 5 %
2 0 0 %
1 7 8 % - 2 2 5 %
4 7 %
T hese esti mates are base d o n data fr o m pre vi o us i nter nal D DI st u dies of mi daz ola m, 
o me praz ole, a n d a n oral c o ntrace pti ve c o ntai ni n g L E/ E E. T hese esti mates are base d o n t he 
ass u m pti o n t hat wit hi n -partici pa nt sta n dar d de viati o ns are 0. 2 9 4 a n d 0. 1 3 7 f or l n A U C i nf of 
mi daz ola m a n d L E or E E, res pecti vel y, as o btai ne d fr o m pre vi o us Pfizer st u dies i n o bese 
partici pa nts.  F or o me praz ole, t hese esti mates are base d o n a n ass u me d c o nser vati ve 
wit hi n -partici pa nt sta n dar d de viati o n of 0. 2 9 3 f or l n A U C i nf  i n o bese partici pa nts.
Partici pa nts w h o fail t o c o m plete t he st u d y  ma y be re place d at t he discreti o n of t he s p o ns or.
9. 6. D at a M o nit ori n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee
T his st u d y  will n ot use a D M C.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 udi n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui deli nes ;

A p plica ble I C H G C P g ui deli nes ;

A p plica ble la ws a n d re g ulati o ns , i ncl u di n g a p plica ble pri vac y la ws.
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C D, S R S D(s) , a n d ot her rele va nt d oc u me nts 
(e g, a d vertise me nts) m ust be re vie we d a n d a p pr o ve d b y  t he s p o ns or, 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 ote ct 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. I nvesti 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 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 
pa rtici 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 p a nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he s p o ns or, b y 
a p pr o priate I RB/ E C me m bers, a n d b y i ns 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
Partici pa nts m ust be rec o nse nte d t o t he m ost c urre nt versi o n of t he I C D (s) d uri n g t heir 
partici pati o n i n t he st u d y .
A c o p y of t he I C D (s) m ust be pr o vi de d t o t he partici pa nt.
Partici pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C D.
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 
disast er. 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 ms of partici pa nts wit h re gar d t o t he pr ocessi n g of pers o nal 
data, partici pa nts will be assi g ne d a si n gle, partici pa nt s pecific - n u merical c o de. A n y 
partici pa nt rec or ds or data sets t hat are tra 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 t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E u dra C T, a n d/ or 
w w w. pfizer.c o m, a n d ot her p u blic re gistries i n acc or da nce wit h a p plica ble l ocal 
la ws/re g ulati o ns. I n a d diti o n, Pfizer re p orts st u d y res ults o utsi de of t he re q uire me nts of l ocal 
la ws/re g ulati o ns p urs ua nt t o its S O Ps.
I n all cases, st u dy res ults are re p orte d b y Pfizer i n a n o bjecti ve, acc urate, bala nce d, a n d 
c o m plete ma n ner a n d a re re p orte d re gar dless of t he o utc o me of t he st u dy or t he c o u ntr y i n 
w hic h t he st u d y  was c o n d ucte d.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 i n 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 clinical trial r es 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 p atie 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 pletio n. Patie nt le vel - data will be a n o n y m ize d i n acc or da nce wit h 
a p plica ble pri vac y la ws a n d re g ulati o ns. C S Rs will ha ve pers o nall y i de ntifia ble i nf or mati o n 
re dacte d.
Data re q 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 y ses. 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 C o 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 ypte 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 parties.
Q T L s are pre defi ne d para meters t hat are m o nit ore d d uri n g t he st u d y . I m p orta nt de viati o ns 
fr o m t he Q T Ls a n d a n y re me dial acti o ns ta ke n will be s u m marize d i n t he cli nical st u d y  
re p ort.
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 m a 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 detai ls descri bi n g strate g y, i ncl u di n g defi niti o n of st u d y critical data ite ms 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- mo 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 gnee .
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 party wit h o ut writte n n otificati o n t o t he s p o ns or. T he 
i n vesti gat or m ust e ns ure t hat t he rec or ds c o nti n ue t o be st ore d sec urely 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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 he i n vesti gat or(s) will n otif y  t he s p o ns or or its a ge nts i m me diatel y of a n y re g ulat or y 
i ns pecti o n n otificati o n i n relati o n t o t he st u d y. F urt her m ore, t he i n vesti gat or will c o o pera te 
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  
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 in vesti gat or will pr o vi de t he s p o ns or or its 
a ge nts wit h a n o p p ort u nit y t o re vie w a n d c o m me nt o n res p o nses t o a n y s uc h fi n di n gs.
1 0. 1. 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 grit y of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or 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.
I n t his st u dy, t he C R F will ser ve as t he s o urce d oc u me nt. A d oc u me nt m ust be a vaila ble at 
t he i n vesti gati ve site t hat i de ntifies t h ose data t hat will be rec or de d o n t he C R F a n d f or w hic h 
t he C R F will be t he s o urce d oc u me nt.
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 cli nical 
m o nit ori n g pla n , 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 Data Ma na ge me nt 
Pla n , 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 first act of recr uit me nt is t he date of t he first partici pa nt’s first visit a n d will be t he st u d y  
start date.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 an 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 
or desi g nee/ C R O if re q ueste d t o d o s o b y  t he res p o nsi ble IR 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.
Reas o ns f or t he early 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 n es;

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 ny 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 gat or 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
T he s p o ns or will c o m pl y  wit h t he re q uire me nts f or p u blicati o n of t he o verall st u d y res ults 
c o veri n g all i n vesti gat or sites. I n acc or da nce wit h sta n dar d e dit orial a n d et hical practice, t he 
s p o ns or will s u p p ort p u blicati o n of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as 
i n di vi d ual site data. 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 Inter nati o nal C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p 
re q uire me nts. 
If p u blicati o n is a d 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 ns or's a p pr o priatel y  q ualifie d me dical pers o n nel f or t he 
st u d y is d oc u me nte d i n t he st u d y c o ntact list l ocate d i n t he S T o D s yste 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 urs/ 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 Pfize r Call Ce nter n u m ber 
is n ot i nte n de d f or use by t he partici pa nt directl y; if a partici pa nt calls t hat n u m ber directl y, 
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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 secti o n of 
t his pr ot oc ol. 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 nalys is or t he t ype of a nal yz er 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 ny percei ve d safet y iss ues.
T a ble 1 5 . Pr ot oc ol -Re q uire d S afet y L a b or at or y Assess me nts
He m at ol o g y
C he mi str y
Uri n al ysis
Ot her
He m o gl o bi n
He mat 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 ( Abs)
B U N 
Creati ni ne
e G F R
C y stati n- C
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
Direct bilir u bi n
I n direct bilir u bi n
G G T
Al kali ne p h os p hatase
Uric aci d
Al b u mi n
T otal pr otei n
Uri nal ysis:

p H

Gl uc ose ( q ual)

Pr otei n ( q ual)

Bl o o d ( q ual)

Ket o nes

Nitrites

Le u k oc yte 
esterase

Ur o bili n o ge n

Uri ne bilir u bi n

Micr osc o p y a
H b A 1c
Ser u m pre g na nc y test 
(-h C G) b
Li pi d pa nel:

T otal c h olester ol

Direct L D L - C

H D L - C

Tri gl yceri des
T S H
Free T 4
Calcit o ni n
A m ylase
Li pase
Ser u m T B A
S A R S -C o V - 2 test
Uri ne dr u g scree ni n g c
Scree ni n g o nl y:
F S H d
C- pe pti de (fasti n g)
HI V
H B s A gH C V A b
H C V R N A
A d diti o n al Tests ( Nee de d 
f or H y’s L a w)
A S T, A L T (re peat)
T otal bilir u bi n (re peat)
Al b u mi n (re peat)
Al kali ne p h os p hatase 
(re peat)
Direct bilir u bi n (re peat)
I n direct bilir u bi n (re peat)
C K
G G T (re peat)
P T /I N R
T otal bile aci ds (re peat)
Aceta mi n o p he n dr u g a n d/ or 
pr otei n a d d uct le vels
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.
Ser u m -h C G f or all W O C B P.
c.
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).  At scree ni n g, Peri o d 1 Da y -1a n d at t he 
discreti o n of t he i n vesti gat or.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
d .
F or c o nfir mati o n of p ost me n o pa usal stat us o nl y. 
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.
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 safety 
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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. 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 ny 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 pecte d dr u g -dr u g - i nteracti o n.

S i g ns, s ym 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 ossi ble s uici dal/ self-
har mi n g - i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of se q uelae.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 d a 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 os pit aliz ati o n
I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n 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 was 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 bi lit 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.  
g.
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.
h.
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 part ici 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 A cti ve 
C ollecti 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 ypes 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. 
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 S A E 
Re p ort F or m f or re p orti n g of S A E i nf or mati o n.
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E 
Re p ort F or m t o Pfizer 
S afet y Wit hi n 2 4 H o urs of 
A w are ness
S A E
All
All
N o nseri o us A E
All
N o ne
E x p os ure t o t he st u d y 
i nter ve nti o n u n der st u d y 
d uri n g pre g na nc y  or 
breastfee di n g
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. 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

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.

It is n ot acce pta ble f or t he in 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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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 “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve y s 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.

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 asses s 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 m ati 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. B ut 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 req uire me nts.

If t he i n vesti gat or d oes n ot k n o w w het her or n ot t he st u d y i nter ve nti o n ca use d t he 
e ve nt, t he n t he e ve nt will be ha n dle d as “relate d t o st u d y i nter ve nti o n” f or re p orti n g 
p ur p oses, as defi ne d b y t he s p o ns or . I n a d diti o n, if t he i n vesti gat or deter mi nes t hat 
a n S A E is ass ociate d wit h st u d y  pr oce d ures, t he i n vesti gat or m ust rec or d t his 
ca usal relati o ns hi p i n t he s o urce d oc u me nts a n d C R F, a n d re p ort s uc h a n 
assess me nt i n t he de dicate d secti o n of t he C T S A E Re p ort F or m a n d i n acc or da nce 
wit h t he S A E re p orti n g re q uire me nts.
F oll o w - 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 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

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 ny 
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.
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 u rs.

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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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
Males will n ot partici pate i n t his st u d y . 
1 0. 4. 2. Fe m ale P artici p a nt Re pr o d ucti ve I ncl usi o n Criteri a
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt or breastfee di n g, a n d at 
least 1 of t he f oll o wi n g c o n diti o ns a p plies:

Is n ot a W O C B P (see defi niti o ns bel o w i n Secti o n 1 0. 4. 3 ).
O R

Is a W O C B P a n d usi n g a c o ntrace pti ve met h o d t hat is hi g hl y effecti ve ( wit h a fail ure 
rate of < 1 % per year), prefera bl y wit h l o w user de pe n de nc y , as descri be d bel o w 
d uri n g t he i nter ve nti o n peri o d a n d f or at least 2 8 da 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 a n y re pr o d ucti ve 
safety ris k of t he st u d y i nter ve nti o n(s).  T he i n vesti gat or s h o ul d e val uate t he 
effecti ve ness of t he c o ntrace pti v e met h o d i n relati o ns hi p t o t he first d ose of st u d y  
i nter ve nti o n.

Is a W O C B P a n d usi n g a c o ntrace pti ve met h o d t hat is hi g hl y effecti ve ( wit h a fail ure 
rate of < 1 % per year), wit h hi g h user de pe n de nc y, as descri be d bel o w d uri n g t he 
i nter ve nti o n peri o d a n d for at least 2 8 da 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 a n y  re pr o d ucti ve safety ris k of t he 
st u d y i nter ve nti o n(s).  I n a d diti o n, a sec o n d effecti ve met h o d of c o ntrace pti o n, as 
descri be d bel o w, m ust b e use d.  T he i n vesti gat or s h o ul d e val uate t he effecti ve ness of 
t he c o ntrace pti ve met h o d i n relati o ns hi p t o t he first d ose of st u d y i nter ve nti o n.
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 t he 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 y cle ca n n ot 
be c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, a d diti o nal e val uati o n s h o ul d be 
c o nsi dere d.
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P:
1.
Pre me n o pa usal fe m ale wit h 1 of t he f oll o wi n g: 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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 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 his t 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.  In a d diti o n, a

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. 
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 vail a 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 nc y 
1.
I ntra uteri ne de vice.
2.
Bilateral t u bal occl usi o n.
3.
Vasect o mize d part ner.

Vasect 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 hl y effecti ve met h o d of n o n h or m o nal .

N o n h or m o nal 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.
4.  
Hi g hl y Effecti ve Met h o ds T h at Are User De pe n de nt 
Se x ual a bsti ne nce.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

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 lifestyl e of t he 
partici pa nt.
O ne of t he f oll o wi n g effecti ve barrie r met h o ds m ust be use d i n a d diti o n t o t he hi g hly 
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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 ur y, c o m m o nl y 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 s e veral da ys or wee ks. T he i ncrease i n T Bili t y picall y  occ urs w hile 
A S T/ A L T is/are still ele vate d a b o ve 3 × U L N (ie, A S T/ A L T a n d T B ili 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, by 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 e it 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 y s 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 par tici pa nt s h o ul d ret ur n t o t he i n vesti gat or site a n d be e val uate d as s o o n as p ossi ble, 
prefera bl y wit hi n 4 8 h o urs fr o m a ware ness of t he a b n or mal res ults. T his e val uati o n s h o ul d 
i ncl u de la b orat or y tests, detaile d hist or y, a n d p h ysical assess me nt.  
I n a d diti o n t o re peati n g meas ure me nts of A S T a n d A LT a n d T Bili 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 B A, 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 
d ra 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 rele va nt i nf or mati o n, s uc h 
as re vie w of et ha n ol, aceta mi n o p he n/ paraceta m ol (eit her b y itself or as a c of or m ulate d 
pr o d uct i n prescri pti o n or o ver -t he-c o u nter me dicati o ns) , recreati o nal dr u g, 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 Bili ele vati o n defi ne d a b o ve s h o ul d be c o nsi dere d p ote ntial DI LI ( H y ’s la w) cases if n o 
ot her reas o n f or t he L F T a b n or malities has yet bee n f o u n d. S uc h p ote nti al D I LI ( H y’s l a w) 
c ases are t o be re p orte d as S A Es, irres pecti ve of a v ail a bilit y of all t he res ults of t he 
i n vesti g ati o ns perf or me d t o deter mi ne eti ol o g y of t he L F T a b n or m alities.
A p ote ntial DI LI ( H y ’s la w) case bec o mes a c o nfir me d case o nly after all res ul ts 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. 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 ( Scr meas ure me nt t o e G F R [ Scr- base d e G F R] or [e Cr Cl]). Baseli ne a n d 
p ost baseli ne 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 
Scr 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-S c y s e G F R calc ulati o n (f or a d ults o nly).
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 ni t 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 a ti o n Rec o m me n d ati o ns
1 0. 7. 2. 1. A d ults ( 1 8 Y e ars a n d A b o ve)- 2 0 2 1 C K D- E P I E q u ati o ns
2 0 2 1 C K D -
E PI 
Scr 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 
Scr- 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
I n ker L A et al. N E n gl J Me d. 2 0 2 1; 3 8 5: 1 7 3 7- 4 9.
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.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
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 dyc ar 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 by ≥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 pe 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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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

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 y t 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 ycar dia ( H R > 1 0 0 b p m (s uc h as
torsa des de p oi ntes) ).

T y pe 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 maker place me nt .

Atrial fl utter or fi brillati o n wit h ra pi d ve ntric ular res p o nse re q uiri n g car di o versi o n .

Ve ntric ular fi brillati o n/fl utter.

At t he discreti o n of t he i n vesti gat or, a n y arr h yt h mia classifie d as a n a d verse 
e x perie nce.
T he e n u merate d list of maj or e ve nts of p ote ntial cli nical c o ncer n are rec o m me n de d as “alerts” or 
n otificati o ns fr o m t he c ore E C G la b orat or y t o t he i n vesti gat or a n d Pfizer st u d y tea m, a n d n ot t o be 
c o nsi dere d as all i ncl usi ve of w hat t o be re p orte d as A Es/ S AEs.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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. 9. A p pe n di x 9 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 KI
ac ute ki d ne y i nj ur y
A L T
ala ni ne a mi n otra nsferase
A M
bef ore n o o n
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 i nf
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
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 ( Clast)
A U C t
area u n der t he plas ma c o nce ntrati o n -ti me pr ofile w here t = 0 t o 2 4 
h o urs
A U C ta u
area u n der t he plas ma c o nce ntrati o n-ti me pr ofile o ver t he d osi n g 
i nter val, ta u
A U C 2 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 2 4 h o urs
A V
atri o ve ntric ular
B B S
Bi os peci me n Ba n ki n g S yste m
-h C G
b eta h u ma n c h ori o nic g o na d otr o pi n
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 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 L
cleara nce
C L / F
a p pare nt oral cleara nce
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 p
plas ma cleara nce
C ma x
ma xi 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 R F
case re p ort f or m
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
A b bre vi ati o n
Ter m
C R O
c o ntract researc h or ga nizati o n
C R U
cli nical researc h u nit
C S R
C li nical S t u d y R e p ort
C -S S R S
C ol u m bia S uici de Se verit y  Rati n g Scale
C T
cli nical trial
% C V
perce nt c oefficie nt of variati o n 
C Y P
c yt oc hr o me P 4 5 0
D/ C
disc har ge
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
D ata M o nit ori n g C o m mittee
E C
et hics c o m mittee
E C C
E mer ge nc y  C o ntact Car d
e Cr Cl
esti mate d creati ni ne cleara nce
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E D 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 E
et hi n yl estra di ol
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 S B G
fi n gerstic k bl o o d gl uc ose
F S H
f ollicle-sti m ulati n g h or m o ne
F/ U
f oll o w-u p
G C P
G o o d Cli nical Practice
G E R D
gastr oes o p ha geal refl u x disease
G G T
ga m ma -gl uta m y l tra nsferase
G L P -1 
gl uca g o n -li ke pe pti de 1 
G L P -1 R
gl uca g o n -li ke pe pti de 1 rece pt or 
H A E
h y p o gl yc e mic a d verse e ve nt
H b A 1c
he m o gl o bi n A 1c
H Bs A g 
he patitis B s urface a nti ge n
H C V
h e patitis C vir us
H C V A b
he patitis C a nti b o d y
H D L -C
hi g h -de nsit y li p o pr otei n c h olester ol
He p
he patitis
HI V
h u ma n i m m u n o deficie nc y vir us
H R
heart rate
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)
C CI


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
A b bre vi ati o n
Ter m
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 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
I nterle u ki n
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 
i n vesti gati o nal pr o d uct 
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
intra ve n o us (ly)
K DI G O
Ki d ne y  Disease: Im pr o vi n g Gl o bal O utc o mes
k el
first-or der eli mi nati o n rate c o nsta nt
K 2E D T A
di p otassi u m et h y le ne dia mi netetraacetic aci d 
L B B B
left b u n dle bra nc h bl oc k
L D L -C
l o w de nsit y li p o pr otei n c h olester ol
L E
le v o n or gestrel
L F T
li ver f u ncti o n test
L L N
L o wer li mit of n or mal
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 D
m ulti ple d ose
M D Z
mi daz ola m
M E N 2
m ulti ple e n d ocri ne ne o plasia s y n dr o me t y pe 2 
M H P
me ntal healt h pr ofessi o nal
M R
meta b olite t o pare nt rati o
m R N A
messe n ger ri b o n ucleic aci d
M T C
me d ullar y  t h yr oi d carci n o ma
N/ A
n ot a p plica ble
N O A E L
n o o bser ve d a d verse effect le vel
O A T P
or ga nic a ni o n tra ns p orti n g p ol y pe pti des
O C
oral c o ntrace pti ve
O H
h y dr o x y
O M P
o me praz ole
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 H
p ote ntial of h y dr o ge n
P H Q -9
Patie nt Healt h Q uesti o n naire -9
P K
p har mac o ki netic(s)
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
A b bre vi ati o n
Ter m
P M
p ost -me n o pa usal
P R
p ulse rate
P T
pr ot hr o m bi n ti me
P V C
pre mat ure ve ntric ular c o ntracti o n/c o m ple x
Q D
o nce dail y
Q Tc
c orrecte d Q T
Q Tc F
c orrecte d Q T ( Fri dericia met h o d)
q ual
q ualitati ve
Q T L
q ualit y  t olera nce li mits
R A
rhe u mat oi d art hritis
R B C
re d bl o o d cell
R S E
Relati ve Sta n dar d Err or
S A E
seri o us a d verse e ve nt
S A P
S tatistical A nal y sis P la 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
Scr
ser u m creati ni ne
Sc y s
ser u m c ystati n C
S D
si n gle d ose; sta n dar d de viati o n
SI B
S uici dal I deati o n a n d Be ha vi or 
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 T o D
st u d y tea m o n de ma n d
S T -T
S T se g me nt t o T wa ve c ha n ges o n 1 2 -lea d E C G
S SI D
st u d y-s pecific s u bject i de ntificati o n n u m be r
S U S A R
S us pecte d U ne x pecte d S eri o us A d verse R eacti o n
t1/ 2
ter mi nal eli mi nati o n half -life
T 2 D M
t ype 2 dia betes mellit us
T 4
t h yr o xi ne
T B A
t otal bile aci ds
T Bili
t otal bilir u bi n
T E A E
treat me nt e mer ge nt a d verse e ve nt 
T H C
tetra hy dr oca n na bi n ol
T ma x
ti me t o C ma x
T N F -
t u m or necr osis fact or al p ha
T S H
t h yr oi d sti m ulati n g h or m o ne
U G T
uri di ne 5' -di p h os p h o gl uc ur o n os yl tra nsferase 
U L N
u p per li mit of n or mal
U S
U nite d States
U S PI
U nite d States P ac ka ge Insert 
V ss
v ol u me of distri b uti o n at stea d y  state
V z / F
a p pare nt v ol u me of distri b uti o n
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
A b bre vi ati o n
Ter m
W B C
w hite bl o o d cell
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 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
1 1. R E F E R E N C E S
1.
Ørs k o v C, H olst JJ, K n u htse n S,et al. Gl uca g o n -li ke pe pti des G L P -1 a n d G L P - 2, 
pre dicte d pr o d ucts of t he gl uca g o n ge ne, are secrete d se paratel y fr o m pi g s mall i ntesti ne 
b ut n ot pa ncreas. E n d ocri n ol o g y . 1 9 8 6; 1 1 9( 4): 1 4 6 7 - 7 5.
2.
Kre y ma n n B, Willia ms G, G hatei M A, et al. Gl uca g o n -li ke pe pti de- 1 7-3 6: a 
p h y si ol o gical i ncreti n i n ma n. La ncet. 1 9 8 7; 2( 8 5 7 1): 1 3 0 0 - 3.
3.
Na uc k M A, Nie dereic h h olz U, Ettler R, et al. Gl uca g o n -li ke pe pti de 1 i n hi biti o n of 
gastric e m pt yi n g o ut wei g hs its i ns uli n otr o pic effects i n healt h y  h u ma ns. A m J P h ysi ol.
1 9 9 7; 2 7 3( 5): E 9 8 1 - 8.
4. 
Fli nt A, Ra be n A, Astr u p A, et al. Gl uca g o n -li ke pe pti de 1 pr o m otes satiety a n d 
s u p presses e ner g y i nta ke i n h u ma ns. J Cli n In vest . 1 9 9 8; 1 0 1( 3): 5 1 5 - 2 0.
5.
I DF Dia betes Atlas; 9 t h E diti o n . A vaila ble fr o m: I D F Dia betes Atlas.  Accesse d 
5 N o v 2 0 2 2.   
6.
Me n ke A, Casa gra n de S, Geiss L ,et al. Pre vale nce of a n d tre n ds i n d ia betes am o n g 
ad ults i n t he U nite d States , 1 9 8 8-2 0 1 2. J A M A . 2 0 1 5; 3 1 4( 1 0): 1 0 2 1 - 9.
7.
Stratt o n I M, A dler AI, Neil H A, et al. Ass ociati o n of gl yc ae mia wit h macr o vasc ular a n d 
micr o vasc ular c o m plicati o ns of t y pe 2 dia b etes ( U K P D S 3 5): pr os pecti ve o bser vati o nal 
st u d y. B MJ. 2 0 0 0; 3 2 1: 4 0 5 - 1 2.
8.
G u h D P, Z ha n g W, Ba ns bac k N, et al. T he i nci de nce of c o -m or bi dities relate d t o 
o besit y  a n d o ver wei g ht: a s yste matic re vie w a n d meta-a nal ys is. B M C P u blic Healt h.
2 0 0 9; 9: 8 8.
9.
Fle gal K M, K it B K, Or pa na H, et al. Ass ociati o n of all-ca use m ortalit y wit h o ver wei g ht 
a n d o besit y usi n g sta n dar d b o d y mass i n de x cate g ories: a sys te matic re vie w a n d 
meta -a nal ys is. J A M A. 2 0 1 3; 3 0 9( 1): 7 1 - 8 2.
1 0.
T he G B D 2 0 1 5 O besit y C olla b orat ors. Healt h effects of o ver wei g ht a n d o besit y  i n 
1 9 5 c o u ntries o ver 2 5 ye ars. N E n gl J Me d. 2 0 1 7; 3 7 7( 1): 1 3 - 2 7.
1 1.
A n ders o n J W, K o nz E C, Fre deric h R C, et al. L o n g -ter m wei g ht-l oss mai nte na nce: a 
meta -a nal ys is of U S st u dies. A m J Cli n N utr. 2 0 0 1; 7 4( 5): 5 7 9 - 8 4.
1 2.
Dr uc ker D J. T he asce n di n g G L P -1 r oa d fr o m cli nical safet y  t o re d ucti o n of 
car di o vasc ular c o m plicati o ns. Dia betes . 2 0 1 8; 6 7: 1 7 1 0 - 9. 
1 3.
Mi daz ola m I njecti o n, U S P. U nite d States Prescri bi n g I nf or mati o n.  Marc h 2 0 1 7. 
A vaila ble fr o m: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 7/ 2 0 8 8 7 8 Ori g 1s 0 0 0l bl
Accesse d 3 N o v 2 0 2 2 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
1 4.
Pril osec ( o me praz ole) .  Hi g hli g hts of Prescri bi n g Inf or mati o n. Dece m ber 2 0 1 4. 
A vaila ble fr o m: 0 2 2 0 5 6s 0 1 7l bl 0 1 9 8 1 0s 1 0 1l bl. p df (f da. g o v).  Accesse d 5 N o v 2 0 2 2.  
1 5.
Le v o n or gestrel a n d Et hi n yl Estra di ol Ta blets U S P, 0. 1 5 m g / 0. 0 3 m g. U nite d States 
Prescri bi n g I nf or mati o n. Re vise d Ma y , 2 0 1 6. A vaila ble fr o m:
htt ps:// dail y me d. nl m. ni h. g o v/ dail y m e d/f da/f da Dr u g Xsl.cf m?seti d = 0 6 8 1 9 9a 9 -ef 2 2-
4 0 6 1 - b b 7 6-1ee 5 8f 7 2 6 0 1 8 . Accesse d 3 N o v 2 0 2 2.
1 6.
We g o v y ® (se ma gl uti de). U nite d States Prescri bi n g I nf or mati o n. J u ne 2 0 2 1.  A vaila ble 
fr o m: htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 2 1/ 2 1 5 2 5 6s 0 0 0l bl. p df . 
Accesse d 2 7 Oct 2 0 2 2.
1 7.
O Z E M PI C ® (se ma gl uti de). U nite d States Prescri bi n g I nf or mati o n. Ja n uar y 2 0 2 0.  
A vaila ble fr o m:
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 2 0/ 2 0 9 6 3 7s 0 0 3l bl   Accesse d 
3 N o v 2 0 2 2.
1 8.
T ur pa ult S, Bria n W, Va n H or n R, et al. P har mac o ki netic assess me nt of a fi ve- pr o be 
c oc ktail f or C Y Ps 1 A 2, 2 C 9, 2 C 1 9, 2 D 6 a n d 3 A. Br J Cli n P har mac ol. 
2 0 0 9; 6 8( 6): 9 2 8 - 3 5.
1 9.
R y u, J Y, Si n g, I S, S u n w o o I E, et al., De vel o p me nt of t he "I nje c oc ktail" f or hi g h -
t hr o u g h p ut e val uati o n of fi ve h u ma n c yt oc hr o me P 4 5 0 is of or ms i n viv o. Cli n P har mac ol 
T her . 2 0 0 7; 8 2( 5 ): 5 3 1- 4 0.
2 0.
Ka petas AJ, S or ic h  MJ, R o dri g ues A D, a n d R o wla n d A. G ui da n ce f or rifa m pi n a n d 
m i daz ola m d osi n g p r ot oc ols t o st u d y intesti nal a n d h e patic c yt oc hr o me P 4 5 0 ( C Y P) 
3 A 4 in d ucti o n a n d d e-i n d ucti o n.  T he A A P S J o ur nal . 2 0 1 9; 2 1( 7 8): 1- 1 1.
2 1.
Gree n blatt DJ, A ber net h y D R, L oc nis kar A, et.al. Effect of a ge, ge n der, a n d o besit y  o n
mi daz ola m ki netics. A nest hesi ol o g y . 1 9 8 4; 6 1( 1): 2 7- 3 5.
2 2.
Brill MJ , Die pstrate n J, va n R o n ge n A, et al.  I m pact of o besit y o n d r u g m eta b olis m a n d 
eli mi nati o n i n ad ults a n d chil dre n. Cli n P har mac o ki net . 2 0 1 2; 5 1( 5): 2 7 7 - 3 0 4.
2 3.
Desta Z, Z ha o X, S hi n J -G, a n d Fl oc k hart D A.  Cli nical si g nifica nce of t he cyt oc hr o me 
P 4 5 0 2 C 1 9 g e netic p ol y m or p his m .  Cli n P har mac o ki net . 2 0 0 2; 4 1( 1 2): 9 1 3 - 5 8.
2 4.
Tassa nee y a k ul W , Tassa nee y a k ul W, Va n na prasa ht S, a n d Ya maz oe Y.  F or mati o n of 
o me praz ole s ul p h o ne b ut n ot 5- h y dr o x y o m e praz ole is i n hi bite d b y gra pefr uit j uice.  Br J 
Cli n P har mac ol . 2 0 0 0; 4 9: 1 3 9 – 4 4.
2 5.
Der u n gs A, D o nzelli M, Ber ger B, et al. Effects of C yt oc hr o me P 4 5 0 in hi biti o n a n d 
i n d ucti o n o n t he p he n ot y pi n g m etrics of t he Basel coc ktail: A ra n d o mize d cr oss o ver 
st u d y.  Cli n P har mac o k i net. 2 0 1 6; 5 5: 7 9 – 9 1 .
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
2 6.
F u r uta T, O has hi K, K o ba y as hi K, et al. Effects of clarit hr o m yci n o n t he meta b olis m of 
o me praz ole i n relati o n t o C Y P 2 C 1 9 g e n ot ype stat us i n h u ma ns . Cli n P har mac T her. 
1 9 9 9; 6 6( 3): 2 6 5 - 7 4.
2 7.
Nic h ols M, R o bi ns o n, G, B o u n ds, W, et al.  Effect of f o ur c o m bi ne d oral c o ntrace pti ves 
o n bl o o d press ure i n t he pill -free i nter val. C o ntrace pti o n. 1 9 9 3; 4 7: 3 6 7- 7 6.
2 8.
E der K, Baff y  N, Fal us A, a n d F ul o p A K . T he maj or i nfla m mat or y  me diat or 
i nterle u ki n-6 a n d o besit y. I nfla m m Res. 2 0 0 9,5 8: 7 2 7 – 3 6 .
2 9.
Ell ul u M S, Pat i ma h I, K haza’ai H, et al.  O besit y a n d i nfla m mati o n: t he li n ki n g 
mec ha nis m a n d t he c o m plicati o ns.  A rc h Me d Sci. 2 0 1 7; 1 3 ( 4): 8 5 1– 8 6 3 .
3 0.
Welle n K E a n d H ota misli gil G S . I nfla m mati o n, stress, a n d dia betes. J Cli n I n vest. 
2 0 0 5; 1 1 5( 5): 1 1 1 1 - 1 1 1 9.
3 1.
Tra y h ur n P a n d W o o d I S. Si g nalli n g r ole of a di p ose tiss ue: a di p o ki nes a n d 
i nfla m mati o n i n o besit y.  Bi oc he mical S ociet y  Tra nsacti o ns. 2 0 0 5; 3 3( 5):1 0 7 8 - 1 0 8 1.
3 2.
Mara nt os G, Das k ala kis N, Kar ka vitsas N, et al. C ha n ges i n m eta b olic p r ofile a n d 
a di p oi ns ular axis i n m or bi dl y  obese p re me n o pa usal fe males treate d wit h restricti ve 
b ariatric sur ger y . W orl d J S ur g. 2 0 1 1; 3 5: 2 0 2 2– 3 0.
3 3.
Bastar d J -P, Jar del C, Br uc kert E, et al. Ele vate d le vels of interle u ki n 6 are re d uce d i n 
ser u m a n d su bc uta ne o us adi p ose tiss ue of o bese w o me n after w ei g ht loss. J Cli n 
E n d ocri n ol o g y  Meta b olis m. 2 0 0 0; 8 5( 9):3 3 3 8 - 4 2.
3 4.
Br u u n J M, Ver dic h C, T o u br o S, et al. Ass ociati o n bet wee n meas ures of i ns uli n 
se nsiti vit y a n d circ ulati n g le vels of i nterle u ki n-8, i nterle u ki n - 6 a n d t u m or necr osis 
fact or- α. Effect of wei g ht l oss i n o bese me n.  E ur o pea n J E n d ocri n ol o g y. 
2 0 0 3 ; 14 8 : 5 3 5– 4 2 .
3 5.
Sc h mitt C, K u h n B, Z ha n g X, et al. Disease – d r u g– d r u g interacti o n in v ol vi n g 
tociliz u ma b a n d si m vastati n i n p atie nts wit h rhe u mat oi d art hritis. Cli n P har mac ol T her. 
2 0 1 1 ;8 9( 5) : 7 3 5- 4 0.
3 6.
Lee E B, Das kala kis N, X u C, et al. Disease– d r u g interacti o n of saril u ma b a n d 
si m vastati n i n p atie nts wit h rhe u mat oi d art hritis. Cli n P har mac o ki net. 2 0 1 7 ;5 6: 6 0 7 – 6 1 5 .
3 7.
A ber net h y D R, Gree n blatt DJ, Di v oll M, et al.  T he infl ue nce of o besit y o n t he 
p har mac o ki n etics of o ral al praz ola m a n d triaz ola m.  Cli n P har mac o ki net. 
1 9 8 4; 9 ( 2): 1 7 7- 8 3.
3 8.
Carac o Y, Z y l ber-Katz E, Berr y  E M, a n d Le v y M. Si g nifica nt wei g ht re d ucti o n i n o bese 
s u bjects e n ha nces car ba maze pi ne eli mi nati o n. Cli n P har mac ol T her. 1 9 9 2;5 1( 5) : 5 0 1- 6.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
3 9.
Ll oret -Li nares C , Daali Y, A b bara C, et al. C Y P 4 5 0 acti vities bef ore a n d after R o u x -e n-
Y gastric b y pass: c orrelati o n wit h t heir i ntesti nal a n d li ver c o nte nt. S ur g O bes Relat Dis. 
2 0 1 9; 1 5( 8): 1 2 9 9 – 1 3 1 0.
4 0.
R o drí g uez -M orat ó J, G o da y A, La n g o hr K, et al.  S h ort - a n d me di u m-ter m i m pact of 
bariatric s ur ger y  o n t he acti vities of C Y P 2 D 6, C Y P 3 A 4, C Y P 2 C 9, a n d C Y P 1 A 2 i n 
m or bi d o besit y . Sci Re p. 2 0 1 9;9( 1): 1 – 9.
4 1.
Brill MJ E, va n R o n ge n A, va n D o n ge n E P, et al.  T he p har mac o ki netics of t he C Y P 3 A 
su bstrate m i daz ola m i n m or bi dl y o bese p atie nts b ef ore a n d o ne y ear after b ariatric 
sur ger y . P har m Res. 2 0 1 5; 3 2: 3 9 2 7– 3 6.
4 2.
Sall C, Alifra n gis L, Da hl K, et al. I n vitr o C Y P 4 5 0 e nz y me d o w n -re g ulati o n b y 
G L P- 1/ gl uca g o n c o - a g o nist d oes n ot tra nslate t o o bser ve d dr u g-dr u g i nteracti o ns i n t he
cli nic. Dr u g Meta b Dis p os. 2 0 2 2;J u n 9. d oi: 1 0. 1 1 2 4/ d m d. 1 2 2. 0 0 0 8 6 5. O nli ne a hea d of 
pri nt.
4 3.
T R U LI CI T Y ® ( d ula gl uti de). U nite d States Prescri bi n g I nf or mati o n. Fe br uar y  2 0 2 0. 
A vaila ble fr o m: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 2 0/ 1 2 5 4 6 9s 0 3 3l bl. p df
Accesse d 3 N o v 2 0 2 2 .
4 4.
S A X E N D A ® (lira gl uti de). U nite d States Prescri bi n g I nf or mati o n. Marc h 2 0 2 0 .  
A vaila ble fr o m: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 2 0/ 2 0 6 3 2 1s 0 1 1l bl. p df.  
Accesse d 3 N o v 2 0 2 2.
4 5.
VI C T O Z A ® (lira gl uti de). U nite d States Prescri bi n g I nf or mati o n. J u ne 2 0 1 9.  A vaila ble 
fr o m: htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 9/ 0 2 2 3 4 1s 0 3 1l bl. p df
Accesse d 3 N o v 2 0 2 2 .
4 6.
B Y E T T A ® ( ex e nati de ). U nite d States Prescri bi n g I nf or mati o n. J u ne 2 0 2 2.  A vaila ble 
fr o m: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 2 2/ 0 2 1 7 7 3s 0 4 6s 0 4 7l bl. p df .
Accesse d 2 7 Oct 2 0 2 2.
4 7.
P os ner K, Br o w n G K, Sta nle y  B, et al. T he C ol u m bia-S uici de Se verit y Rati n g Scale: 
i nitial vali dit y a n d i nter nal c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h 
a d olesce nts a n d a d ults. A m J Ps y c hiatr y. 2 0 1 1; 1 6 8( 1 2): 1 2 6 6 - 7 7.
4 8.
Kr oe n ke K, S pitzer R L , Willia ms J B. T he P H Q-9: vali dit y  of a brief de pressi o n se verit y
meas ure. J Ge n I nter n Me d . 2 0 0 1; 1 6( 9): 6 0 6 - 1 3.
4 9.
Cra wf or d P, C ha d wic k DJ, Marti n C, et al. T he i n teracti o n of p he nyt oi n a n d 
car ba maze pi ne wit h c o m bi ne d oral c o ntrace pti ve ster oi ds. Br J Cli n P har mac. 
1 9 9 0; 3 0: 8 9 2 - 96.
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)


P F -0 7 0 8 1 5 3 2
Pr ot oc ol C 3 9 9 1 0 4 0
Fi nal Pr ot oc ol , x x 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
5 0.
J or d y A B, Al ba y at y M, Breitsc haft A, et al. Effect of o ral se ma gl uti de o n t he 
p har mac o ki netics of le v o n or gestrel a n d et hi n ylestra di ol i n h ealt h y p ost me n o pa usal 
w o me n a n d fur ose mi de a n d ros u vastati n i n h ealt h y su bjects. Cli n P har mac o ki net .
2 0 2 1 ; 6 0( 9): 1 1 7 1– 8 5 .
5 1.
A merica n Dia betes Ass ociati o n. Sta n dar ds of me dical care i n dia betes -2 0 1 9. Dia betes 
Care . 2 0 1 9; 4 2( S u p pl 1): S 1 -S 1 9 3.
5 2.
R o dri g ues A D, va n D y k M, S oric h MJ, et al. E x pl ori n g t he use of ser u m -deri ve d s mall 
e xtracell ular vesicles as li q ui d bi o ps y t o st u d y t he i n d ucti o n of he patic c yt oc hr o mes 
P 4 5 0 a n d or ga nic a ni o n tra ns p orti n g p ol y pe pti des. Cli n P har mac ol T her. 
2 0 2 1; 1 1 0( 1): 2 4 8 - 5 8. 
0 9 0 1 7 7 e 1 9 b c 4 d 2f 4\ A p pr o v e d\ A p pr o v e d O n: 0 8- N o v- 2 0 2 2 1 7: 5 2 ( G M T)

SAP_001.pdf: 
Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
Pr ot oc ol C 3 9 9 1 0 4 0
A P h ase 1, O pe n -L a bel, Fi xe d -Se q ue nce St u dy t o Ev al u ate t he Effect of T w o Ste a dy -St ate 
D ose Levels of P F -0 7 0 8 1 5 3 2 o n t he P h ar m ac o ki netics of Si n gle -D ose Mi d az ol a m, 
O me pr az ole a n d a n Or al C o ntr ace ptive, a n d t he Effect of Ste a dy -St ate Se m a gl uti de o n t he 
P h ar m ac o ki netics of Si n gle -D ose Mi d az ol a m, i n O bese A d ult Fe m ale P artici p a nts
St atistic al A n al ysis Pl a n 
( S A P)
Versi o n :
1
D ate:
2 3 Dec 2 0 2 2
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
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 .....................................................................................................................4
LI S T O F FI G U R E S ...................................................................................................................4
A P P E N DI C E S ...........................................................................................................................4
1. V E R SI O N HI S T O R Y ............................................................................................................5
2. I N T R O D U C TI O N .................................................................................................................5
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..................................5
2. 2. St u d y  O bjecti ves a n d E n d p oi nts ...............................................................................5
2. 3. St u d y  Desi g n.............................................................................................................8
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S:  D E FI NI TI O N S A N D 
C O N V E N TI O N S ................................................................................................................1 0
3. 1. Pri mar y  E n d p oi nts...................................................................................................1 0
3. 2. Sec o n dar y  E n d p oi nts...............................................................................................1 0
3. 3. Ot her E n d p oi nts .......................................................................................................1 1
3. 4. Bas eli ne Varia bles ...................................................................................................1 4
3. 5. Safet y E n d p oi nts .....................................................................................................1 4
3. 5. 1. A d verse E ve nts ...........................................................................................1 4
3. 5. 2. L a b orat or y Data..........................................................................................1 4
3. 5. 3. B o d y Wei g ht ...............................................................................................1 5
3. 5. 4. Vit al Si g ns ..................................................................................................1 5
3. 5. 5. Electr ocar di o gra ms..................................................................................... 1 5
3. 5. 6. Me ntal healt h ..............................................................................................1 5
3. 5. 6. 1. C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S) .................1 5
3. 5. 6. 2. Patie nt Healt h Q uesti o n naire- 9 ( P H Q - 9) ..................................1 5
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)................................................... 1 6
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 ....................................................1 7
5. 1. H y p ot heses a n d Decisi o n R ules ..............................................................................1 7
5. 2. Ge neral Met h o ds .....................................................................................................1 7
5. 2. 1. A nal y ses f or Bi nar y/ Cate g orical E n d p oi nts ...............................................1 7
5. 2. 2. A nal y ses f or C o nti n u o us E n d p oi nts ...........................................................1 7
5. 3. Met h o ds t o Ma na ge Missi n g Data ..........................................................................1 7
5. 3. 1. P har mac o ki netic Data .................................................................................1 7
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
5. 3. 2. Safet y Data ..................................................................................................1 8
6. A N A L Y S E S A N D S U M M A RI E S ......................................................................................1 8
6. 1. Pri mar y  E n d p oi nts...................................................................................................1 8
6. 2. Sec o n dar y  E n d p oi nts...............................................................................................1 9
6. 3. Ot her E n d p oi nts .......................................................................................................2 0
6. 3. 1. P K C o nce ntrati o n ........................................................................................2 1
6. 3. 2. P K para meter ..............................................................................................2 2
6. 4. S u bset A nal y ses.......................................................................................................2 3
6. 5. Baseli ne a n d Ot her S u m maries a n d A nal ys es .........................................................2 3
6. 5. 1. De m o gra p hic S u m maries ............................................................................2 3
6. 5. 2. St u d y  C o n d uct a n d Partici pa nt Dis p ositi o n................................................2 3
6. 5. 3. St u d y  Treat me nt E x p os ure .........................................................................2 3
6. 5. 4. C o nc o mita nt Me dicati o ns a n d N o n dr u g Treat me nts.................................. 2 3
6. 6. Safet y S u m maries a n d A nal yses .............................................................................2 3
6. 6. 1. A d verse E ve nts ...........................................................................................2 3
6. 6. 2. L a b orat or y Data..........................................................................................2 4
6. 6. 3. B o d y Wei g ht ...............................................................................................2 4
6. 6. 4. Vital Si g ns ..................................................................................................2 4
6. 6. 5. Electr ocar di o gra ms .....................................................................................2 4
6. 6. 6. Me ntal Healt h .............................................................................................2 4
7. I N T E RI M A N A L Y S E S .......................................................................................................2 4
A P P E N DI C E S .........................................................................................................................2 5
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
LI S T O F T A B L E S
Ta ble 1.
S u m mar y  of C ha n ges..................................................................................5
Ta ble 2.
Plas ma P K Para meters f or Mi daz ola m, 1- O H -Mi daz ola m, 
O me praz ole, 5 -O H -O me praz ole, Le v o n or gestrel a n d Et hi n y l 
Estra di ol ....................................................................................................1 3
Ta ble 3. 
Plas ma P K Para meters f or P F- 0 7 0 8 1 5 3 2 ................................ .................1 4
Ta ble 4.
P K Para meters t o be S u m marize d Descri pti vel y b y  Treat me nt ...............2 3
LI S T O F FI G U R E S
Fi g ure 1.
St u d y  Sc he ma .............................................................................................9
A P P E N DI C E S
A p pe n di x 1. S A S C o de f or A nal ys es .......................................................................................2 5
A p pe n di x 2. L ist of A b bre viati o ns...........................................................................................3 3
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
N O T E : It alicize d te xt wit hi n t his d oc u me nt has bee n ta ke n ver bati m fr o m t he Pr ot oc ol.
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 /
2 3 Dec 2 0 2 2
Ori gi nal 
0 7 N o v 2 0 2 2
N/ A
N/ A
2. I N T R O D U C TI O N
P F - 0 7 0 8 1 5 3 2 is a n or ally a d mi nistere d, p ote nt a n d selective G L P-1 R a g o nist i n devel o p me nt 
as a dj u nct t o diet a n d exercise, t o i m pr ove glyce mic c o ntr ol i n T 2 D M, a n d f or c hr o nic wei g ht 
m a n a ge me nt i n a p o p ul ati o n t h at is over wei g ht wit h c o- m or bi dities or w h o h ave o besity.
T he p ur p ose of t his P h ase 1, o pe n -l a bel, fixe d-se q uence st u dy is t o ev al u ate t he effect of 2 
d ose levels of P F - 0 7 0 8 1 5 3 2 a d mi nistere d t o ste a dy st ate o n t he S D p h ar m ac oki netics of 
mi d az ol a m, o me pr az ole, a n d a n O C ( L E/ E E) ( C o h ort 1), a n d t o ev al u ate t he effect of ste a dy -
st ate se m a gl uti de o n t he S D p h ar m ac oki netics of mi d az ol a m ( C o h ort 2), i n ot her wise 
he alt hy, o bese, a d ult fe m ale p artici p a nts. T he i nte nt of t his st u dy is t o ge ner ate s afety, 
t oler a bility, a n d P K d at a f or f urt her cli nic al devel o p me nt.
T his 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 3 9 9 1 0 4 0 .
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 o ne .
2. 2. St u d y O bjecti ves a n d E n d p oi nts
O bjectives
E n d p oi nts
C o h ort 1
Pri m ary: 
Pri m ary: 

T o ev al u ate t he effects of P F- 0 7 0 8 1 5 3 2 
o n t he p h ar m ac oki netics of mi d az ol a m, 
o me pr az ole, a n d a n or al c o ntr ace ptive 
( O C; lev o n or gestrel [ L E]/et hi nyl 
estr a di ol [ E E]) i n o bese a d ult fe m ale 
p artici p a nts.

Mi d az ol a m pl as m a p h ar m ac oki netic 
p ar a meters: A U C i nf (if d at a per mit*
ot her wise A U C l ast) i n Peri o ds 1, 4 a n d 7.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
O bjectives
E n d p oi nts

O me pr az ole pl as m a p h ar m ac oki netic 
p ar a meters: A U C i nf (if d at a per mit*
ot her wise A U C l ast) i n Peri o ds 1, 4 a n d 7.

L E pl as m a p h ar m ac oki netic p ar a meters: 
A U C i nf (if d at a per mit* ot her wise A U C l ast) 
i n Peri o ds 2, 5 a n d 8.

E E pl as m a p h ar m ac oki netic p ar a meters: 
A U C i nf (if d at a per mit* ot her wise A U C l ast) 
i n i n Peri o ds 2, 5 a n d 8.
Sec o n d ary: 
Sec o n d ary: 

T o ev al u ate t he s afety a n d t oler a bility of 
P F - 0 7 0 8 1 5 3 2 a d mi nistere d se p ar ately 
a n d i n c o m bi n ati o n wit h mi d az ol a m, 
o me pr az ole, a n d a n O C ( L E/ E E) i n 
o bese a d ult fe m ale p artici p a nts.

Assess me nt of T E A Es, cli nic al l a b or at ory 
a b n or m alities, a n d b o dy wei g ht.

Assess me nt of me nt al he alt h as 
deter mi ne d by C -S S R S a n d P H Q - 9.

T o ev al u ate t he p h ar m ac oki netics of S D 
mi d az ol a m f oll o wi n g t he disc o nti n u ati o n 
of P F -0 7 0 8 1 5 3 2 a d mi nistr ati o n i n o bese 
a d ult fe m ale p artici p a nts.

Mi d az ol a m pl as m a p h ar m ac oki netic 
p ar a meters: A U C i nf (if d at a per mit*
ot her wise A U C l ast) i n Peri o d 9.

T o ev al u ate t he effects of P F- 0 7 0 8 1 5 3 2 
o n a d diti o n al p h ar m ac oki netic 
p ar a meters of mi d az ol a m, o me pr az ole, 
a n d a n O C ( L E/ E E) i n o bese a d ult 
fe m ale p artici p a nts.

A d diti o n al pl as m a p h ar m ac oki netic 
p ar a meters f or mi d az ol a m a n d 
o me pr az ole ( Peri o ds 1, 4 a n d 7), a n d L E 
a n d E E ( Peri o ds 2, 5 a n d 8): C m ax a n d 
T m ax ; a n d C L/ F, Vz/ F, t½ , as d at a per mit.

T o ev al u ate t he effects of P F- 0 7 0 8 1 5 3 2 
o n t he met a b olite/ p are nt r ati os f or 
mi d az ol a m a n d o me pr az ole i n o bese 
a d ult fe m ale p artici p a nts.

M R A U C
i nf ( 1-hy dr oxy mi d az ol a m 
A U C i nf/ mi d az ol a m A U Ci nf).

M R A U C
i nf ( 5-hy dr oxy o me pr az ole 
A U C i nf/ o me pr az ole A U Ci nf).

T o ev al u ate t he M D p h ar m ac oki netics of 
P F -0 7 0 8 1 5 3 2 i n o bese a d ult fe m ale 
p artici p a nts.

P F -0 7 0 8 1 5 3 2 pl as m a p h ar m ac oki netic 
p ar a meters at D ays 3 4 a n d 1 0 3: A U C 2 4, 
C m ax , Tm ax .
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
O bjectives
E n d p oi nts
Terti ary/ E x pl or at ory : 
Terti ary/ E x pl or at ory :

T o ev al u ate t he effects of P F- 0 7 0 8 1 5 3 2 
o n t he p h ar m ac oki netics of 1-
hy dr oxy mi d az ol a m i n o bese a d ult fe m ale 
p artici p a nts.

1- hy dr oxy mi d az ol a m pl as m a 
p h ar m ac oki netic p ar a meters: A U C l ast, 
C m ax , Tm ax ; a n d A U Ci nf a n d t ½ as d at a 
per mit i n Peri o ds 1, 4 a n d 7.

Met a b olite/ p are nt ( 1 -
hy dr oxy mi d az ol a m/ mi d az ol a m) r ati os f or 
A U C i nf ( as d at a per mit), A U Cl ast, a n d Cm ax
will als o be c alc ul ate d.

T o ev al u ate t he effects of P F- 0 7 0 8 1 5 3 2 
o n t he p h ar m ac oki netics of 5-
hy dr oxy o me pr az ole i n o bese a d ult 
fe m ale p artici p a nts.

5- hy dr oxy o me pr az ole pl as m a 
p h ar m ac oki netic p ar a meters: A U C l ast, 
C m ax , Tm ax ; a n d A U Ci nf a n d t ½ as d at a 
per mit i n Peri o ds 1, 4 a n d 7. 

Met a b olite/ p are nt ( 5 -hy dr oxy o me pr az ole 
/ o me pr az ole) r ati os f or A U Ci nf ( as d at a 
per mit), A U C l ast, a n d Cm ax will als o be 
c alc ul ate d.

T o ev al u ate t he effects of P F- 0 7 0 8 1 5 3 2 
o n bi o m arkers of C Y P 3 A i n d ucti o n. 
[ O pti o n al].

M or ni n g pre d ose 4 β -
hy dr oxyc h olester ol/c h olester ol pl as m a 
r ati o o n D ay 1 i n Peri o ds 1, 4, a n d 7. 
C o h ort 2
Pri m ary: 
Pri m ary: 

T o ev al u ate t he effects of se m a gl uti de 
(s u bc ut a ne o us se m a gl uti de) o n t he S D 
P K of mi d az ol a m i n o bese a d ult fe m ale 
p artici p a nts.

Mi d az ol a m pl as m a p h ar m ac oki netic 
p ar a meters: A U C i nf (if d at a per mit*
ot her wise A U C l ast) i n Peri o ds 1 a n d 3.
Sec o n d ary: 
Sec o n d ary: 

T o ev al u ate t he s afety a n d t oler a bility of 
se m a gl uti de a d mi nistere d se p ar ately a n d 
i n c o m bi n ati o n wit h mi d az ol a m i n o bese 
a d ult fe m ale p artici p a nts.

Assess me nt of T E A Es, cli nic al l a b or at ory 
a b n or m alities, a n d b o dy wei g ht. 

Assess me nt of me nt al he alt h as 
d eter mi ne d by C -S S R S a n d P H Q -9.

T o ev al u ate t he p h ar m ac oki netics of S D 
mi d az ol a m f oll o wi n g t he disc o nti n u ati o n 

Mi d az ol a m pl as m a p h ar m ac oki netic 
p ar a meters: A U C i nf (if d at a per mit*
ot her wise A U C l ast) i n Peri o d 4.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)
C CI


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
O bjectives
E n d p oi nts
of se m a gl uti de a d mi nistr ati o n i n o bese 
a d ult fe m ale p artici p a nts.

T o ev al u ate t he effects of se m a gl uti de o n 
a d diti o n al p h ar m ac oki netic p ar a meters 
of mi d az ol a m i n o bese a d ult fe m ale 
p artici p a nts.

A d diti o n al pl as m a p h ar m ac oki netic 
p ar a meters f or mi d az ol a m (i n Peri o ds 1 
a n d 3): C m ax , Tm ax , a n d C L/ F, Vz/ F, t½ as 
d at a per mit.

T o ev al u ate t he effects of se m a gl uti de o n 
t he met a b olite/ p are nt r ati o f or 
mi d az ol a m i n o bese a d ult fe m ale 
p artici p a nts.

M R A U C
i nf ( 1-hy dr oxy mi d az ol a m 
A U C i nf/ mi d az ol a m A U Ci nf).
Terti ary/ E x pl or at ory : 
Terti ary/ E x pl or at ory :

T o ev al u ate t he effects of se m a gl uti de o n 
t he p h ar m ac oki netics of 1-
hy dr oxy mi d az ol a m i n o bese a d ult fe m ale 
p artici p a nts.

1- hy dr oxy mi d az ol a m pl as m a 
p h ar m ac oki netic p ar a meters: A U C l ast, 
C m ax , Tm ax ; a n d A U Ci nf a n d t ½ as d at a 
per mit i n Peri o ds 1 a n d 3. 

Met a b olite/ p are nt ( 1 -
hy dr oxy mi d az ol a m/ mi d az ol a m) r ati os f or 
A U C i nf ( as d at a per mit), A U Cl ast, a n d Cm ax
will als o be c alc ul ate d.

T o ev al u ate t he effects of se m a gl uti de o n 
bi o m arkers of C Y P 3 A i n d ucti o n. 
[ O pti o n al]

M or ni n g pre d ose 4 β -
hy dr oxyc h olester ol/c h olester ol pl as m a 
r ati o o n D ay 1 i n Peri o ds 1 a n d 3. 
* S h o ul d it be dee me d t h at t o o fe w A U Ci nf esti m ates (e g, less t h a n 1 2 f or a si n gle tre at me nt) are o bt ai ne d 
fr o m t he ev al u a ble p artici p a nts, A U Cl ast m ay be selecte d as t he pri m ary e n d p oi nt f or C S R re p orti n g. T his will 
be c o nsi dere d f or t he mi d az ol a m, 1 -hy dr oxy mi d az ol a m, o me pr az ole, 5 -hy dr oxy o me pr az ole, L E, a n d E E 
o bjectives se p ar ately.
2. 3. St u d y Desi g n
T his st u dy will be c o n d ucte d wit h 2 c o h orts. C o h ort 1 will ev al u ate t he effect of 2 ste a dy -
st ate d ose levels of P F- 0 7 0 8 1 5 3 2 o n t he S D p h ar m ac oki netics of mi d az ol a m, o me pr az ole, 
a n d a n O C ( L E/ E E). C o h ort 2 will ev al u ate t he effect of ste a dy- st ate se m a gl uti de o n t he S D 
p h ar m ac oki netics of mi d az ol a m. Titr ati o n will be i m ple me nte d i n b ot h c o h orts i n or der t o 
e n h a nce g astr oi ntesti n al t oler a bility si mil arly t o t he a p pr o ac h i m ple me nte d f or m arkete d 
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)
C CI


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
G L P -1 R a g o nists. P artici p a nts will p artici p ate i n eit her C o h ort 1 or C o h ort 2 ( n ot b ot h), a n d 
C o h ort 1 a n d C o h ort 2 are preferre d t o be c o n d ucte d i n p ar allel, if p ossi ble.
C o h ort 1 is a n o pe n -l a bel, 9-peri o d, fixe d -se q ue nce desi g n t o ev al u ate t he effect of 2 ste a dy-
st ate d ose levels of P F-0 7 0 8 1 5 3 2 o n t he S D p h ar m ac oki net ics of mi d az ol a m a n d o me pr az ole, 
a d mi nistere d si m ult a ne o usly, a n d a n O C ( L E/ E E) i n ot her wise he alt hy o bese a d ult fe m ale 
p artici p a nts wit h a B MI ≥3 0 k g/ m 2. A p pr oxi m ately 1 6 p artici p a nts will be e nr olle d i n C o h ort 
1.
C o h ort 2 is a n o pe n -l a bel, 4-peri o d, fixe d- se q ue nce desi g n t o ev al u ate t he effect of ste a dy-
st ate se m a gl uti de o n t he S D P K of mi d az ol a m i n o bese a d ult fe m ale p artici p a nts wit h a B MI 
≥3 0 k g/ m 2. A p pr oxi m ately 1 6 p artici p a nts will be e nr olle d i n C o h ort 2.
Fi g ure 1.
St u d y Sc he m a
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
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 nts
C o h ort 1
T he pri mar y  e n d p oi nts are t he A U Ci nf (if data per mit , ot her wise A U C last) of mi daz ola m a n d 
o me praz ole i n Peri o ds 1, 4 a n d 7; a n d A U C i nf (if data per mit , ot her wise A U C last) of L E a n d 
E E i n Peri o ds 2, 5 a n d 8. I n a d diti o n, t he test/refere nce rati os f or A U C i nf (if data per mit , 
ot her wise A U C last) a n d C ma x will be deri ve d f or t he f oll o wi n g c o m paris o ns:

test treat me nts will be “ mi daz ola m ( or o me praz ole) a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D” 
( Peri o d 4) a n d “ mi daz ola m ( or o me praz ole) a n d P F- 0 7 0 8 1 5 3 2 2 6 0 m g Q D” ( Peri o d 
7) a n d t he refere nce treat me nt will be “ mi daz ola m ( or o me praz ole) wit h o ut P F -
0 7 0 8 1 5 3 2” ( Peri o d 1);

test treat me nts will be “ L E ( or E E) a n d P F- 0 7 0 8 1 5 3 2 8 0 m g Q D” ( Peri o d 5) a n d “ L E 
( or E E) a n d P F-0 7 0 8 1 5 3 2 2 6 0 m g Q D” ( Peri o d 8) a n d t he refere nce treat me nt will be 
“ L E ( or E E) al o ne” ( Peri o d 2).
C o h ort 2
T he pri mar y  e n d p oi nts are t he A U Ci nf (if data per mit , other wise A U C last) of mi daz ola m i n 
Peri o ds 1 a n d 3. I n a d diti o n, t he test/refere nce rati os f or A U C i nf (if data per mit , ot her wise 
A U C last) a n d C ma x will be deri ve d f or t he f oll o wi n g c o m paris o n:

test treat me nt will be “ mi daz ola m a n d se ma gl uti de 2. 4 m g wee kl y” ( Peri o d 3) a n d t he 
refere nce treat me nt will be “ mi daz ola m al o ne” ( Peri o d 1).
3. 2. Sec o n d ar y E n d p oi nt s
C o h ort 1
T he sec o n dar y  e n d p oi nts are t he f oll o wi n g:

Safet y  a n d t olera bilit y data, disc usse d i n Secti o n 3. 5 .

A U C i nf (if data per mit, ot her wise A U C last) of mi daz ola m i n Peri o d 9. In a d diti o n, t he 
test/refere nce rati os f or A U Ci nf (if data per mit, ot her wise A U C last) a n d Cma x will be 
deri ve d f or t he f oll o wi n g c o m paris o ns:
o
test treat me nt will be “ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of P F-
0 7 0 8 1 5 3” ( Peri o d 9) a n d refere nce treat me nts will be “ mi daz ola m wit h o ut P F -
0 7 0 8 1 5 3 2” ( Peri o d 1) a n d “ mi daz ola m a n d P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D” ( Peri o d 7).

A d diti o nal plas ma P K para meters ( C ma x , Tma x , C L/ F, Vz/ F, t1/ 2, as data per mit) f or 
mi daz ola m a n d o me praz ole i n Peri o ds 1, 4 a n d 7, a n d f or L E a n d E E i n Peri o ds 2, 5 
a n d 8.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4

M R A U C
i nf ( 1-h y dr o x y mi daz ola m A U C i nf/ mi daz ola m A U Ci nf) i n Peri o ds 1, 4 a n d 7. 

M R A U C
i nf ( 5-h y dr o x y o me praz ole A U C i nf/ o me praz ole A U Ci nf) i n Peri o ds 1, 4 a n d 7. 

A U C 2 4, Cma x a n d T ma x of P F - 0 7 0 8 1 5 3 2 at Da ys 3 4 a n d 1 0 3.
C o h ort 2
T he sec o n dar y  e n d p oi nts are t he f oll o wi n g:

Safet y  a n d t olera bilit y data, disc usse d i n Secti o n 3. 5 .

A U C i nf (if data per mit , ot her wise A U C last) of mi daz ol a m i n Peri o d 4. I n a d diti o n, t he 
test/refere nce rati os f or A U Ci nf (if data per mit, ot her wise A U C last) a n d Cma x will be 
deri ve d f or t he f oll o wi n g c o m paris o ns:
o
test treat me nt will be “ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of 
se ma gl uti de” ( Peri o d 4) a n d refere nce treat me nts will be “ mi daz ola m wit h o ut 
se ma gl uti de” ( Peri o d 1) a n d “ mi daz ola m a n d se ma gl uti de 2.4 m g o nce wee kl y ” 
( Peri o d 3).

A d diti o nal plas ma P K para meters ( C ma x , Tma x , C L/ F, Vz/ F, t1/ 2, as data per mit) f or 
mi daz ola m i n Peri o ds 1 a n d 3 .

M R A U C
i nf ( 1-h y dr o x y mi daz ola m A U C i nf/ mi daz ola m A U Ci nf) i n Peri o ds 1 a n d 3.
3. 3. Ot her E n d p oi nt s
C o h ort 1
T he tertiar y /e x pl orat or y e n d p oi nts are t he f oll o wi n g:

A U C last, Cma x , Tma x , A U Ci nf a n d t 1/ 2 as data per mit f or 1 -h y dr o x y m i daz ola m i n Peri o ds 
1, 4 a n d 7

Test/refere nce rati os f or m eta b olite/ pare nt ( 1 -h y dr o x y mi daz ola m/ mi daz ola m) f or 
A U C i nf (as data per mit), A U Clast a n d C ma x w here test treat me nts will be “ mi daz ola m 
a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D” ( Peri o d 4) a n d “ mi daz ola m a n d P F -0 7 0 8 1 5 3 2 2 6 0 m g 
Q D” ( Peri o d 7) a n d t he refere nce treat me nt s will be “ mi daz ola m wit h o ut P F -
0 7 0 8 1 5 3 2” ( Peri o d 1) a n d “ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of P F-
0 7 0 8 1 5 3” ( Peri o d 9)

A U C last, Cma x , Tma x , A U Ci nf a n d t 1/ 2 as data per mit f or 5- h y dr o x y o me praz ole i n 
Peri o ds 1, 4 a n d 7

Test/ refere nce rati os f or meta b olite/ pare nt ( 5 -h y dr o x y o me praz ole/ o me praz ole ) f or 
A U C i nf (as data per mit), A U Clast a n d C ma x w here test treat me nts will be “ o me praz ole
a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D” ( Peri o d 4) a n d “ o me praz ole a n d P F-0 7 0 8 1 5 3 2 2 6 0 m g 
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
Q D” ( Peri o d 7) a n d t he refere nce treat me nt will be “ o me praz ole wit h o ut P F -
0 7 0 8 1 5 3 2” ( Peri o d 1)

M or ni n g pre d ose 4 β -h y dr o x y c h olester ol/c h olester ol plas ma rati o o n Da y  1 i n Peri o ds 
1, 4, a n d 7
C o h ort 2
T he tertiar y /e x pl orat or y e n d p oi nts are t he f oll o wi n g:

A U C last, Cma x , Tma x , A U C i nf a n d t 1/ 2 as data per mit f or 1 -h y dr o x y m i daz ola m i n Peri o ds 
1 a n d 3

Test/refere nce rati os f or m eta b olite/ pare nt ( 1 -h y dr o x y mi daz ola m/ mi daz ola m) f or 
A U C i nf (as data per mit), A U Clast a n d C ma x w here test treat me nt will be “ mi daz ola m 
a n d se ma gl uti de 2. 4 m g o nce wee kl y ” ( Peri o d 3 ) a n d t he refere nce treat me nts will be 
“mi daz ola m al o ne ” ( Peri o d 1) a n d “ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of 
se ma gl uti de” ( Peri o d 4)

M or ni n g pre d ose 4 β -h y dr o x y c h olester ol/c h olester ol plas ma rati o o n Da y  1 i n Peri o ds 
1 a n d 3
T he pl as m a P K p ar a meters f or mi d az ol a m, 1- hy dr oxy mi d az ol a m, o me pr az ole, 5 -
hy dr oxy o me pr az ole, L E a n d E E f oll o wi n g S D a d mi nistr ati o n (eit her al o ne or d uri n g
c o a d mi nistr ati o n wit h P F -0 7 0 8 1 5 3 2 or se m a gl uti de [ mi d az ol a m o nly ]) will be derive d fr o m
t he c once ntr ati o n- ti me pr ofiles as det aile d i n T a ble 2 bel o w. T he pl as m a P K p ar a meters f or
P F -0 7 0 8 1 5 3 2 f oll o wi n g M D a d mi nistr ati o n will be derive d fr o m t he c o nce ntr ati o n -ti me
pr ofiles as det aile d i n Ta ble 3 bel o w.
Act u al P K s a m pli n g ti mes will be use d i n t he deriv ati o n of P K p ar a meters. I n t he c ase t h at 
act u al P K s a m pli n g ti mes are n ot av ail a ble, n o mi n al P K s a m pli n g ti me will be use d i n t he 
deriv ati o n of P K p ar a meters.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
T a ble 2 .
Pl as m a P K P ar a meters f or Mi d az ol a m, 1 -O H -Mi d az ol a m, O me pr az ole, 5 -
O H - O me pr az ole, Le v o n or gestrel a n d Et hi n yl Estr a di ol
P a r a meter
Defi niti o n
Met h o d of Deter mi n ati o n
A U C l ast
Are a u n der t he pl as m a c o nce ntr ati o n- ti me 
pr ofile fr o m ti me zer o t o t he ti me of t he 
l ast q u a ntifi a ble c o nce ntr ati o n ( Cl ast).
Li ne ar/ L o g tr a pez oi d al met h o d.
A U C i nf* 
Are a u n der t he pl as m a c o nce ntr ati o n- ti me
pr ofile fr o m ti me zer o extr a p ol ate d t o 
i nfi nite ti me.
A U C l ast + ( C l ast*/k el), w here 
C l ast* is t he pre dicte d pl as m a 
c o nce ntr ati o n at t he l ast 
q u a ntifi a ble ti me p oi nt esti m ate d 
fr o m t he l o g-li ne ar re gressi o n 
a n alysis.
C m ax
M axi m u m o bserve d c o nce ntr ati o n.
O bserve d directly fr o m d at a.
T m ax
Ti me f or C m ax .
O bserve d directly fr o m d at a as 
ti me of first occ urre nce.
t½ *
Ter mi n al h alf -life.
L o g e( 2)/kel,
w here kel is t he ter mi n al p h ase 
r ate c o nst a nt c alc ul ate d by a 
li ne ar re gressi o n of t he l o g-
li ne ar c o nce ntr ati o n-ti me c urve. 
O nly t h ose d at a p oi nts j u d ge d t o 
descri be t he ter mi n al l o g -li ne ar 
decli ne will be use d i n t he 
re gressi o n.
C L/ F *
A p p are nt or al cle ar a nce.
D os e/ A U C i nf.
V z/ F *
A p p are nt v ol u me of distri b uti o n
D ose/ A U C i nf • kel).
M R
Mi d az ol a m met a b olite/ p are nt r ati o.
1 -hy dr oxy mi d az ol a m/ mi d az ol a m 
f or A U Ci nf, A U Cl ast, a n d Cm ax
( a dj uste d t o acc o u nt f or 
differe nces i n m olec ul ar wei g ht).
M R
O me pr az ole met a b olite/ p are nt r ati o.
5 -
hy dr oxy o me pr az ole/ o me pr az ole 
f or A U Ci nf, A U Cl ast, a n d Cm ax
( a dj uste d t o acc o u nt f or 
differe nces i n m olec ul ar wei g ht).
* as d at a per mit; C L/ F a n d V z/ F will n ot be c alc ul ate d f or 1-O H -mi d az ol a m or 5 -O H -o me pr az ole.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
T a ble 3 . 
Pl as m a P K P ar a meters f or P F- 0 7 0 8 1 5 3 2 
P ar a meter
Defi niti o n
Met h o d of Deter mi n ati o n
A U C 2 4
Are a u n der t he pl as m a c o nce ntr ati o n-
ti me pr ofile fr o m ti me zer o t o ti me 2 4 
h o urs.
Li ne ar/ L o g tr a pez oi d al met h o d
C m ax
M axi m u m pl as m a c o nce ntr ati o n o bserve d 
fr o m ti me zer o t o 2 4 h o urs.
O bserve d directly fr o m d at a .
T m ax
Ti me f or C m ax .
O bserve d directly fr o m d at a as 
ti me of first occ urre nce.
A si n gle tr o u g h c o nce ntr ati o n s a m ple will be o bt ai ne d f or se m a gl uti de at 0 h o n Weeks 5, 9, 1 3, a n d 1 7 
d uri n g Peri o d 2 a n d pri or t o d osi n g i n Peri o d 3, D ay 1.
3. 4. B aseli ne V ari a bles
Baseli ne c haracteristics will be c ollecte d acc or di n g t o t he sc he d ule of acti vities ( S o A) as 
s pecifie d i n t he pr ot oc ol.
3. 5. S afet y E n d p oi nts
T he f oll o wi n g data are c o nsi dere d i n sta n dar d safet y  s u m maries (see pr ot oc ol f or c ollecti o n
da y s, baseli ne assess me nt, a n d list of para meters):

a d verse e ve nts ( A E)

la b orat or y data

b o d y  wei g ht

me ntal healt h

vital si g ns data

electr ocar di o gra m (E C G ) res ults
3. 5. 1. A d verse E ve nts
A n y  a d verse e ve nts occ urri n g f oll o wi n g start of treat me nt will be c o nsi dere d as treat me nt 
e mer ge nt a d verse e ve nt ( T E A E) . E ve nts t hat occ ur d uri n g f oll o w -u p wit hi n t he la g ti me of 
u p t o 3 5 da y s after t he last d ose of st u d y  i nter ve nti o n 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 last treat me nt ta ke n. T he ti me peri o d f or c ollecti n g 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.
3. 5. 2. L a b or at or y D at a
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. 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 he mat ol o gical, cli nical c he mistr y  
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
(ser u m) a n d uri nalys is 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’s re p orti n g sta n dar ds. T he assess me nt will n ot ta ke i nt o acc o u nt w het her eac h 
partici pa nts ’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.
F or b ot h c o h orts, t he b a seli ne meas ure me nt is t he latest pre d ose meas ure me nt o n Peri o d 1 .
3. 5. 3. B o d y Wei g ht
B o d y wei g ht will be meas ure d at ti mes s pecifie d i n t he S o A gi ve n i n t he pr ot oc ol.
F or b ot h c o h orts, t he baseli ne meas ure me nt is t he pre d ose meas ure me nt o n Peri o d 1 Da y  1.
3. 5. 4. Vit al Si g ns
S u pi ne bl o o d press ure ( B P) , p ulse rate ( P R) a n d te m perat ure will be meas ure d at ti mes 
s pecifie d i n t he S o A gi ve n i n t he pr ot oc ol.
F or b ot h c o h orts , the baseli ne meas ure me nt is t he latest pre d ose meas ure me nt o n Peri o d 1 .
3. 5. 5. Electr oc ar di o gr a ms
Q T i nter val , Q Tc F, P R, Q R S a n d heart rate ( H R) will be rec or de d at eac h assess me nt ti me 
i n dicate d i n t he S o A gi ve n i n t he pr ot oc ol. 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)
F or b o t h c o h orts, the baseli ne meas ure me nt is t he latest meas ure me nt at Scree ni n g .
3. 5. 6. Me nt al he alt h
3. 5. 6. 1. C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)
T he C- S S R S is a n i ntervie w - b ase d r ati n g sc ale t o syste m atic ally assess s uici d al i de ati o n a n d 
s uici d al be h avi or. T he “si nce l ast visit ”versi o n of t he C -S S R S will be a d mi nistere d at t he 
ti me p oi nts s pecifie d i n t he S o A. A partici pa nt wit h a p ost baseli ne assess me nt wit h res p o nse 
of “ yes” t o q uesti o n 4 or 5, or o n a n y s uici dal be ha vi oral q uesti o n o n t he C -S S R S s h o ul d be
referre d t o a Me ntal Healt h Pr ofessi o nal ( M H P). Partici pa nts w h o ha ve rec urre nt s uici dal 
i deati o n or be ha vi or  d uri n g t he st u dy ( partici pa nt e n d orses a 4 or 5 o n t he i deati o n s u bscale 
or a n y be ha vi oral ite m of t he C -S S R S o n 2 or m ore occasi o ns a n d is c o nf ir me d t o ha ve acti ve 
s uici dal i deati o n or be ha vi or o n b ot h occasi o ns b y a ris k assess me nt c o n d ucte d b y a q ualifie d 
M H P) s h o ul d be disc o nti n ue d fr o m t he st u d y a n d treate d a p pr o priatel y.
3. 5. 6. 2. P atie nt He alt h Q uesti o n n aire -9 ( P H Q - 9)
T he P H Q -9 is a 9 ite m self -re p ort sc ale f or t he assess me nt of de pressive sy m pt o ms. T he 
P H Q - 9 will be c o m plete d by p artici p a nts a n d revie we d by site st aff at t he pre-defi ne d ti me 
p oi nts o utli ne d i n t he S o A. T he t otal sc ore will be deri ve d by a d di n g t he c orres p o n di n g val ues 
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
of res p o nses t o eac h ite m. T he t otal sc ore ra n ges fr o m 0 t o 2 7, wit h t he f oll o wi n g 
i nter pretati o n: 
T ot al Sc ore
De pressi o n Se verit y
1 -4
Mi ni mal de pressi o n
5 -9
Mil d de pressi o n
1 0 -1 4
M o derate de pressi o n
1 5 -1 9
M o deratel y se vere de pressi o n
2 0 -2 7
Se vere de pressi o n
A partici pa nt wit h a p ost baseli ne assess me nt wit h a sc ore of > 1 5 s h o ul d be referre d t o a 
M H P.
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 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
" Enr 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 pleti o n of t he i nf or me d c o nse nt
pr ocess. 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.
S afety
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.
P K C o nce ntr ati o n Set
T he P K c o nce ntr ati o n p o p ul ati o n is defi ne d as all p artici p a nts
w h o receive d at le ast 1 d ose of mi d az ol a m, o me pr az ole, a n
or al c o ntr ace ptive, a n d/ or P F -0 7 0 8 1 5 3 2 a n d i n w h o m at le ast
1 pl as m a c o nce ntr ati o n v al ue is re p orte d.
P K P ar a meter Set
T he P K p ar a meter a n alysis p o p ul ati o n is defi ne d as all
p artici p a nts w h o receive d at le ast 1 d ose of mi d az ol a m,
o me pr az ole, a n or al c o ntr ace ptive, a n d/ or P F -0 7 0 8 1 5 3 2 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.
S h o ul d v o miti n g occ ur after c o a d mi nistr ati o n of mi d az ol a m,
o me pr az ole, or t he or al c o ntr ace ptive wit h P F- 0 7 0 8 1 5 3 2, t he
res ulti n g P K p ar a meters fr o m t h at p artici p a nt fr o m t he
c orres p o n di n g peri o d m ay be excl u de d.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
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
Fi nal a nal ys is will be perf or me d after st u d y partici pa nt data set release f oll o wi n g last 
partici pa nt last visit.
5. 1. H y p ot heses a n d Decisi o n R ules
N o statistical h y p ot hesis will be teste d i n t his st u d y.
5. 2. Ge ner al Met h o ds
5. 2. 1. A n al yses f or Bi n ar y/ C ate g oric al E n d p oi nts
F or bi nar y  or cate g orical varia bles, n u m ber of partici pa nts, a n d 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 prese nte d i n acc or da nce wit h t he Cli n ical 
Data I nterc ha n ge Sta n dar ds C o ns orti u m a n d Pfizer Sta n dar ds ( Ca P S).
5. 2. 2. A n al yses f or C o nti n u o us E n d p oi nts
F or c o nti n u o us varia bles, t he data will be s u m marize d usi n g t he n u m ber of partici pa nts, 
mea n, me dia n, sta n dar d de viati o n ( S D ), mi ni m u m, a n d ma xi m u m i n acc or da nce wit h t he 
Ca P S. F or a p pr o priate P K para meters, ge o metric mea n a n d ge o metric c oefficie nt of variati o n 
( % C V) will als o be s u m marize d.
5. 3.
Met h o ds t o M a n a ge Missi n g D at a
5. 3. 1. P h ar m ac o ki netic D at a
Met h o ds t o ha n dle missi n g P K data are
descri be d bel o w. 
C o nce ntr ati o ns Bel o w t he Li mit of Q u a ntific ati o n:
I n all data prese ntati o ns (e xce pt listi n gs), c o nce ntrati o ns bel o w t he li mit of q ua ntificati o n 
( B L Q) will be set t o zer o. (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 
wil l be re place d wit h t he val ue f or t he l o wer li mit of q ua ntificati o n.).
De vi ati o ns, Missi n g C o nce ntr ati o ns a n d A n o m al o us V al ues:
I n 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 1 of t he f oll o wi n g cases is tr ue:
1.
A c o nce ntrati o n has bee n c ollecte d as N D (ie, n ot d o ne) or N S (ie, n o sa m ple).
2.
A de viati o n i n 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 bee n
fla g ge d a n o mal o us by t he p har mac o ki neticist.
N ote t hat s u m mar y  statistics will n ot be prese nte d at a partic ular ti me p oi nt if m ore t ha n 5 0 % 
of t he data are missi n g.
A n a n o mal o us c o nce ntrati o n val ue is o ne t hat, after verificati o n of bi oa nal ytical vali dit y , is 
gr ossl y i nc o nsiste nt wit h ot her c o nce ntrati o n data fr o m t he sa me i n di vi d ual or fr o m ot her 
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
partici pa nts. F or e xa m ple, a B L Q c o nce ntrati o n t hat is bet wee n q ua ntifia ble val ues fr o m t he 
sa me d ose is c o nsi dere d as a n o mal o us. A n o mal o us c o nce ntrati o n val ues ma y be e xcl u de d 
fr o m P K a nalys is at t he discreti o n of t he P K a nalyst.
P K 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. 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 
(ie, n ot calc ulate d). ( N ote t hat N C val ues will n ot be generate 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 n ot be prese nte d f or a partic ular treat me nt gr o u p if m ore 
t ha n 5 0 % of t he data are N C. F or statistical a nalys es, P K para meters c o de d as N C will als o 
be set t o missi n g.
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 d osi n g err or or 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 fr o m t he gastr oi ntesti nal tract), 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 nalys es.  F or 
i nsta nce, if a partici pa nt has a v o miti n g e ve nt p ost d ose t hat is wit hi n a d urati o n of ti me t hat 
is 2 -ti mes t he deri ve d me dia n T ma x f or t he p o p ulati o n f or t he a d mi nistere d treat me nt, t he n t he 
p har mac o ki neticist s h o ul d c o nsi der t he e xcl usi o n of t he P K c o nce ntrati o n data c ollecte d 
f oll o wi n g t he i nitial v o miti n g e ve nt i n t hat treat me nt peri o d a n d t he P K para meter data 
re p orte d f or t hat treat me nt peri o d fr o m t he datasets use d t o calc ulate s u m mar y  statistics or 
statistical a nal yses.
5. 3. 2. S afet y D at a
Missi n g val ues i n sta n dar d s u m maries of A Es, la b orat or y data, vital si g ns, a n d E C Gs will be 
i m p ute d acc or di n g t o Ca P S.
6. A N A L Y S E S A N D S U M M A RI E S
6. 1. Pri m ar y E n d p oi nts
C o h ort 1
F or t he e val uati o n of t he effects of P F - 0 7 0 8 1 5 3 2 o n t he p har mac o ki netics of o me praz ole, 
n at ur al l o g e-tr a nsf or me d A U Ci nf ( as d at a per mit), Cm ax a n d A U C l ast of o me pr az ole 
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c o a d mi nistere d wit h P F- 0 7 0 8 1 5 3 2 will be a n alyze d
usi n g a mixe d effect 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. 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 % 
CIs will be o bt ai ne d fr o m t he m o dels. T he a dj uste d me a n diffe re nces a n d 9 0 % CIs f or t he 
differe nces will be ex p o ne nti ate d t o pr ovi de 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 % CIs f or t he r ati os.. T he 2 test tre at me nts will be 
‘o me pr az ole a n d P F -0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 4) a n d ‘o me pr az ole a n d P F - 0 7 0 8 1 5 3 2 
2 6 0 m g Q D’ ( Peri o d 7), w hic h will be re p orte d se p ar ately i n c o m p aris o n t o t he refere nce 
tre at me nt of ‘o me pr az ole wit h o ut P F - 0 7 0 8 1 5 3 2’ ( Peri o d 1).
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
F or t he e val uati o n of t he effects of P F - 0 7 0 8 1 5 3 2 o n t he p har mac o ki netics of mi daz ol a m, 
n at ur al l o ge-tr a nsf or me d A U C i nf ( as d at a per mit), Cm ax a n d A U C l ast of mi d az ol a m
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c o a d mi nistere d wit h P F-0 7 0 8 1 5 3 2 i n C o h ort 1 will be
a n alyze d a n d re p orte d se p ar ately usi n g t he s a me mixe d effect m o del as descri be d a b ov e f or
o me pr az ole . T he 2 test tre at me nts will be ‘ mi d az ol a m a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 
4) a n d ‘ mi d az ol a m a n d P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 7), w hic h will be re p orte d
se p ar ately i n c o m p aris o n t o t he refere nce tre at me nt of ‘ mi d az ol a m wit h o ut P F- 0 7 0 8 1 5 3 2’
( Peri o d 1).
F or t he e val uati o n of t he effects of P F - 0 7 0 8 1 5 3 2 o n t he p har mac o ki netics of a n oral 
c o ntrace pti ve, n at ur al l o ge-tr a nsf or me d A U C i nf ( as d at a per mit), C m ax a n d A U C l ast of L E a n d 
E E a d mi nistere d al o ne or c o a d mi nistere d wit h P F -0 7 0 8 1 5 3 2 will be a n alyze d a n d re p orte d 
se p ar ately usi n g t he s a me mixe d effect m o del as descri be d a b ove f or o me pr az ole . F or L E, t he 
2 test tre at me nts will be ‘ L E a n d P F - 0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 5) a n d ‘ L E a n d P F -
0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 8), w hic h will be re p orte d se p a r ately i n c o m p aris o n t o t he
refere nce tre at me nt of ‘ L E al o ne’ ( Peri o d 2). Si mil arly f or E E, t he 2 test tre at me nts will be
‘ E E a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 5) a n d ‘ E E a n d P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D’
( Peri o d 8), w hic h will be re p orte d se p ar ately i n c o m p aris o n t o t he refere nce tre at me nt of 
‘ E E al o ne’ ( Peri o d 2).
F or all mi xe d effect m o dels, r esi d uals will be e xa mi ne d f or n or malit y a n d t he prese nce of 
o utliers via vis ual i ns pecti o n of pl ots of resi d uals vs pre dicte d val ues a n d n or mal pr o ba bilit y  
pl ots of resi d u als, b ut t hese will n ot be i ncl u de d i n t he C S R . If t here are maj or de viati o ns 
fr o m n or malit y or o utliers, t he n t he effect of t hese o n t he c o ncl usi o ns will 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 d y.
C o h ort 2
F or t he e val uati o n of t he effects of se ma gl uti de o n t he p har mac o ki netics of mi daz ola m, 
n at ur al l o g e-tr a nsf or me d A U Ci nf ( as d at a per mit), Cm ax a n d A U C l ast of mi d az ol a m 
a d mi nistere d al o ne or c o a d mi nistere d wit h se m a gl uti de will be a n alyze d a n d re p orte d 
se p ar ately usi n g t he s a me mixe d effect m o del as descri be d a b ove f or o me pr az ole. T he test 
tre at me nt will be ‘ mi d az ol a m a n d se m a gl uti de 2. 4 m g weekly’ ( Peri o d 3) w hic h will be 
re p orte d se p ar ately i n c o m p aris o n t o t he refere nce tre at me nt of ‘ mi d az ol a m al o ne’ ( Peri o d 
1).
6. 2. Sec o n d ar y E n d p oi nts
C o h ort 1
A nal y ses a n d s u m maries of safety data are descri be d i n Secti o n 6. 6 .
F or t he e val uati o n of t he p har mac o ki netics of mi daz ola m f oll o wi n g disc o nti n uati o n of P F -
0 7 0 8 1 5 3 2 , n at ur al l o g e-tr a nsf or me d A U Ci nf ( as d at a per mit), Cm ax a n d A U C l ast of mi d az ol a m 
a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or c o a d mi nistere d wit h P F-0 7 0 8 1 5 3 2 i n C o h ort 1 will be 
a n alyze d a n d re p orte d se p ar ately usi n g t he s a me mixe d effect m o del as descri be d a b ove f or 
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
o me pr az ole. T he test tre at me nt will be ‘ mi d az ol a m al o ne f oll o wi n g disc o nti n u ati o n of P F -
0 7 0 8 1 5 3 2’ ( Peri o d 9), w hic h will be re p orte d se p ar ately i n c o m p aris o n t o t he 2 refere nce 
tre at me nts of ‘ mi d az ol a m wit h o ut P F-0 7 0 8 1 5 3 2’ ( Peri o d 1) a n d ‘ mi d az ol a m a n d P F -
0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 7).
F or t he e val uati o n o f t he effects of P F - 0 7 0 8 1 5 3 2 o n a d diti o nal p har mac o ki netic para meters 
( Cma x , Tma x , C L/ F, Vz/ F, t1/ 2, as data per mit) f or mi daz ola m a n d o me praz ole ( Peri o ds 1, 4 a n d 
7 [i ncl u di n g Peri o d 9 f or mi daz ola m]), a n d L E a n d E E ( Peri o ds 2, 5 a n d 8), descri pti ve 
statistics will be pr o vi de d, as o utli ne d i n Ta ble 4 .
F or t he e val uati o n of t he effects of P F -0 7 0 8 1 5 3 2 o n t he meta b olite/ pare nt rati os ( M R A U Ci nf) 
f or mi daz ola m a n d o me praz ole ( Peri o ds 1, 4 a n d 7 [i ncl u di n g Peri o d 9 f or mi daz ola m]), 
descri pti ve statistics will be pr o vi de d, as o utli ne d i n Ta ble 4 .
F or t he e val uati o n of M D p har mac o ki netics of
P F - 0 7 0 8 1 5 3 2 ( A U C2 4, Cma x , Tma x ), descri pti ve 
statistics at Da ys 2 8 a n d 6 3 of Peri o ds 3 a n d 6, res pecti vel y, will be pr o vi de d, as o utli ne d i n 
Ta ble 4 .
C o h ort 2
A nal y ses a n d s u m maries of safety data are descri be d i n Secti o n 6. 6 .
F or t he e val uati o n of t he p har mac o ki netics of mi daz ola m f oll o wi n g disc o nti n uati o n of 
se ma gl uti de, n at ur al l o g e-tr a nsf or me d A U Ci nf ( as d at a per mit), Cm ax a n d A U C l ast of 
mi d az ol a m a d mi nistere d wit h o ut se m a gl uti de or c o a d mi nistere d wit h se m a gl uti de will be 
a n alyze d a n d re p orte d se p ar ately usi n g t he s a me mixe d effect m o del as descri be d a b ove f or 
o me pr az ole. T he test tre at me nt will be ‘ mi d az ol a m al o ne f oll o wi n g disc o nti n u ati o n of 
se m a gl uti de’ ( Peri o d 4), w hic h will be re p orte d se p ar ately i n c o m p aris o n t o t he 2 refere nce 
tre at me nts of ‘ mi d az ol a m wit h o ut se m a gl uti de’ ( Peri o d 1) a n d ‘ mi d az ol a m a n d se m a gl uti de 
2. 4 m g weekly’ ( Peri o d 3).
F or t he e val uati o n of t he effects of se ma gl uti de o n a d diti o nal p har mac o ki netic para meters 
( Cma x , Tma x , C L/ F, Vz/ F, t1/ 2, as data per mit) f or mi daz ola m ( Peri o ds 1, 3 a n d 4), descri pti ve 
statistics will be pr o vi de d, as o utli ne d i n Ta ble 4 .
F or t he e val uati o n of t he effects of se ma gl uti de o n t he meta b olite/ pare nt rati os ( M R A U Ci nf) 
f or mi daz ola m ( Peri o ds 1, 3 a n d 4), descri pti ve statistics will be pr o vi de d, as o utli ne d i n 
Ta ble 4 .
6. 3. Ot her E n d p oi nts
C o h ort 1
F or t he e val uati o n of t he effects of P F - 0 7 0 8 1 5 3 2 o n t he p har mac o ki netics of 1-
h y dr o x y m i daz ola m ( A U Clast, Cma x , Tma x , A U Ci nf, t1/ 2, as data per mit) i n Peri o ds 1, 4, 7 a n d 9 , 
descri pti ve statistics will be pr o vi de d, as o utli ne d i n Ta ble 4 . I n a d diti o n, n at ur al l o g e-
tr a nsf or me d A U Ci nf ( as d at a per mit), A U Clast a n d C ma x of t he 1 -hyr oxy mi d az ol a m/ mi d az ol a m 
r ati os a d mi nistere d wit h o ut P F -0 7 0 8 1 5 3 2 or c o a d mi nistere d wit h P F -0 7 0 8 1 5 3 2 i n C o h ort 1 
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
will be a n alyze d a n d re p orte d se p ar ately usi n g t he s a me mixe d effect m o del as descri be d 
a b ove f or o me pr az ole. T he 2 test tre at me nts will be ‘ mi d az ol a m a n d P F-0 7 0 8 1 5 3 2 8 0 m g 
Q D’ ( Peri o d 4) a n d ‘ mi d az ol a m a n d P F -0 7 0 8 1 5 3 2 2 6 0 m g Q D’ ( Peri o d 7), w hic h will be 
re p orte d se p ar ately i n c o m p aris o n t o t he refere nce tre at me nts of ‘ mi d az ol a m wit h o ut P F -
0 7 0 8 1 5 3 2’ ( Peri o d 1) a n d ‘ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of P F -0 7 0 8 1 5 3 2’ 
( Peri o d 9).
F or t he e val uati o n of t he effects of P F - 0 7 0 8 1 5 3 2 o n t he p har mac o ki netics of 5-
h y dr o x y o m e praz ole ( A U Clast, Cma x , Tma x , A U Ci nf, t1/ 2, as data per mit) i n Peri o ds 1, 4 a n d 7, 
descri pti ve statistics will be pr o vi de d, as o utli ne d i n Ta ble 4 . I n a d diti o n, n at ur al l o g e-
tr a nsf or me d A U Ci nf ( as d at a per mit), A U Clast a n d C ma x of t he 5 -
hyr oxy o me pr az ole/ o me pr az ole r ati os ( MR) a d mi nistere d wit h o ut P F - 0 7 0 8 1 5 3 2 or 
c o a d mi nistere d wit h P F- 0 7 0 8 1 5 3 2 will be a n alyze d a n d re p orte d se p ar ately usi n g t he s a me 
mixe d effect m o del as descri be d a b ove f or o me pr az ole . T he 2 test tre at me nts will be 
‘ o me pr az ole a n d P F-0 7 0 8 1 5 3 2 8 0 m g Q D’ ( Peri o d 4) a n d ‘ o me pr az ole a n d P F - 0 7 0 8 1 5 3 2 
2 6 0 m g Q D’ ( Peri o d 7), w hic h will be re p orte d se p ar ately i n c o m p aris o n t o t he refere nce 
tre at me nt of ‘ o me pr az ole wit h o ut P F-0 7 0 8 1 5 3 2’ ( Peri o d 1).
F or t he e val uati o n of t he effects of P F - 0 7 0 8 1 5 3 2 o n bi o mar kers of C Y P 3 A i n d ucti o n, 
o bser ve d val ue a n d perce nt c ha n ge fr o m baseli ne i n m or ni n g pre d ose 4 β -
h y dr o x yc h olester ol/c h olester ol plas ma rati o will be s u m marize d descri pti vel y  b y peri o d (Da y  
1 i n Peri o ds 1 [ baseli ne], 4, 7 a n d 9).
C o h ort 2
F or t he e val uati o n of t he effects of se ma gl uti de o n t he p har mac o ki netics of 1-
h y dr o x y m i daz ola m ( A U Clast, Cma x , Tma x , A U Ci nf, t1/ 2, as data per mit) i n Peri o ds 1, 3 a n d 4, 
descri pti ve statistics will be pr o vi de d, as o utli ne d i n Ta ble 4 . I n a d diti o n, n at ur al l o g e-
tr a nsf or me d A U Ci nf ( as d at a per mit), A U Clast a n d C ma x of t he 1 -hyr oxy mi d az ol a m/ mi d az ol a m 
r ati os a d mi nistere d al o ne or c o a d mi nistere d wit h se m a gl uti de will be a n alyz e d a n d re p orte d
se p ar ately usi n g t he s a me mixe d effect m o del as descri be d a b ove f or o me pr az ole. T he test
tre at me nt will be ‘ mi d az ol a m a n d se m a gl uti de 2. 4 m g weekly’ ( Peri o d 3) w hic h will be
re p orte d se p ar ately i n c o m p aris o n t o t he refere nce tre at me nts of ‘ mi d az ol a m al o ne’ ( Peri o d 
1 ) a n d ‘ mi daz ola m al o ne f oll o wi n g disc o nti n uati o n of se ma gl uti de’ ( Peri o d 4).
F or t he e val uati o n of t he effects of se ma gl uti de o n bi o mar kers of C Y P 3 A i n d ucti o n, 
o bser ve d val ue a n d perce nt c ha n ge fr o m baseli ne i n m or ni n g pre d ose 4 β -
h y dr o x yc h olester ol/c h olester ol plas ma rati o will be s u m marize d descri pti vel y  b y peri o d ( Da y 
1 i n Peri o ds 1 [ baseli ne], 3 a n d 4).
6. 3. 1. P K C o nce ntr ati o n
Pl as m a c o nce ntr ati o ns will be liste d a n d s u m m arize d descri ptively by P K s a m pli n g ti me a n d 
tre at me nt ( d osi n g al o ne vs. c o a d mi nistr ati o n or d ose by C o h ort of st u dy, as a p plic a ble). 
I n divi d u al p artici p a nt a n d me di a n pr ofiles of t he c o nce ntr ati o n-ti me d at a will be pl otte d by 
tre at me nt. F or s u m m ary st atistics a n d me di a n pl ots by s a m pli n g ti me, t he n o mi n al P K
s a m pli n g ti me will be use d. F or i n divi d u al p artici p a nt pl ots by ti me, t he act u al P K s a m pli n g
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
ti me f or pl as m a s a m ples will be use d. Me di a n pr ofiles will be prese nte d o n b ot h li ne ar-li ne ar
a n d l o g -li ne ar sc ales.
Prese ntati o ns of c o nce ntrati 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 
statistics will i ncl u de n, mea n, me dia n, S D , % 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 L Q .

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 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).

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  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).

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 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 pl ots f or eac h partici pa nt (c o ntai ni n g
all treat me nts) per scale].
6. 3. 2. P K p ar a meter
T he P K para meters will be s u m marize d descri pti vel y  b y treat me nt gr o u p i n acc or da nce wit h 
Pfizer data sta n dar ds o n t he P K Para meter A nal ys is Set, as data per mit. F or A U C i nf (if d at a 
per mits), A U C l ast, a n d Cm ax , a listi n g of t he i n divi d u al p artici p a nt r ati os ( Test/ Refere nce) will 
be pr ovi de d. B ox a n d w hisker pl ots f or A U C i nf (if d at a per mits), A U C l ast, a n d Cm ax , will be 
pl otte d by tre at me nt. Missi n g val ues will be ha n dle d as detaile d i n Secti o n 5. 3. 1 . Eac h P K 
para meter will be s u m marize d b y  treat me nt gr o u p a n d will i ncl u de t he set of s u m mar y 
statistics as s pecifie d i n Ta ble 4 .
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
T a ble 4 .
P K P ar a meters t o be S u m m arize d Descri pti vel y b y Tre at me nt 
P ar a meter
S u m m ar y St atistics
A U C i nf, A U C last, C ma x , 
C L / F, Vz/ F, M R, A U C 2 4
N, arit h metic mea n, me dia n, S D, % C V, 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
t½
N, arit h metic mea n, me dia n, S D, % C V, mi ni m u m, m a xi m u m
S u p p orti n g data fr o m t he esti mati o n of t ½ a n d A U C i nf will be liste d b y  a nal yte a n d gr o u p: 
ter mi nal p hase rate c o nsta nt ( k el); g o o d ness of fit statistic fr o m t he l o g- li near re gressi o n (r2); 
t he perce nt of A U Ci nf base d o n e xtra p olati o n ( A U C e 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 his data ma y be i ncl u de d i n t he cli nical st u d y 
re p ort.
6. 4. S u bset A n al yses
T here are n o pla n ne d s u bset a nal ys es.
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. De m o gr a p hic S u m m aries
De m o gra p hic c haracteristics will be s u m marize d f or t he e nr olle d p o p ulati o n i n acc or da nce 
wit h t he Ca P S.
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. Fre q ue nc y 
c o u nts 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. Data will be re p orte d 
i n acc or da nce wit h t he Ca P S.
6. 5. 3. St u d y Tre at me nt E x p os ure
St u d y  treat me nt e x p os ure will be liste d.
6. 5. 4. 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
All 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 re p orte d i n t he 
listi n gs.
6. 6. S afet y S u m m aries a n d A n al yses
All safet y a nal ys es will be perf or me d o n t he S afet y A nal y sis Set.
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 
d escri pti vel y, w here a p pr o priate.
6. 6. 1. A d verse E ve nts
A d verse e ve nts will be re p orte d i n acc or da nce wit h t he Ca P S.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
Partici pa nt disc o nti n uati o ns d ue t o a d verse e v e nts will be detaile d b y treat me nt. Data will be 
re p orte d i n acc or da nce wit h t he Ca P S.
6. 6. 2. L a b or at or y D at a
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 Ca P S.
6. 6. 3. B o d y Wei g ht
O bser ve d val ue a n d c ha n ge fr o m baseli ne i n b o d y wei g h t will be s u m marize d descri pti vely 
b y  treat me nt.
6. 6. 4. Vit al Si g ns
V ital si g n data will be data base d a n d a vaila ble u p o n re q uest.
6. 6. 5. Electr oc ar di o gr a ms
E C G data will be data base d a n d a vaila ble u p o n re q uest.
6. 6. 6. Me nt al He alt h
C- S S R S a n d P H Q- 9 data will be liste d.
7. I N T E RI M A N A L Y S E S
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 n o pe n -l a bel 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 P K m o deli n g, a n d/ or s u p p orti n g cli nic al 
devel o p me nt.
Fi nal a nal ys is will f oll o w t he official data base release.  As t his will be a n o pe n-la bel st u dy, 
t here is n o f or mal u n bli n di n g of t he ra n d o mizati o n c o de.
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
A P P E N DI C E S
A p pe n di x 1. S A S C o de f or A n al yses
A n e xa m ple of t he P R O C MI X E D c o de is pr o vi de d bel o w:
F or pri m ar y o bjecti ve s:
C o h ort 1
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 4”) a n d p pcat =“mi daz ola m” ;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'D vs A ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 7”) a n d p pcat =“mi daz ola m ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'G vs A ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 4”) a n d p pcat = “o me praz ole”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'D vs A ' trt - 1 1 /cl al p ha = 0. 1;
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
o ds ' Esti mates' o ut =est & var;
o ds 'ls m ea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 7”) a n d p pcat = “o me praz ole”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'G vs A ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 2”, “ 5”) a n d p pcat =“ L E” ;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'E vs B ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 2”, “ 8”) a n d p pcat =“ L E” ;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'H vs B ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 2”, “ 5”) a n d p pcat = “E E”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'E vs B ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 2”, “ 8”) a n d p pcat =“E E”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'H vs B ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
/ * Letter assi g n me nts f or treat me nts (trt) wit hi n t he esti mate state me nt a b o ve are as f oll o ws
A: S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Refere nce);
B: S D O C ( L E 0 1 5 m g/ E E 0. 0 3 m g) ( Refere nce);
D: P F - 0 7 0 8 1 5 3 2 8 0 m g Q D + S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Test)
E: P F - 0 7 0 8 1 5 3 2 8 0 m g Q D + S D O C ( L E 0. 1 5 m g/ E E 0. 0 3 m g) ( Test)
G: P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D + S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Test)
H: P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D + S D O C ( L E 0. 1 5 m g/ E E 0. 0 3 m g) ( Test)
*/
C o h ort 2
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 3”) a n d p pcat =“ mi daz ola m”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
esti mate 'L vs J' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
/ * Letter assi g n me nts f or treat me nts (trt) wit hi n t he esti mate state me nt a b o ve are as f oll o ws
J: S D mi daz ola m 2 m g ( Refere nce);
L : se ma gl uti de 2. 4 m g o nce wee kly + S D mi daz ola m 2 m g (Test ); */
F or sec o n d ar y o bjecti ve s:
C o h ort 1
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 9”) a n d p pcat = “mi daz ola m”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate ' I vs A ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 7”, “ 9”) a n d p pcat “mi daz ola m”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate ' I vs G ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
/ * Letter assi g n me nts f or treat me nts (trt) wit hi n t he esti mate state me nt a b o ve are as f oll o ws;
A: S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Refere nce);
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
G: P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D + S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Refere nce)
I: S D mi daz ola m 2 m g o nl y ( Test)
*/
C o h ort 2
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 4”);
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'M
vs J' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds ' c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 3”, “ 4”);
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'M
vs L ' trt - 1 1 /cl al p ha = 0.1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
/ * Letter assi g n me nts f or treat me nts (trt) wit hi n t he esti mate state me nt a b o ve are as f oll o ws;
J: S D mi daz ola m 2 m g ( Refere nce);
L : se ma gl uti de 2. 4 m g o nce wee kly + S D mi daz ola m 2 m g ( Refere nce);
M: S D mi daz ola m 2 m g o nl y ( Test) */
F or terti ar y/e x pl or at or y o bjecti ve s:
C o h ort 1
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 4”) a n d p pcat =“ 1 -h y r o x ymi daz ola m/ mi daz ola m ”;
class trt partici pa nt;
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'D vs A ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r un;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 7”) a n d p pcat =“ 1 -h y r o x ymi daz ola m/ mi daz ola m ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'G vs A ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 4”) a n d p pcat =“ 5 -h y r o x yo me praz ole/ o me praz ole ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'D vs A ' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here pe ri o d i n (“ 1”, “ 7”) a n d p pcat =“5 -h y r o x yo me praz ole/ o me praz ole ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'G vs A ' trt - 1 1 /cl al p ha = 0. 1;
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
o ds ' Esti mates' o ut =est & var;
o ds ' ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 9”, “ 4”) a n d p pcat =“ 1 -h y r o x ymi daz ola m/ mi daz ola m ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'D vs I' trt 1 - 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 9”, “ 7”) a n d p pcat =“ 1 -h y r o x ymi daz ola m/ mi daz ola m ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'G vs I' trt 1 - 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut = c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
/ * Letter assi g n me nts f or treat me nts (trt) wit hi n t he esti mate state me nt a b o ve are as f oll o ws
A: S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Refere nce);
D: P F - 0 7 0 8 1 5 3 2 8 0 m g Q D + S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Test)
G: P F - 0 7 0 8 1 5 3 2 2 6 0 m g Q D + S D mi daz ola m 2 m g + S D o me praz ole 2 0 m g ( Test)
I: S D mi daz ola m 2 m g o nl y ( Refere nce) */
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
C o h ort 2
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 1”, “ 3”) a n d p pcat =“ 1 -h y r o x ymi daz ola m/ mi daz ola m ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'L vs J' trt - 1 1 /cl al p ha = 0. 1;
o ds ' Esti mates' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
pr oc mi xe d data =ta b. p k;
w here peri o d i n (“ 4”, “ 3”) a n d p pcat =“ 1 -h y r o x ymi daz ola m/ mi daz ola m ”;
class trt partici pa nt;
m o del l & var = trt/ d df m = K R;
ra n d o m partici pa nt /s u bject= partici pa nt;
ls mea ns trt;
esti mate 'L vs M ' trt 1 - 1 /cl al p ha = 0. 1;
o ds ' Esti ma tes' o ut =est & var;
o ds 'ls mea ns' o ut =ls & var;
o ds 'c o v par ms' o ut =c o v & var;
o ds 'tests 3' o ut =tst & var;
r u n;
/ * Letter assi g n me nts f or treat me nts (trt) wit hi n t he esti mate state me nt a b o ve are as f oll o ws
J: S D mi daz ola m 2 m g ( Refere nce);
L : se ma gl uti de 2. 4 m g o nce wee kl y + S D mi daz ola m 2 m g (Test );
M: S D mi daz ola m 2 m g o nl y ( Refere nce)
*/
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
A p pe n di x 2. List o f A b bre vi ati o ns
A b bre vi ati o n
Ter m
% C V
c oefficie nt of variati o n
A E
a d verse e ve nt
A U C 2 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 2 4 h o urs
A U C i nf
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
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 ( Clast)
B L Q
bel o w t he li mit of q ua ntitati o n
B MI
b o d y  mass i n de x
B P
bl o o d press ure
Ca P S
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m a n d Pfizer 
Sta n dar ds
CI
c o nfi de nce i nter val
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 oral cleara nce
C ma x
ma xi m u m plas ma c o nce ntrati o n
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
E C G
electr ocar di o gra m
E E
et hi n yl estra di ol
G L P -1 R
gl uca g o n -li ke pe pti de 1 rece pt or
H R
heart rate
k el
t he ter mi nal p hase rate c o nsta nt calc ulate d by a li near re gressi o n of 
t he l o gli near c o nce ntrati o n-ti me c ur ve
L E
le v o n or gestrel
L L Q
l o wer li mit of q ua ntitati o n
M D
m ulti ple d ose
m g
milli gra m
M H P
me ntal healt h pr ofessi o nal
M R
meta b olite t o pare nt rati o
M R A U C
i nf
1 -h y dr o x y mi daz ola m A U C i nf/ mi daz ola m A U Ci nf; 5 -
h y dr o x y o m e praz ole A U C i nf/ o me praz ole A U Ci nf
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
O C
oral c o ntrace pti ve
P H Q -9
Patie nt Healt h Q uesti o n naire -9
P K
p har mac o ki netic(s)
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)


Pr ot oc ol C 3 9 9 1 0 4 0 (P F -0 7 0 8 1 5 3 2 ) 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 3 4
A b bre vi ati o n
Ter m
P R
p ulse rate
Q D
o nce dail y
Q R S
C o m bi nati o n of Q -, R- a n d S - wa ve o n a n electr ocar di o gra m 
re prese nti n g ve ntric ular de p olarizati o n
Q Tc
c orrecte d Q T
Q Tc F
c orrecte d Q T ( Fri dericia met h o d)
R R
res pirat or y rate
S A P
statistical a nal ysis pla n
S D
si n gle d ose; sta n dar d de viati o n
S o A
sc he d ule of acti vities
t1/ 2
ter mi nal eli mi nati o n half-life
T 2 D M
t ype 2 dia betes mellit us
T E A E
treat me nt e mer ge nt a d verse e ve nt
T ma x
ti me t o Cma x
V z/ F
a p pare nt v ol u me of distri b uti o n
0 9 0 1 7 7 e 1 9 c 3 d 8 5 a a\ Fi n al\ Fi n al O n: 0 4- J a n- 2 0 2 3 0 3: 1 5 ( G M T)