A PHASE 3 MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE SAFETY OF DAILY ORAL DOSING OF TAFAMIDIS MEGLUMINE (PF-06291826-83) 20 MG OR 80 MG [OR TAFAMIDIS (PF-06291826-00) 61 MG] IN SUBJECTS DIAGNOSED WITH TRANSTHYRETIN CARDIOMYOPATHY (ATTR-CM)
Phase: PHASE3
Conditions: Transthyretin (TTR) Amyloid Cardiomyopathy
Sponsor: Pfizer

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1
A P H A S E 3 M U L TI C E N T E R, O P E N -L A B E L S T U D Y T O E V A L U A T E T H E 
S A F E T Y O F D AI L Y O R A L D O SI N G O F T A F A MI DI S M E G L U MI N E 
( P F- 0 6 2 9 1 8 2 6-8 3) 2 0 M G O R 8 0 M G [ O R T A F A MI DI S ( P F - 0 6 2 9 1 8 2 6- 00) 6 1 M G] I N 
S U B J E C T S DI A G N O S E D W I T H T R A N S T H Y R E TI N C A R DI O M Y O P A T H Y 
( A T T R-C M)
C o m p o u n d:
P F - 0 6 2 9 1 8 2 6
C o m p o u n d N a me:
Tafa mi dis 
U nite d St ates ( U S) I n vesti g ati o n al Ne w 
Dr u g (I N D) N u m ber:
I ND 7 1, 8 8 0
E ur o pe a n Cli nic al Tri als D at a b ase 
( E u dr a C T) N u m ber:
2 0 1 6 - 0 0 0 8 6 8- 4 2
Pr ot oc ol N u m ber:
B 3 4 6 1 0 4 5
P h ase:
3
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or m ati o n bel o n gi n g t o Pfizer.  E xce pt as ot her w ise a gree d t o i n writi n g, 
b y acce pti n g or re vie wi n g t his d oc u me nt, y o u a gree t o h ol d t his i nf or mati o n i n c o nfi de nce a n d n ot c o p y or 
discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or use it f or u na ut h orize d p ur p oses.  I n t he e ve nt 
of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer m ust be pr o m ptl y n otifie d.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2
D oc u me nt Hist or y
D oc u me nt
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
A me n d me nt 5 
(c o u ntr y s pecific)
2 4 Ja n uar y 2 0 2 0 
1. F or ne wl y e nr olle d s u bjects i n c o u ntries 
liste d i n A p pe n di x 6, a d diti o n of bl o o d a n d 
uri ne sa m ple c ollecti o n f or a d diti o nal 
ba n ke d bi o mar ker sa m ple c ollecti o n , as 
descri be d i n A p pe n di x 7 .
2.
F or ne wl y  e nr olle d s u bjects i n c o u ntries 
liste d i n A p pe n di x 6, a d diti o n of blo o d a n d 
uri ne sa m ple c ollecti o n t o s u p p ort 
i de ntificati o n a n d c haracterizati o n of 
bi o mar kers of tra nst h yreti n a m yl oi d osis, as 
descri be d i n A p pe n di x 7 .
3.
F or ne wl y e nr oll e d s u bjects i n c o u ntries 
i de ntifie d i n A p pe n di x 6, ad diti o n of 
c ollecti o n of ec h ocar di o gr a p h y para meters 
fr o m me dical hist or y, as descri be d i n 
A p pe n di x 7 .
A me n d me nt 4 
( Gl o bal)
0 9 A u g ust 2 0 1 9
1.
U p date t otal s u bject e nr oll me nt fr o m 
1 4 0 0 t o 2 0 0 0 a n d A p pe n di x 5 co u ntries 
partici pati n g i n C o h ort B.
2.
A d diti o n of bl o o d sa m ple c ollecti o n f or 
testi n g of car diac bi o mar kers N -ter mi nal 
pr o - h or m o ne brai n natri uretic pe pti de 
( N T-pr o B N P) a n d tr o p o ni n I. 
3.
Clarificati o n t hat pre vi o usl y  e x peri me ntal 
t hera pies patisira n a n d i n oterse n re mai n 
st u d y pr o hi bite d as c o m mercial t hera pies.
4.
Clarificati o n of a d verse e ve nt m o nit ori n g 
tele p h o ne c o ntact f or s u bjects e nr olle d i n 
Ja pa n i n A p pe n di x 4. 2.
5.
Mi n or f or matti n g/ gra m mar/rea da bilit y  
i m pr o ve me nts i n ge neral.
A me n d me nt 3 
( Gl o bal)
2 0 J ul y  2 01 8 
1.
A d diti o n of a sec o n d c o h ort t o e nr oll 
A T T R - C M dia g n ose d s u bjects w h o di d n ot 
partici pate i n pare nt st u d y  B 3 4 6 1 0 2 8.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3
2.
Tra nsiti o n of all s u bjects t o o pe n la bel 
6 1 m g d ose ( w here a vaila ble) as a res ult of 
t he pare nt st u dy d ose decisi o n 
c o nfir mati o n.
3.
Tra nsiti o n of I P pac ka gi n g fr o m bli n de d 
blister pac ks t o o pe n la bel b ottle 
pac ka gi n g.
4.
Re q uire d c o ntrace pti o n, hi g hl y effecti ve 
c o ntrace pti o n met h o ds, a n d defi niti o n of 
w o ma n of c hil d beari n g p ote ntial u p date d 
t o ali g n wit h ne w c o m m o n pr ot oc ol 
te m plate la n g ua ge.
5.
A d d ba n ke d bi os peci me n c ollecti o n f or 
ne w c o h ort. 
6.
Mi n or f or matti n g/ gra m mar/rea da bilit y  
i mpr o ve me nts i n ge neral.
A me n d me nt 2 
C o u ntr y  S pecific 
( Ger ma ny)
2 8 Marc h 2 0 1 7
1.
A d diti o n of Ger ma n y t o t he Fra nce - o nly 
c o u ntr y s pecific pr oce d ures at M o nt h 3 
v isit.
A me n d me nt 1 
C o u ntr y  S pecific 
( Fra nce a n d 
Ger ma n y) 
3 1 Ja n uar y  2 0 1 7 
1. ( Fra nce a n d Ger ma ny) Title Pa ge:
A d de d E ur o pea n Cli nical Trials Data base 
( E u dra C T) N u m ber.
2.
( Fra nce a n d Ger ma ny) Pr ot oc ol S u m mar y, 
Secti o n 3 St u d y  Desi g n: S pecifie d st u d y 
will e n d 2 4 m o nt hs after t he i nitial pr ot oc ol 
a p pr o val date b y t he l ocal C o m pete nt 
A ut h orit y .  C o nti n uati o n after t he i nitial 
pr ot oc ol a p pr o val peri o d will de pe n d o n 
re vie w of t he fi nal Cli nical St u d y Re p ort 
f or pare nt st u d y B 3 4 6 1 0 2 8 b y t he l ocal 
C o m pete nt A ut h orit y.
3.
( Fra nce o nly) S c he d ule of Acti vities: 
A d de d t he f oll o wi n g pr oce d ures t o 
M o nt h
3 visit: 1) P h y sical exa mi nati o n a n d 
wei g ht meas ure me nt 2) 1 2 -Lea d E C G 
3) Vital si g ns meas ure me nt 4) Bl o o d/ uri ne 
sa m ple c ollecti o n 5) Pre g na nc y testi n g 
6) A d mi nister Ka nsas Ci t y 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4
Car di o m y o pat h y Q uesti o n naire ( K C C Q) 
7) Ne w Y or k Heart Ass ociati o n ( N Y H A) 
classificati o n 8) Dr u g c o m p lia nce a n d 
acc o u nta bilit y. 
4.
( Fra nce o nly) S ecti o n 6. 2. 2 Tele p h o ne visit 
pr oce d ures: S pecifie d a d diti o nal 
pr oce d ures at M o nt h 3 visit.
5.
( Fra nce o nly) S ectio n 7. 1. 2 P h y sical 
E xa mi nati o n a n d Hei g ht Meas ure me nts: 
S pecifie d brief p h ys ical e xa mi nati o n at 
M o nt h
3 visit.
6.
( Fra nce o nly) S ecti o n 7. 1. 3 Vital Si g ns: 
S pecifie d Vital si g ns meas ure me nt at 
M o nt h
3 visit.
7.
( Fra nce o nly) S ecti o n 7. 1. 4 
Electr ocar di o gra m: S pecif ie d E C G 
meas ure me nt at M o nt h 3 visit.
8.
( Fra nce o nly) S ecti o n 7. 1. 5 Cli nical 
La b orat or y  Tests: S pecifie d bl o o d/ uri ne 
sa m ple c ollecti o n f or He mat ol o g y, Ser u m 
C he mistr y , C oa g ulati o n, Uri nal ysis at 
M o nt h
3 visit.
9.
( Fra nce o nly) S ecti o n 7. 2 Pre g na nc y 
Testi n g: S pe cifie d pre g na nc y test t o be 
perf or me d at M o nt h 3.
1 0. ( Fra nce o nly) S ecti o n 7. 4. 1 Ne w Y or k 
Heart Ass ociati o n Classificati o n: S pecifie d 
N Y H A classificati o n at M o nt h 3 visit.
1 1. ( Fra nce o nly) S ecti o n 7. 4. 2 Ka nsas Cit y 
Car di o m y o pat h y Q uesti o n naire: S pecifie d 
K C C Q a d mi nistrati o n at M o nt h 3 visit.
Ori gi nal pr ot oc ol
2 9 Ja n uar y  2 0 1 6
N ot a p plica ble ( N/ A)
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d i nstit uti o nal re vie w b oar ds (IR Bs)/et hics c o m mittees 
( E Cs). 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5
T A B L E O F C O N T E N T S
LI S T O F T A B L E S .....................................................................................................................9
LI S T O F FI G U R E S ...................................................................................................................9
A P P E N DI C E S ...........................................................................................................................9
P R O T O C O L  S U M M A R Y.......................................................................................................1 0
S C H E D U L E O F A C TI VI TI E S ................................................................................................1 9
1. I N T R O D U C TI O N ...............................................................................................................2 2
1. 1. I n dicati o n .................................................................................................................2 2
1. 2. Bac k gr o u n d .............................................................................................................2 2
1. 3. D ose Rati o nale ........................................................................................................2 3
2. S T U D Y O BJ E C TI V E S A N D E N D P OI N T S .......................................................................2 5
2. 1. O bjecti ves ................................................................................................................2 5
2. 2. E n d p oi nts .................................................................................................................2 6
3. S T U D Y D E SI G N .................................................................................................................2 6
4. S U BJ E C T S E L E C TI O N ......................................................................................................2 7
4. 1. I ncl usi o n Criteria .....................................................................................................2 7
4. 1. 1. C o h ort A I ncl usi o n Criteria ........................................................................2 7
4. 1. 2. C o h ort B I ncl usi o n Criteria ........................................................................2 8
4. 2. E xcl usi o n Criteria ....................................................................................................2 9
4. 2. 1. C o h ort A E xcl usi o n Criteria....................................................................... 2 9
4. 2. 2. C o h ort B E xcl usi o n Criteria .......................................................................3 0
4. 3. L ifest yle G ui deli nes ................................................................................................3 1
4. 3. 1. W o ma n of C hil d beari n g P ote ntial ( W O C B P) ............................................3 2
4. 4. S p o ns or’s Q ualifie d Me dical Pers o n nel ..................................................................3 3
5. S T U D Y T R E A T M E N T S .....................................................................................................3 3
5. 1. All ocati o n t o Treat me nt ................................ ..........................................................3 3
5. 1. 1. C o h ort A Treat me nt Assi g n me nt ................................................................3 4
5. 1. 2. C o h ort B Trea t me nt Assi g n me nt ................................................................3 5
5. 2. Brea ki n g t he Bli n d ..................................................................................................3 5
5. 3. S u bject C o m plia nce .................................................................................................3 6
5. 4. I n vesti gati o nal Pr o d uct S u p plies .............................................................................3 6
5. 4. 1. D osa ge F or m(s ) a n d Pac ka gi n g ..................................................................3 7
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6
5. 4. 2. Pre parati o n a n d Dis pe nsi n g ........................................................................3 8
5. 5. A d mi nistrati o n .........................................................................................................3 8
5. 5. 1. D ose -re d ucti o n............................................................................................3 9
5. 6. I n vesti gati o nal Pr o d uct St ora ge ..............................................................................4 0
5. 7. I n vesti gati o nal Pr o d uct Acc o u nta bilit y................................ ...................................4 1
5. 7. 1. Destr ucti o n of I n vesti gati o nal Pr o d uct S u p plies........................................ 4 1
5. 8. C o nc o mita nt Treat me nt(s) .......................................................................................4 1
5. 8. 1. Pr o hi bite d T hera pies................................................................................... 4 1
6. S T U D Y P R O C E D U R E S................................ .....................................................................4 2
6. 1. Scree ni n g Visit ........................................................................................................4 2
6. 1. 1. Scree ni n g Visit C o h ort A ( Da y  0)..............................................................4 2
6. 1. 2. Scree ni n g Visit C o h ort B ( wit h disease d oc u me ntati o n) ( Da y  0) .............. 4 4
6. 1. 3. Scree ni n g Visit ( Da y  - 3 0) C o h ort B S u bjects wit h o ut D oc u me ntati o n 
of Dia g n osis .....................................................................................................4 5
6. 1. 4. Scree ni n g Visit ( Da y  0) Co h ort B ( wit h o ut disease d oc u me ntati o n)......... 4 6
6. 2. St u d y  Peri o d............................................................................................................4 7
6. 2. 1. Da y  1...........................................................................................................4 7
6. 2. 2. Tele p h o ne Visits ( M o nt hs 3, 9, 1 5, 2 1 , 2 7, 3 3, 3 9, 4 5, 5 1, 5 7) 2 
Wee ks ...............................................................................................................4 8
6. 2. 3. Cli nic Visits ( M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4) 2 Wee ks ............4 9
6. 2. 4. E n d of St u d y  Visit ( M o nt h 6 0) 2 wee ks or Earl y St u d y 
Disc o nti n uati o n ................................................................................................5 0
6. 3. P ost -st u d y F oll o w-u p Vis it......................................................................................5 1
6. 4. S u bject Wit h dra wal a n d Vital Stat us/ Tra ns pla nt/ Car diac Mec ha nical Assist 
De vice Stat us F oll o w - u p ........................................................................................... 5 1
6. 4. 1. S u bject Wit h dr a wal f or Heart or Li ver Tra ns pla ntati o n or 
I m pla ntati o n of Car diac Mec ha nical Assist De vice.........................................5 2
7. A S S E S S M E N T S ..................................................................................................................5 3
7. 1. Safet y Assess m e nts .................................................................................................5 3
7. 1. 1. Me dical Hist or y ..........................................................................................5 3
7. 1. 2. P h y sical E xa mi nati o n a n d Hei g ht Meas ure me nts ......................................5 3
7. 1. 3. Vital Si g ns ..................................................................................................5 3
7. 1. 4. Electr ocar di o gra m .......................................................................................5 4
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7
7. 1. 5. Cli nical L a b orat or y Tests ...........................................................................5 5
7. 2. Pre g na nc y  Testi n g...................................................................................................5 6
7. 3. C o ntrace pti o n C hec k ...............................................................................................5 6
7. 4. Ot her Assess me nts ..................................................................................................5 6
7. 4. 1. Ne w Y or k Heart Ass ociati o n Classificati o n ...............................................5 6
7. 4. 2. K a nsas Cit y Car di o m yo pat h y Q uesti o n naire ..............................................5 7
7. 4. 3. B o d y Mass I n de x/ M o difie d B o d y Mass I n de x ...........................................5 7
7. 4. 4. Testi n g f or L i ght C hai n A m y l oi d ...............................................................5 7
7. 4. 5. Bi o ps y D oc u me nta ti o n of A m yl oi d De p ositi o n .........................................5 8
7. 4. 6. T T R Ge n ot y pi n g .........................................................................................5 8
7. 5. Ba n ke d Bi os peci me ns .............................................................................................5 8
7. 5. 1. A d diti o nal Researc h ....................................................................................5 9
7. 6. Car diac Bi o mar kers N -Ter mi nal Pr o - H or m o ne Brai n Natri uretic Pe pti de 
(N T -pr o B N P) a n d Tr o p o ni n I ....................................................................................5 9
8. A D V E R S E E V E N T R E P O R TI N G ......................................................................................5 9
8. 1. A d verse E ve nts ........................................................................................................5 9
8. 2. Re p orti n g Peri o d .....................................................................................................6 0
8. 3. Defi niti o n of a n A d verse E ve nt ...............................................................................6 0
8. 4. Me dicati o n Err ors ....................................................................................................6 1
8. 5. A b n or mal Test Fi n di n gs ..........................................................................................6 2
8. 6. Seri o us A d verse E ve nts ...........................................................................................6 2
8. 6. 1. Pr ot oc ol- S pecifie d Seri o us A d verse E ve nts............................................... 6 2
8 . 6. 2. P ote ntial Cases of Dr u g-I n d uce d Li ver I nj ur y............................................6 3
8. 7. H os pitalizati o n ........................................................................................................6 4
8. 8. Se verit y  Assess me nt................................................................................................6 5
8. 9. Ca usalit y  Assess me nt..............................................................................................6 5
8. 1 0. E x p os ure D uri n g Pre g na nc y ..................................................................................6 6
8. 1 1. Occ u pati o nal E x p os ure .........................................................................................6 7
8. 1 2. Wit h dra wal D ue t o A d vers e E ve nts ( See Als o t he Secti o n o n S u bject 
Wit h dra wal)................................ ...............................................................................6 7
8. 1 3. Eliciti n g A d verse E ve nt I nf or mati o n ....................................................................6 7
8. 1 4. Re p orti n g Re q uire me nts ........................................................................................6 7
8. 1 4. 1. Seri o us A d verse E ve nt Re p orti n g Re q uire me nts ..................................... 6 8
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8
8. 1 4 . 2. N o nseri o us A d verse E ve nt Re p orti n g Re q uire me nts ...............................6 8
8. 1 4. 3. S p o ns or’s Re p orti n g Re q uire me nts t o Re g ulat or y  A ut h orities................6 8
9. D A T A A N A L Y SI S/ S T A TI S TI C A L  M E T H O D S...............................................................6 8
9. 1. Sa m ple Size Deter mi nati o n .....................................................................................6 9
9. 2. A nal y sis of Ot her E n d p oi nts ...................................................................................6 9
9. 2. 1. M ortalit y  ( Car di o vasc ular-relate d)............................................................. 6 9
9. 2. 2. H os pitalizati o n ............................................................................................6 9
9. 2. 3. Ka nsas Cit y  Car di o m yo pat h y Q uesti o n naire ..............................................6 9
9. 2. 4. Ne w Y or k Heart Ass ociati o n ......................................................................7 0
9. 2. 5. B o d y Mass I n de x/ m o difie d B o d y Mass I n de x ...........................................7 0
9. 2. 6. Car diac Bi o mar kers N T -pr o B N P a n d Tr o p o ni n I ......................................7 0
9. 3. Safet y A nal ys is........................................................................................................7 0
9. 3. 1. M ortalit y  ( All-ca use) ..................................................................................7 0
9. 3. 2. A d verse E ve nts ...........................................................................................7 1
9. 3. 3. P h y sical E xa mi nati o ns a n d Vital Si g ns......................................................7 1
9. 3. 4. Use of C o nc o mita nt Me dicati o ns............................................................... 7 1
9. 3. 5. Cli nical L a b orat or y Tests ...........................................................................7 1
9. 3. 6. Elect r ocar di o gra ms.....................................................................................7 2
9. 4. I nteri m A nal ys is......................................................................................................7 2
9. 5. Data M o nit ori n g C o m mittee ...................................................................................7 2
1 0. Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E................................................. 7 2
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G .............................................................7 3
1 1. 1. Case Re p ort F or ms/ Electr o nic Data R ec or d .........................................................7 3
1 1. 2. Rec or d Rete nti o n ...................................................................................................7 4
1 2. E T HI C S ..............................................................................................................................7 4
1 2. 1. I nstit uti o nal R e vie w B oar d/ Et hics C o m mit tee......................................................7 4
1 2. 2. Et hical C o n d uct of t he St u d y ................................................................................7 4
1 2. 3. S u bject I nf or mati o n a n d C o nse nt ..........................................................................7 5
1 2. 4. S u bject Recr uit me nt ..............................................................................................7 5
1 2. 5. Re p orti n g of Safet y I ss ues a n d Seri o us Breac hes of t he Pr ot oc ol or I C H 
G C P ...........................................................................................................................7 6
1 3. D E FI NI TI O N O F E N D O F T RI A L ...................................................................................7 6
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 9
1 3. 1. E n d of Trial i n a Me m ber State................................ .............................................7 6
1 3. 2. E n d of Trial i n All Ot her Part ici pati n g C o u ntries................................................. 7 6
1 4 . S P O N S O R DIS C O N TI N U A TI O N C RI T E RI A ................................................................7 6
1 5. P U B LI C A TI O N O F S T U D Y R E S U L T S ..........................................................................7 6
1 5. 1. C o m m u nicati o n of Res ults b y  Pfizer ....................................................................7 6
1 5. 2. P u blicati o ns b y  In vesti gat ors ................................................................................7 7
1 6. R E F E R E N C E S ..................................................................................................................7 9
LI S T O F T A B L E S
Ta ble 1. 
I n vesti gati o nal Pr o d uct S u p plies................................ ..........................................3 7
LI S T O F FI G U R E S
Fi g ure 1.
Scatter Pl ot of T T R Perce nt Sta bilizati o n vs Tafa mi dis: T T R M olar Rati o 
b y  Treat me nt i n St u d y B 3 4 6 1 0 4 0.........................................................................2 4
Fi g ure 2.
Fl o wc hart of St u d y  Partici pati o n..........................................................................2 7
Fi g ure 3.
St u d y Treat me nts ..................................................................................................3 5
A P P E N DI C E S
A p pe n di x 1. A b bre viati o ns ......................................................................................................8 0
A p pe n di x 2. Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire ......................................................8 2
A p pe n di x 3. Ne w Y or k Heart Ass ociati o n Classif icati o n.......................................................8 6
A p pe n di x 4. C o u ntr y -s pecific Pr ot oc ol Re q uire me nts ............................................................8 7
A p pe n di x 4. 1. St u d y  D urati o n.................................................................................................8 7
A p pe n di x 4. 2. St u d y  Pr oce d ures..............................................................................................8 7
A p pe n di x 4. 3. Fra nce C o ntrat U ni q ue .....................................................................................8 7
A p pe n di x 5. C o u ntries Partici pat i n g i n C o h ort B....................................................................8 8
A p pe n di x 6. C o u ntries t hat will Partici pate i n A p pe n di x 7 f or Ne wl y E nr olli n g 
S u bjects................................................................................................................. 8 9
A p pe n di x 7. A d diti o nal Sa m ple a n d Ba n ke d Bi os peci me n C ollecti o n f or Ne wl y 
E nr olle d S u bjects i n C o u ntries L iste d i n A p pe n di x 6 .......................................... 9 0
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0
P R O T O C O L S U M M A R Y 
B ac k gr o u n d a n d R ati o n ale:
Pfizer is de vel o pi n g tafa mi dis, a n oral s mall m olec ule, f or t he treat me nt of tra nst h y reti n 
a m yl oi d diseases.  Tra nst h yreti n car di o my o pat h y ( T T R -C M or A T T R -C M) occ urs w he n 
tra nst h yreti n ( T T R) a myl oi d fi brils i nfiltrate t he m y ocar di u m, lea di n g t o de p osits of 
e xtracell ular a m yl oi d.  De p ositi o n of tra nst h y reti n fi brils occ urs bet ween t he m y ocar dial cells 
a n d pr o d uces a t hic ke ni n g a n d stiffe ni n g of t he m y o c a r dial tiss ue.  T his i nfiltrati o n of t he 
m y ocar di u m res ults i n diast olic d y sf u ncti o n pr o gressi n g t o restricti ve car di o m yo pat h y, 
c o n gesti ve heart fail ure, a n d ulti matel y  deat h.
Tafa m i dis is a n o vel s pecific sta bilizer of b ot h wil d-t ype a n d a m yl oi d o ge nic vari a nts of T T R.  
Tafa mi dis bi n ds t o T T R at t he t h y r o xi ne bi n di n g sites a n d i n hi bits T T R tetra mer diss ociati o n, 
t he rate-li miti n g ste p i n t he a myl oi d o ge nic pr ocess.  I t is h yp ot hesize d t hat tafa mi dis w o ul d 
st o p or sl o w t he pr o gressi o n of A T T R-C M a n d t heref ore re prese nts a disease m o dif yi n g 
t hera py. 
St u d y  B 3 4 6 1 0 2 8 was a 3 0-m o nt h, P hase 3, d o u ble -bli n d, place b o -c o ntr olle d, ra n d o mize d, 
parallel - gr o u p trial desi g ne d t o e val uate t he efficacy, safet y a n d t olera bilit y of oral d osi n g of 
tafa mi dis me gl u mi ne 2 0 m g or 8 0 m g  i n c o m paris o n t o place b o i n s u bjects dia g n ose d wit h 
tra nst h yreti n car di o m yo pat h y  a n d heart fail ure.  S u bject p o p ulati o n was 4 4 1 male a n d fe male 
s u bjects a ge d 1 8 t o 9 0 ye ars, wit h A T T R-C M d ue t o eit her varia nt, or wil d t y pe T T R.  T he 
st u d y c o m plete d with sites i n N ort h a n d S o ut h A merica, t he E ur o pea n U ni o n, a n d Ja pa n.  
T he pri mar y  a nalys is was all-ca use m ortalit y a n d t he fre q ue nc y of car di o vasc ular-relate d 
h os pitalizati o ns.  T he pri mar y a nal ys is de m o nstrate d a statisticall y si g nifica nt re d ucti o n i n 
t he co m bi nati o n of all- ca use m ortalit y a n d fre q ue nc y of car di o vasc ular-relate d 
h os pitalizati o ns c o m pare d t o place b o.  T he preli mi nar y safet y data s h o we d t hat tafa mi dis was 
ge nerall y we ll t olerate d i n t his p o p ulati o n a n d n o ne w safet y si g nals were i de ntifie d. 
T he B 3 4 6 1 0 4 5 pr ot oc ol was desi g ne d as a l o n g- ter m e xte nsi o n safet y st u d y f or s u bjects 
c o m pleti n g 3 0 m o nt hs of bli n de d treat me nt o n St u d y B 3 4 6 1 0 2 8.  Gi ve n t he p ositi ve res ults 
of t h e B 3 4 6 1 0 2 8 st u d y a n d t he fa v ora ble be nefit t o ris k pr ofile t here is a j ustifi cati o n t o 
pr o vi de patie nts wit h a n o pti o n f or earl y access t o tafa mi dis.  C o nse q ue ntl y, t he B 3 4 6 1 0 4 5 
st u d y pr ot oc ol will be a me n de d herei n t o i ncl u de a n a d diti o nal c o h ort of patien ts wit h 
A T T R -C M w h o ha ve n ot pre vi o usl y  partici pate d i n t he B 3 4 6 1 0 2 8 pare nt st u d y.  T he p ur p ose 
of t he a d diti o nal c o h ort is t o pr o vi de t hese patie nts earl y access t o tafa mi dis, u ntil l ocal 
a vaila bilit y b y prescri pti o n f or t he A T T R-C M i n dicati o n.
A d diti o na ll y, a ne w f or m ulati o n w hic h is bi oe q ui vale nt t o tafa mi dis me gl u mi ne 8 0 m g ha s 
bee n de vel o pe d a n d is prese nte d as tafa mi dis 6 1 m g (as t he free aci d).  T his f or m ulati o n, 
w here a vaila ble, will re place t he tafa mi dis me gl u mi ne 8 0 m g d ose after pr ot oc ol 
a me n d men t 3. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1
O bjecti ves a n d E n d p oi nts:
Pri mar y  O bjecti ves:

T o o btai n a d diti o nal, l o n g- ter m, safet y data f or tafa mi dis i n s u bjects wit h 
tra nst h yreti n a myl oi d car di o m y o pat h y ( A T T R -C M). 

T o pr o vi de i n vesti gati o nal pr o d uct, tafa mi dis, t o e nr olle d s u bjects u ntil l oca l
a vaila bilit y b y prescri pti o n f or t he A T T R-C M i n dicati o n.
Pri mar y  E n d p oi nts:
Safet y  as meas ure d b y:

All- ca use m ortalit y.

I nci de nce of treat me nt -e mer ge nt a d verse e ve nts.
Ot her E n d p oi nts:

Car di o vasc ular -relate d m ortalit y.

Fre q ue nc y  of all-ca use h os pitalizat i o n.

Fre q ue nc y  of car di o vasc ular-relate d h os pitalizati o n (i ncl u di n g heart fail ure, 
arr h yt h mia, m y ocar dial i nfarcti o n, str o ke a n d ot her car di o vasc ular -relate d e ve nts).

C ha n ge fr o m baseli ne at eac h visit i n Ka nsas Cit y  Car di o m yo pat h y Q uesti o n naire 
O verall S u m mar y  sc ore, d o mai n sc ores ( P h ysical li mitati o n, S y m pt o m sta bilit y, 
S y m pt o m f re q ue nc y, S y m pt o m b ur de n, T otal s y m pt o m, Self-efficac y, S ocial 
li mitati o n, a n d Q ualit y of life), a n d Cli nical s u m mar y sc ore.

Ne w Y or k Heart Ass ociati o n ( N Y H A) classificati o n at eac h visit.

C ha n ge fr o m baseli ne i n B o d y Mass I n de x/ m o difie d B o d y Mass I n de x ( B MI/ m B MI) 
at eac h visit.

C ha n ge fr o m baseli ne i n N -ter mi nal pr o-h or m o ne brai n natri uretic pe pti de 
( N T-pr o B N P) c o nce ntrati o n at eac h visit. 

C ha n ge fr o m baseli ne i n Tr o p o ni n I c o ncen trati o n at eac h visit. 

Assess me nt of p h ys ical e xa mi nati o ns, use of c o nc o mita nt me dicati o ns, 
electr ocar di o gra ms ( E C Gs), cli nical la b orat or y  testi n g, vital si g ns at eac h visit.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2
St u d y Desi g n:
T his is a P hase 3, o pe n -la bel l o n g-ter m e xte nsi o n safety st u d y de si gne d t o o btai n a d diti o nal 
safety data f or tafa mi dis me gl u mi ne 2 0 m g a n d 8 0 m g ( or tafa mi dis 6 1 m g w here a vaila ble), 
a n d t o c o nti n ue t o pr o vi de e nr olle d s u bjects wit h tafa mi dis f or u p t o 6 0 m o nt hs, or u ntil 
s u bject has access t o tafa mi dis f or A T T R-C M via p rescri pti o n, w hic he ver occ urs first.  T he 
st u d y will als o e n d bef ore 6 0 m o nt hs if t he s p o ns or disc o nti n ues t he st u d y .  S u bjects 
wit h dra w n fr o m t he st u d y d ue t o c o m mercial access t o prescri pti o n tafa mi dis i n t heir 
res pecti ve c o u ntries will be c o nsi dere d st ud y  c o m pleters.  T he decisi o n t o wit h dra w s u bjects 
f or tra nsiti o n t o c o m mercial tafa mi dis will be ma de b y t he s p o ns or. 
Eli gi ble st u d y  partici pa nts will be e nr olle d i n 2 c o h orts: 

C o h ort A – S u bjects dia g n ose d wit h A T T R -C M w h o c o m plete d 3 0 m o nt hs of 
partic ipati o n i n St u d y B 3 4 6 1 0 2 8. 

C o h ort B – S u bjects dia g n ose d wit h A T T R - CM w h o ha ve n ot pre vi o usl y partici pate d 
i n St u d y B 3 4 6 1 0 2 8 ( A p pe n di x 5 ). 
St u d y P artici p ati o n Fl o w
S u bjects i n C o h ort A will be assi g ne d t o o pe n la bel treat me n t after pr ot oc ol a me n d me nt 3.
D ur ati o n of St u d y P artici p ati o n
St u d y  d urati o n is f or u p t o 6 0 m o nt hs or u ntil l ocal c o m mercial a vaila bilit y of tafa mi dis b y 
prescri pti o n f or A T T R -C M i n dicati o n is ac hie ve d, w hic he ver occ urs first.  T he st u d y  will 
als o e n d before 6 0 m o nt hs if t he s p o ns or disc o nti n ues t he st u d y . 
Selecti o n of S u bjects:
C o h ort A I ncl usi o n Crite ria:
S u bjects i n C o h ort A m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or 
e nr oll me nt i nt o t he st u d y:
1.
Male a n d fe male s u bjects wit h T T R a m yl oi d car di o m yo pat h y w h o ha ve c o m plete d 
3 0 m o nt hs of st u d y  treat me nt o n Pr ot oc ol B 3 4 6 1 0 2 8.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
2.
E vi de nc e of a pers o nall y si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n dicati n g t hat 
t he s u bject has bee n i nf or me d of all perti ne nt as pects of t he st u d y. 
3.
S u bject s w h o are willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, 
la b orat or y tests, a n d ot he r st u d y pr oce d ures.
4.
Male s u bjects
a ble t o fat her c hil dre n a n d fe male s u bjects of c hil d beari n g p ote ntial a n d
at ris k f or pre g na nc y m ust a gree t o use 2 hi g h l y effecti ve met h o ds of c o ntrace pti o n
t hr o u g h o ut t he st u dy a n d f or at least 2 8 da y s after t he last d os e of assi g ne d treat me nt.
Fe male s u bjects w h o are n ot of c hil d beari n g p ote ntial (ie, meet at least 1 of t he
f oll o wi n g criteria):

Ha ve u n der g o ne a d oc u me nte d h y sterect o m y a n d/ or bilateral o o p h orect o m y;

Ha ve me dicall y  c o nfir me d o varia n fail ure; or

Ac hie ve d p ost me n o pa usal stat us, defi ne d as f oll o ws: cessati o n of re g ular me nses 
f or at least 1 2 c o nsec uti ve m o nt hs wit h n o alter nati ve pat h ol o gical or 
p h y si ol o gical ca use; stat us ma y be c o nfir me d by ha vi n g a ser u m 
f ollicle- sti m ulati n g h or m o ne ( F S H) le vel c o nfir mi n g t he p ost - me n o pa usal state.
All ot her fe male s u bjects (i ncl u di n g fe males wit h t u bal li gati o ns) will be c o nsi dere d
t o be of c hil d beari n g p ote ntial.
C o h ort B I ncl usi o n Criteria:
S u bjects i n C o h ort B m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or 
e nr oll me nt i nt o t he st u d y:
1.
Male or fe male s u bject of at least 1 8
ye ars of a ge ( or t he mi ni m u m c o u ntr y s pecific 
a ge of c o nse nt if > 1 8) a n d partici pates at a st u d y s ite i n a n eli gi ble c o u ntr y liste d i n 
Pr o t oc ol A p pe n di x 5 . 
2.
E vi de nce of a pers o nall y  si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n dicati n g t hat 
t he s u bject has bee n i nf or me d of all perti ne nt as pects of the st u d y. 
3.
S u bjects w h o are willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, 
la b orat or y tests, a n d ot her st u d y pr oce d ures.
4.
A fe male s u bject 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 ma n of C hil d beari n g P ote ntial ( W O C B P) (see defi niti o n 
Secti o n 4. 3. 1 ).
O R
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4

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) (see Secti o n 4. 3 ) d uri n g t he i nter ve nti o n peri o d a n d 
f or at least 2 8 d a y s after t he last d ose of st u d y i nter ve nti o n, w hic h c orres p o n ds t o 
t he ti me nee de d t o eli mi nate a ny st u d y i nt er ve nti o n.  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 rela ti 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 early 
u n detecte d pre g na nc y . 
5.
D oc u me ntati o n of t he ge netic testi n g f or tra nst h yr eti n a m yl oi d osis (ie, ori gi nal 
la b orat or y res ult, or c o p y).
6.
D oc u me ntati o n of dia g n osis a n d criteria use d (e g, c o n gesti ve h eart fail ure a n d 
sci nti gra p hy wit h tracer e g, 9 9 m T C D P D [ 9 9 m T C 3, 3 di p h os p h o n o 1, 2 pr o p a n o 
dic ar b o xylic aci d] , 9 9 m T C P Y P [ Pyr o p h os p h ate] a n d als o 9 9 m T C H M D P 
[ hy dr oxy met hyle ne di p h os p h o n ate] or c o n gesti ve heart fail ure a n d prese nce of 
a m yl oi d de p osits i n bio ps y  tiss ue, e g, f at as pir ate, s aliv ary gl a n d, me di a n nerve 
c o n nective tiss ue s he at h, or c ar di ac [ a myl oi d de m o nstr ate d per a p pr o pri ate st ai n 
s uc h as C o n g o re d or alci a n bl ue st ai n]). 
7.
D oc u me ntati o n t hat pri mar y  (li g ht c hai n) a m yl oi d osis disease has bee n e va l uate d a n d 
r ule d o ut (ie, ori gi nal la b orat or y res ult, or c o p y).
8.
E vi de nce of N Y H A classificati o n I , II, III, or I V.
C o h ort A E xcl usi o n Criteria:
S u bjects i n C o h ort A wit h a n y  of t he f oll o wi n g c haracteristics/c o n diti o ns will n ot be i ncl u de d 
i n t he st u d y:
1.
C h ro nic use of difl u nisal, T T R sta bilizer, ta ur o urs o de o x y c h olate, d o x yc yc li ne, 
di gitalis, patisira n, calci u m c ha n nel bl oc kers, i n vesti gati o nal dr u g(s) or ot her 
e x peri me ntal i nter ve nti o ns, ot her t ha n tafa mi dis, i n de pe n de ntl y or as part of a st u d y 
wit hi n 3 0 da y s pri or t o e nr oll me nt or i n oterse n wit hi n 6 m o nt hs pri or t o e nr oll me nt.
2.
Use of certai n n o n -ster oidal a nti -i nfla m mat or y dr u gs ( N S AI Ds) [Secti o n 5. 8. 1 ].
3.
Li ver a n d/ or heart tra ns pla nt, or i m pla nted car diac mec ha nical assist de vice.
4.
Pre g na nt fe male s u bjects ( or pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y i nter val); 
breastfee di n g fe male s u bjects; male s u bjects wit h part ners c urre ntl y pre g na nt.
5.
Re q uire i nitiati o n of treat me nt wit h calci u m c h a n nel blo c kers.
6.
Uri nar y  rete nti o n re q uiri n g c hr o nic self-cat heterizati o n.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5
7.
Breac h of c o m plia nce wit h treat me nt/si g nifica nt pr ot oc ol vi olati o ns d uri n g c o n d uct of 
B 3 4 6 1 0 2 8 f or w hic h t he s u bject was acc o u nta ble.
8.
S u bjects w h o are i n vesti gati o nal site staff me m b ers directl y i n v ol ve d i n t he c o n d uct 
of t he st u d y  a n d t heir fa mil y me m bers, site staff me m bers ot her wise s u per vise d b y t he 
i n vesti gat or, or s u bjects w h o are Pfizer e m pl oye es directl y i n v ol ve d i n t he c o n d uct of 
t he st u d y.
9.
Ot her se vere ac ute or c hr o nic me dic al or ps y c hiatric c o n diti o n or la b orat or y 
a b n or malit y t hat ma y i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or 
i n vesti gati o nal pr o d uct a d mi nistrati o n, or t hat ma y i nterfere wit h t he i nter pretati o n of 
st u d y res ults a n d, i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he s u bject 
i na p pr o priate f or e ntr y i nt o t his st u d y.
C o h ort B E xcl usi o n Criteria:
S u bjects i n C o h ort B wit h a n y  of t he f oll o wi n g c haracteristics/c o n diti o ns will n ot be i ncl u de d 
i n t he st u d y:
1.
C hr o nic use of difl u nisal, T T R sta bilizer, ta ur o urs o de o x y c h olate, d o x yc yc li ne, 
di gitalis, patisira n, calci u m c ha n nel bl oc kers, i n vesti gati o nal dr u g(s) or ot her 
e x peri me ntal i nter ve nti o ns, ot her t ha n tafa mi dis, i n de pe n de ntl y or as part of a st u d y 
wit hi n 3 0 da y s pri or t o e nr oll me nt or i n oterse n wit hi n 6 m o nt hs pri or t o e nr oll me nt.
2.
Use of certai n n o n -ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) [Secti o n 5. 8. 1 ].
3.
Li ver a n d/ or heart tra ns pla nt, or i m pla nte d car diac mec ha nical assist de vice.
4.
Re q uire i nitia ti o n of treat me nt wit h calci u m c ha n nel bl oc kers.
5.
Uri nar y  rete nti o n re q uiri n g c hr o nic self-cat heterizati o n.
6.
S u bjects wit h heart fail ure t hat i n t he o pi ni o n of t he i n vesti gat or is o n t he basis of 
isc he mic heart disease (e g, pri or my o car dial i nfarcti o n wit h d o c u me nte d hist or y of 
car diac e nz ymes a n d E C G c ha n ges), or u nc orrecte d val v ular disease a n d n ot 
pri maril y  d ue t o tra nst h yreti n a m yl oi d car dio m y o pat h y .
7.
S u bjects w h o are i n vesti gati o nal site staff me m bers directl y i n v ol ve d i n t he c o n d uct 
of t he st u d y  a n d t heir fa mil y me m bers, site staff me m bers ot her wise s u per vise d b y t he 
i n vesti gat or, or s u bjects w h o are Pfizer e m pl oye es directl y i n v ol ve d i n t he c o n d uct of 
t he st u d y.
8.
Ot her se vere ac ute or c hr o nic me dical or ps yc hi atric c o n diti o n or la b orat or y 
a b n or malit y t hat m a y  i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or 
i n vesti gati o nal pr o d uct a d mi nistrati o n, or t hat ma y i nterfere wit h t he i nter pretati o n of 
st u d y res ults a n d, i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he s u bject 
i na p pr o priate f or e ntr y i nto t his st u d y . 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6
St u d y Tre at me nts:
S u bject eli gi bilit y  f or partici pati o n i n t he treat me nt p hase of t he pr ot oc ol will be deter mi ne d 
f oll o wi n g t he assess me nts at t he Scree ni n g visit.  S u bjects will be scree ne d f or eli gi bilit y a n d 
t h ose, i n t he j u d g me nt of t he i n vesti gat or, w h o meet t he i ncl usi o n criteria a n d d o n ot meet t he 
e xcl usi o n criteria, will be e nr olle d.  T here will be treat me nt assi g n me n t stratificati o n b y T T R 
ge n ot y p e ( varia nt or wil d -t ype) f or C o h ort A.
C o h ort A Treat me nt Assi g n me nts:
At e nr oll me nt, s u bjects i n C o h ort A were assi g ne d t o bli n de d acti ve treat me nt; 2 0 m g or 
8 0 m g tafa mi dis o nce dail y , i n a d diti o n t o sta n dar d of care (e g, di uretics) f or u p t o 6 0 m o nt hs 
base d o n t he f oll o wi n g:  

S u bjects recei vi n g 2 0 m g or 8 0 m g tafa mi dis i n St u d y B 3 4 6 1 0 2 8 c o nti n ue t he sa me 
bli n de d treat me nt assi g n me nt.

S u bjects assi g ne d t o place b o i n St u d y  B 3 4 6 1 0 2 8 will be ra n d o mize d ( 1: 2) t o bli n de d 
2 0 m g or 8 0 m g  tafa mi dis.  S u bjects assi g ne d t o place b o i n St u d y B 3 4 6 1 0 2 8 a n d 
ra n d o mize d t o 8 0 m g tafa mi dis will be per mitted o ne bli n de d d ose -re d ucti o n t o 
2 0 m g f or a d verse e ve nts relate d t o t olera bilit y.
S u bjects i n C o h ort A will be assi g ne d t o o pe n la bel treat me nt after pr ot oc ol a me n d me nt 3.
S u bjects recei vi n g 2 0 m g or 8 0 m g tafa mi dis me gl u mi ne will be assi g ne d t o 6 1 m g tafa m i dis, 
o nce dail y, i n a d diti o n t o sta n dar d of care (e g, di uretics), f or u p t o 6 0 m o nt hs.  S u bjects will 
be assi g ne d t o 8 0 m g tafa mi dis me gl u mi ne i n re gi o ns w here 6 1 m g  tafa mi dis is u na vaila ble.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
C o h ort B Treat me nt assi g n me nt:
At e nr oll me nt, s u bjects i n C o h ort B will be assi g ne d t o o pe n la bel 6 1 m g  tafa mi dis o nce 
dail y , i n a d diti o n t o sta n dar d of care (e g, di uretics), f or u p t o 6 0 m o nt hs.  O ne d ose re d ucti o n 
t o 2 0 m g tafa mi dis me gl u mi ne will be per mitte d f or a d verse e ve nts relate d t o t olera bilit y .  
S u bjects will be assi g ne d t o 8 0 m g tafa mi dis me gl u mi ne i n re gi o ns w here 6 1 m g tafa mi dis i s 
u na vaila ble.
I n vesti g ati o n al Pr o d uct S u p plies
Tafa mi dis me gl u mi ne is a vaila ble i n 2 0 m g  s oft gel ca ps ules. Tafa mi dis free aci d is 
a vaila ble i n 6 1 m g  s oft gel ca ps ules. 
D os a ge Le vel ( C o m p o u n d)
A p pe ar a nce
N u m ber of C a ps ules Per D a y ( D ose)
Tafa mi dis me gl u mi ne 2 0 m g 
( P F-0 6 2 9 1 8 2 6 -8 3) - bli n de d
Yell o w, o bl o n g s oft gelati n 
ca ps ules
1 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ule)
3 ( Place b o ca ps ules)
Tafa mi dis me gl u mi ne 8 0 m g 
( P F-0 6 2 9 1 8 2 6- 8 3) - bli n de d
Yell o w, o bl o n g s oft gelati n 
ca ps ules
4 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ules)
Tafa mi dis free aci d 6 1 m g 
( P F 0 6 2 9 1 8 2 6-0 0) - o pe n
Re d dis h br o w n, o bl o n g s oft 
gelati n ca ps ules
1 ( Tafa mi dis free aci d 6 1 m g ca ps ule)
Tafa mi dis me gl u mi ne 2 0 m g 
( PF 0 6 2 9 1 8 2 6 -8 3) - o pe n
Yell o w, o bl o n g s oft gelati n 
ca ps ules
1 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ule)
Tafa mi dis me gl u mi ne 8 0 m g 
( P F 0 6 2 9 1 8 2 6-8 3) - o pe n
Yell o w, o bl o n g s oft gelati n 
ca ps ules
4 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ules)
T he st u d y  will use a n E xter nal Data M o nit ori n g C o m mittee ( E -D M C) t hat will be 
res p o nsi ble f or o n g oi n g m o nit ori n g of t he safety of s u bjects i n t he st u d y  acc or di n g t o t he 
E- D M C C harter.
St atistic al Met h o d:
S a m ple Size R ati o n ale
T here is n o f or mal sa m ple size calc ulati o n f or t his pr ot oc ol.   S u bjects w h o meet e nr oll me nt 
criteria are eli gi ble; U p t o 2 0 0 0 s u bjects are e x pecte d t o e nr oll i n St u d y B 3 4 6 1 0 4 5.
A n al ysis P o p ul ati o ns
T he safet y a nal ys is p o p ulati o n c o nsists of all s u bjects w h o are e nr olle d i n t his st u d y a n d w h o 
ha ve ta ke n at least o ne d ose of st u d y  treat me nt.  F or s pecific m ortalit y -relate d a nalys is, 
treate d s u bjects fr o m t he pare nt st u dy B 3 4 6 1 0 2 8 w h o disc o nti n ue pri or t o t he start of t his 
st u d y will als o be i ncl u de d.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
St atistic al O bjecti ve
T his st u d y  is pri maril y descri pti ve i n nat ure. H y p ot hesis testi n g will be a p plie d t o a li mite d 
set of varia bles.
Pl a n ne d I nteri m A n al ysis
I nteri m a nalys es will be perf or me d if re q uire d t o meet re g ulat or y  re q uire me nts (e g, a n n ual 
re p orti n g) a n d as re q ueste d b y t he E xter nal Data M o nit ori n g C o m mittee.  Interi m a nal ys es 
ma y  als o be perf or me d duri n g t he c o urse of t he st u d y  t o all o w f or t he re p orti n g of data t o t he 
scie ntific c o m m u nit y.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
S C H E D U L E O F A C TI VI TI E S
T he sc he d ule of acti vities ta ble pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures.  
Refer t o t he S T U D Y P R O C E D U R E S a n d A S S E S S M E N T S secti o ns of t he pr ot oc ol f or 
detaile d i nf or mati o n o n eac h pr oce d ure a n d ass ess me nt re q uire d f or c o m plia nce wit h t he 
pr ot oc ol. 
T he i n vesti gat or ma y  sc he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d o n t he 
sc he d ule of acti vities, i n or der t o c o n d uct e val uati o ns or assess me nts re q uire d t o pr otect t he 
well -bei n g of t he s u bject.
Visit I de ntifier
Scree ni n g
D a y 1
M o nt h 3
Tele p h o ne 
Visits b
Cli nic 
Visits c
E n d of 
St u d y Visit d
P ost -st u d y 
f oll o w-u p e
P o p ulati o n
C o h ort B u
( wit h o ut disease 
d oc u me ntati o n)
C o h ort A a & 
C o h ort B a,u
( wit h disease 
d oc u me ntati o n)
C o h o rts 
A & B
(A p pe n dix 4. 2
c o u ntry 
re q uire me nt)b
C o h orts A & B
Fre q ue nc y
M o nt h 3
E ver y 6 
m o nt hs
E ver y 6 
m o nt hs
M o nt h 6 0 or 
Earl y St u d y 
Ter mi nati o n
2 8 da ys after 
last d ose
Visit Wi n d o w f
Da y -3 0
Da y 0
Da y 0
Da y 1
2 weeks
2 wee ks
2 
wee ks
2 wee ks
I nf or me d c o nse nt a n d Release 
of Me dical I nf or mati o n F or m
X
X
I ncl usi o n/e xcl usi o n criteria
X
X
X
De m o gra p h y
X
X
Me dical hist or y
X
X
P h ysical e xa mi nati o n (f ull) g
X
X
X
P h ysical e xa mi nati o n ( brief) h
X g
X
X
Hei g ht meas ure me nt i
X
X
Vital Si g ns j
X
X
X
X
X
La b orat or y Testi n g k ,l
He mat ol o g y
X
X l
X
X
X
Ser u m C he mistr y
X
X l
X
X
X
C oa g ulati o n
X
X l
X
X
X
Reti n ol Bi n di n g Pr ote i n
X
X l
X
X
X
Uri nal ysis
X
X
X
X
X
Car diac bi o mar kers 
( N T-pr o B N P, tr o p o ni n I) x
X  
X
X
X  
X
Ser u m/ uri ne test f or pri mar y 
(li g ht c hai n) a m yl oi d osis
X
Ge n ot y pi n g
X
Tiss ue Bi o ps y
X
Ba n ke d bi os peci me ns w
X w
X w
A d diti o nal C o u ntr y -s pecific 
Sa m ple a n d Ba n ke d 
Bi os peci me n C ollecti o n y
X  
X
Pre g na nc y test f or w o me n of 
c hil d beari n g p ote ntial k
X  
X
X
X  
X
C o ntrace pti o n c hec k m
X
X
X
X
X
X
X
E nr oll me nt /ra n d o mizati o nv
X
X
Dis pe nse tafa mi dis n
X
X
X
X
X
First d ose of tafa mi dis
X o
Cli nical Assess me nts
N Y H A Classificati o n
X
X
X
X
X
K C C Q
X
X
X
X
X
1 2 -lea d E C Gp
X
X
X
A n n ual p
X q
H os pitalizati o n deter m i nati o nr
X
X
X
X
I P c o m plia nce/acc o u nta bilit y
X
X
X
X
D oc u me ntati o n of Vital, 
Tra ns pla nt, C M A D Stat us s,t
X  
X  
X
X
X  
X  
X t
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
Visit I de ntifier
Scree ni n g
D a y 1
M o nt h 3
Tele p h o ne 
Visits b
Cli nic 
Visits c
E n d of 
St u d y Visit d
P ost -st u d y 
f oll o w-u p e
P o p ulati o n
C o h ort B u
( wit h o ut disease 
d oc u me ntati o n)
C o h ort A a & 
C o h ort B a, u
( wit h disease 
d oc u me ntati o n)
C o h o rts 
A & B
(A p pe n dix 4. 2
c o u ntry 
re q uire me nt)b
C o h orts A & B
Fre q ue nc y
M o nt h 3
E ver y 6 
m o nt hs
E ver y 6 
m o nt hs
M o nt h 6 0 or 
Earl y St u d y 
Ter mi nati o n
2 8 da ys after 
last d ose
Visit Wi n d o w f
Da y -3 0
Da y 0
Da y 0
Da y 1
2 weeks
2 wee ks
2 
wee ks
2 wee ks
C o nc o mita nt Treat me nts
X  
X  
X


 

X
A d verse E ve nt Re p orti n g
X  
X  
X


 
 

X e
A b bre viati o ns: 
= o n g oi n g/ c o nti n u o us e ve nt; E C G = electr ocar di o gr a m; K C C Q = Ka nsas Cit y Car di o m y o pat h y 
Q uesti o n naire; N Y H A = Ne w Y or k Heart Ass ociati o n.
a.
C o h ort A : Scree ni n g Visit/ Da y 0 is t he E n d of St u d y visit a n d last da y of treat me nt f or St u d y B 3 4 6 1 0 2 8.  St u d y 
pr oce d ures a n d ass ess me nts will be perf or me d o nce per s u bject a n d t he pr ot oc ol -s pecifie d data re p orte d se paratel y f or 
eac h st u d y.  S u bjects pr o vi di n g c o nse nt a n d f ulfilli n g t he i ncl usi o n/e xcl usi o n criteria will be e nr olle d, ra n d o mize d, a n d 
dis pe nse d st u d y me dicati o n f or St u d y B 3 4 6 1 0 4 5 at t he sa me visit.  S u bject s will be i nstr ucte d t o start 
self- a d mi nistrati o n of tafa mi dis t he f oll o win g da y ( Da y 1).  If m ore t ha n 3 0 da ys ha ve ela pse d fr o m t he B 3 4 6 1 0 2 8 E n d 
of St u d y visit, t he n vital si g ns, a brief p h ysical e xa mi nati o n, cli nic al la b orat or y tests, c o ntrace pti o n c hec k, c o nc o mita nt 
me dicati o ns, a d verse e ve nt re p orti n g m ust be perf or me d o n D a y 0 pri or t o e nr oll me nt.  S u bjects i n C o h ort A will be 
assi g ne d t o o pe n la bel treat me nt after pr ot oc ol a me n d me nt 3.
C o h ort B : S u bjects w h o ha ve t he f oll o wi n g a vaila ble at scree ni n g ( d oc u me ntati o n of t he ge netic testi n g f or 
tra nst h yreti n a m yl oi d osis, d oc u me ntati o n of dia g n osis a n d criteria use d a n d d oc u me ntati o n t hat pri mar y li g ht c hai n 
a m yl oi d osis disease has bee n e val uate d a n d r ule d o ut) ma y ha ve all scree ni n g pr oce d ures perf or me d o n Da y 0.  I n 
a d diti o n t o pr o vi di n g c o nse nt a n d f ulfilli n g t he i ncl usi o n/e xcl usi o n criteria will be e nr olle d a n d dis pe nse d st u d y 
me dicati o n f or St u d y B 3 4 6 1 0 4 5 at t he sa me visit.
b.
Tele p h o ne visits will be perf or me d o n M o nt hs 3, 9, 1 5, 2 1, 2 7, 3 3, 3 9, 4 5, 5 1, a n d 5 7.  Tele p h o ne visit pr oce d ures ma y 
als o be perf or me d at t he st u d y sit e.  F or c o u ntries liste d i n A p pe n dix 4. 2 o nly: S u bjects are re q uire d t o ret ur n t o t he 
st u dy site for a d diti o n al pr oce d ures at M o nt h 3.
c.
Cl i nic visits will be perf or me d at M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, a n d 5 4.
d.
E n d of St u d y visit will occ ur u p o n s u bject c o m pleti o n of st u d y at M o nt h 6 0, s u bj ect wit h dra wal (f or a n y reas o n), or 
st u d y disc o nti n uati o n b y t he S p o ns or.
e.
S u bjects s h o ul d be f oll o we d f or 2 8 da ys after t he last d ose of st u d y treat me nt t o c ollect a n y A E/ S A E i nf or mati o n a n d 
perf or m a c o ntrace pti o n c hec k.  T his f oll o w -u p ma y be c o n d ucte d a t t he st u d y site or b y p h o ne.
f.
Visit wi n d o ws are base d o n t ele p h o ne or cli nic visit da ys relati ve t o start of st u d y treat me nt ( Da y 1). 
g.
C o h ort A: F ull p h ysical e xa mi nati o n (i ncl u di n g wei g ht a n d vital si g ns) res ults fr o m t he E n d of St u d y visit fr o m 
B 3 4 6 1 0 2 8 will be use d f or Da y 0 baseli ne assess me nt f or St u d y B 3 4 6 1 0 4 5.  If m ore t ha n 3 0 da ys ha ve ela pse d , a brief 
p h ysical e xa mi nati o n m ust be perf or me d o n Da y 0. 
C o h ort B: A f ull p h ysical e xa mi nati o n is re q uire d o n Da y 0.
h.
Brief p h ysical e xa mi nati o ns, i ncl u di n g assess me nt of ge neral a p peara nce, a n d car di o vasc ular, res p irat or y, a n d 
gastr oi ntesti nal s yste ms, are t o be perf or me d at cli nic visits ( M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4).  F or c o u ntries 
liste d i n A p pe n dix 4. 2 o nly: Brief p hysic al ex a mi n ati o n i ncl u di n g wei g ht me as ure me nt will be perf or me d at M o nt h 3 
visit.
i.
Meas ure me nt of hei g ht i n ce nti meters (c m) will be perf or me d at t he Scree ni n g Da y
0 visit.
j.
S yst olic a n d diast olic bl o o d press ure a n d p ulse rate (s u pi ne at least 3 mi n utes a n d sta n di n g at least 2 mi n utes pri or t o 
assess me nt), res pirati o n rate a n d b o d y te m perat ure.
k.
C o h ort A: Cli nical la b orat or y testi n g i ncl u des ser u m c he mistr y, he mat ol o g y, c oa g ul ati o n, uri nal ysis, a n d pre g na nc y 
testi n g.  C oa g ulati o n (I nter nati o nal n or malize d rati o [I N R] a n d Pr ot hr o m bi n ti me [ P T]) will be deter mi ne d at t he site’s 
l ocal lab orat or y.  S u bjects w h o alrea d y c o nfir me d me n o pa use wit h a n F S H test i n St u d y B 3 4 6 1 0 2 8 d o n ot n ee d t o 
re peat t his test.  T he F S H test is a p plica ble o nl y t o s u bjects ne wl y f ulfilli n g t he 1 2 c o nsec uti ve m o nt hs of a me n or r hea 
re q uire d t o ma ke t he dia g n osis of me n o pa use. 
C o h ort B : Cli nical la b orat or y testi n g i ncl u des ser u m c he mistr y, he mat ol o g y, c oa g ulati o n, uri nal ysis, a n d pre g na nc y 
testi n g.  C oa g ulati o n (I nter nati o nal n or malize d rati o [I N R] a n d Pr ot hr o m bi n ti me [ P T]) will be deter mi ne d at t he site’s 
l ocal la borat or y.  F S H test ma y be use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n 
or h or m o ne re place me nt t hera p y ( H R T).  Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o 
use o ne of t he n o nestr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir H R T d uri n g 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
t he st u d y.  Ot her wise, t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y 
e nr oll me nt.
l.
C o h ort A: Cli n ical la b orat or y test res ults fr o m St u d y B 3 4 6 1 0 2 8 E n d of St u d y visit will be use d f or Da y 0 of Pr ot oc ol 
B 3 4 6 1 0 4 5.  If m ore t ha n 3 0 da ys ha ve ela pse d bet wee n St u d y B 3 4 6 1 0 2 8 E n d of St u d y visit a n d Da y 0, t he n a ne w set 
of cli nical la b orat or y tests m ust be perf or me d pri or t o e nr oll me nt a n d ra n d o miz ati o n. 
C o h ort B: Cli nical la b orat or y tests are re q uire d at Da y 0 pri or t o st u d y e nr oll me nt.
m.
F o r fe male s u bjects of c hil d beari n g p ote ntial as defi ne d i n Secti o n 4. 3. 1 , at eac h tele p h o ne a n d cli nic visit, disc uss wit h 
t he s u bject t he nee d t o use hi g hl y effecti ve c o ntrace pti o n c o nsiste ntl y a n d c orrectl y, i nstr uct t he s u bject t o call 
i m me diatel y if a selecte d birt h c o ntr ol 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 a n d d oc u me nt 
s uc h c o n versati o n i n t he case re p ort f or m.  S u bjects will be i nstr ucte d t o c o nti n ue use of birt h c o ntr ol f or at least 
2 8 da ys after st u d y partici pati o n.  S u bjects w h o ha ve n ot f oll o we d c o ntrace pti o n re q uire me nts as dete r mi ne d at t he ti me 
of t he p ost -st u d y tele p h o ne call will be as ke d t o c o nfir m pre g na nc y stat us. 
n.
S u bjects will be gi ve n a s u p pl y of tafa mi dis o n Da y 0 f or self -a d mi nistrati o n at h o me be gi n ni n g o n Da y 1 (ie , first 
d ose).  At tele p h o ne visits ( M o nt hs 3, 9, 1 5 , 2 1, 2 7, 3 3, 3 9, 4 5, 5 1, 5 7) s u p plies of tafa mi dis will be s hi p pe d t o s u bjects 
fr o m t he cli nical site b y s pecialize d I P c o urier.  Tafa mi dis will n ot be dis pe nse d if t he pr ot oc ol s pecifie d tele p h o ne call 
visit has n ot occ urre d.  S u bjects will ret ur n f or cl i nic visits e ver y 6 m o nt hs ( M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4) f or 
e val uati o n a n d will recei ve a s u p pl y of tafa mi dis f or self -a d mi nistrati o n at h o me.  Tafa mi dis will n ot be dis pe nse d at 
cli nic visi ts if t he pr ot oc ol s pecifie d cli nic visit pr oce d ures ha ve n ot bee n perf or me d. 
o.
S u bjects wil l self-a d mi nister st u d y me dicati o n at h o me at t he sa me ti me e ver y da y be gi n ni n g o n Da y 1. 
p. 
1 2 -lea d E C G will be perf or me d o n a n a n n ual basis (e ver y 1 2 m o nt hs) at cli n ic visits M o nt hs 1 2, 2 4, 3 6, 4 8 a n d t he 
M o nt h
6 0 E n d of St u d y visit or Earl y Disc o nti n uati o n visit.  F or c o u ntries liste d i n A p pe n dix 4. 2 o nly: A n a d diti o n al 
E C G w ill be perf or me d at t he M o nt h 3 visit.
q.
E C G will be perf or me d o nl y if t he pre vi o us assess me nt occ urre d m ore t ha n si x m o nt hs pri or t o t he E n d of St u d y visit.
r.
Sites will deter mi ne at eac h visit (tele p h o ne, cli nic, e n d of st u d y, or earl y disc o nti n uati o n) w het h er t he s u bject has bee n 
h os pitalize d (i ncl u di n g t he reas o n f or h os pitalizati o n).
s.
W he n t he Vital Stat us is deter mi ne d , t he s u bject s h o ul d be as ke d if t he y ha ve u n der g o ne a heart a n d/ or li ver tra ns pla nt 
or i m pla ntati o n of car diac mec ha nical assist de vice.  I f a s u bject i n dicates t hat t he y ha ve ha d a tra ns pla nt a n d t he y are 
still e nr olle d i n t he st u d y, t he y s h o ul d be re m o ve d fr o m t he st u d y. 
t.
I n t he e ve nt of earl y st u d y disc o nti n uati o n, t he site staff will f oll o w-u p o n t he s u bject’s vital stat us/tra ns pla nt stat us 
6 0 m o nt hs after ra n d o mizati o n/assi g n me nt date.
u.
O nl y c o u ntries liste d i n A p pe n di x 5 m a y scree n/e nr oll s u bjects i n C o h ort B. U p o n a vaila bilit y of Da y -3 0 disease 
c o nfir mati o n res ults, s u bjects i n C o h ort B ma y ret ur n t o t he st u d y site f or Da y 0 visit pr oce d ures. 
v.
C o h ort A : O n Da y 0, s u bjects i n C o h ort A will be bli n dl y assi g ne d t o tafa mi d is me gl u mi ne 2 0 m g or 8 0 m g. 
C o h ort B : On Da y 0, s u bjects i n C o h ort B will be assi g ne d t o o pe n la bel tafa mi dis 6 1 m g ( or tafa mi dis me gl u mi ne 
8 0 m g if u na vaila ble).
w.
C o h ort B o nl y: C ollect a ge n o mic ba n ke d bi os peci me n.  If misse d, c ollect at t he ne xt a vaila ble ti me p oi nt w he n 
bi os peci me ns are bei n g c ollecte d i n c o nj u ncti o n wit h a s u bject visit.
x.
Car diac bi o mar kers N T -pr o B N P a n d Tr o p o ni n I sa m ple c ollecti o n effecti ve after Pr ot oc ol A me n d me nt 4.  St u d y 
s u bjects e nr olle d pri or t o Pr ot oc ol A me n d me nt 4 are re q uire d t o si g n a n u p date d i nf or me d c o nse nt prior t o pr o vi di n g 
bl o o d sa m ple f or car diac bi o mar ker assess me nt.
y.
See A p pe n di x 7 f or A d diti o nal sa m ple a n d ba n ke d bi os peci me n c ollecti o n f or ne wl y e nr olli n g s u bjects i n s pecific 
c o u ntries. T h ese sa m ples will be u se d t o s u p p ort i de ntificati o n a n d c haracterizati o n of ser u m, plas ma, or uri nar y 
bi o mar kers of tra nst h yreti n a m yl oi d osis. T his c ollecti o n i ntr o d uce d i n Pr ot oc ol A me n d me nt 5 is rele va nt o nl y t o 
s u bjects partici pati n g i n c o u ntries liste d i n A p pe n di x 6 .  
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
1. I NT R O D U C TI O N
1. 1. I n dic ati o n
Pfizer is de vel o pi n g tafa mi dis, a n oral s mall m olec ule, f or t he treat me nt of tra nst h y reti n 
a m yl oi d diseases.  Tafa mi dis has bee n de m o nstrate d t o sta bilize tra nst h yreti n a n d is bei n g 
de v el o pe d f or t he treat me nt of A T T R -C M i n patie nts w it h varia nt or wil d-t ype T T R t o 
re d uce t he c o m bi nati o n of all-ca use m ortalit y a n d car di o vasc ular-relate d h os pitalizati o n.  
Tafa mi dis is c urre ntl y  a p pr o ve d i n t he U nite d States f or treat me nt of car di o m yo pat h y of 
wil d -t ype or here ditar y  tra nst h yreti n-me diat e d a m yl oi d osis ( A T T R - C M) i n a d ults t o re d uce 
car di o vasc ular m ortality a n d car di o vasc ular -relate d h os pitalizati o n.  Tafa mi dis is als o 
a p pr o ve d f or t he treat me nt of A T T R- C M i n Ja pa n.
Tafa mi dis is c urre ntl y  a p pr o ve d f or treat me nt of A T T R-P N i n 4 1 c o u ntries a n d is 
c o m merciall y a vaila ble i n t he f oll o wi n g 2 6 c o u ntries: Ar ge nti na, A ustria, Bel gi u m, Brazil, 
B ul garia, Czec h Re p u blic, De n mar k, Fi nla n d, Fra nce, Ger ma n y, Greece, H u n gar y, Israel, 
Italy, Ja pa n, Lic hte nstei n, L u xe m b o ur g, Net herla n ds, N or wa y , P ola n d, P ort ugal, R o ma nia, 
Sl o ve nia, S pai n, S we de n a n d U nite d Ki n g d o m.
1. 2. B ac k gr o u n d
Tra nst h y reti n a myl oi d disease is a rare a n d fatal c o n diti o n c haracterize d b y t he de p ositi o n of 
a m yl oi d deri ve d fr o m tra nst h yreti n (a plas ma pr otei n) i n vari o us or ga ns a n d tiss ues.  
De p osi ti o n of T T R a m yl oi d is ass ociate d wit h t w o disti nct cli nical prese ntati o ns: 
tra nst h yreti n fa milial a m yl oi d p ol yne ur o pat h y  ( A T T R-P N) w he n t he peri p heral ner ves are 
pri maril y  affecte d a n d tra nst h yreti n a myl oi d car di o m yo pat h y ( A T T R -C M) w he n t he heart is 
pri ma ril y affecte d.  B ot h A T T R-P N a n d A T T R -C M are as s ociate d wit h ge netic varia nts of 
tra nst h yreti n b ut A T T R-C M ma y  als o occ ur i n t he a bse nce of a n y ge netic m utati o n, a n d ma y 
be d ue t o wil d -t ype T T R a m y l oi d de p ositi o n.  
A T T R -C M occ urs w he n T T R a m y l oi d fi brils i nfiltrate t he my ocar di u m, lea di n g t o de p osits 
of e xtracell ular a m yl oi d.  De p ositi o n of tra nst h y reti n fi brils occ urs bet wee n t he m yocar dial 
cells a n d pr o d uces a t hic ke ni n g a n d stiffe ni n g of t he m y ocar dial ti ss ue.  T his i nfiltrati o n of 
t he m yocar di u m res ult s i n diast olic d ysf u ncti o n pr o gressi n g t o restricti ve car di o m yo pat h y , 
c o n gesti ve heart fail ure, a n d ulti matel y  deat h.
Tafa mi dis is a n o vel s pecific sta bilizer of b ot h wil d- t ype a n d a m yl oi d o ge nic varia nts of T T R.  
Tafa mi dis bi n ds t o T T R at t he t h y r o xi ne bi ndi n g sites a n d i n hi bits T T R tetra mer diss ociati o n, 
t he rate-li miti n g ste p i n t he a myl oi d o ge nic pr ocess.  B y  sta bilizi n g t he tetra meric nati ve state 
of T T R, tafa mi dis i ncreases t he acti vati o n barrier ass ociat e d wit h tetra mer diss ociati o n a n d 
t heref ore mi mics t he tetra meric sta bilizati o n effect o bser ve d wit h nat urall y occ urri n g 
pr otecti ve tra ns -s u p press or varia nts.  It is h yp ot hesize d t hat tafa mi dis w o ul d st o p or sl o w t he 
pr o gressi o n of A T T R -C M a n d t heref ore re prese nt a disease m o dif y i n g t hera p y. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
St u d y  B 3 4 6 10 2 8 was a 3 0 -m o nt h, P hase 3, d o u ble -bli n d, plac e b o-c o ntr olle d, ra n d o mize d, 
parallel -gr o u p trial desi g ne d t o e val uate t he efficac y , safety a n d t olera bilit y of oral d osi n g of 
tafa mi dis me gl u mi ne 2 0 m g or 8 0 m g i n c o m paris o n t o place b o i n s u bjects dia g n ose d wit h 
tra nst h yreti n car di o m yo pat h y  a n d heart failure.  T he st u d y  e nr olle d 4 4 1 male a n d fe male 
s u bjects a ge d 1 8 t o 9 0 ye ars, wit h A T T R -C M d ue t o eit her varia nt, or wil d t y pe T T R fr o m 
sites i n N ort h a n d S o ut h A merica, t he E ur o pea n U ni o n, a n d Ja pa n.  T he pri mary a nal ys is 
i ncl u de d all-ca use m ortalit y a n d t he fre q ue nc y of car di o vasc ular-relate d h os pitalizati o ns a n d 
de m o nstrate d a statisticall y  si g nifica nt re d ucti o n i n t he c o m bi nati o n of all-ca use m ortalit y 
a n d fre q u e nc y of car di o vasc ular-relate d h os pitalizati o ns co m pare d t o place b o.  T he 
preli mi nar y  safet y data s h o we d t hat tafa mi dis was ge nerall y well t olerate d i n t his s u bject 
p o p ulati o n a n d n o ne w safet y  si g nals were i de ntifie d. 
T he B 3 4 6 1 0 4 5 pr ot oc ol was desi g ne d a s a l o n g-ter m e xte nsi o n safet y st u d y f or s u bjects w h o 
ha ve c o m plete d 3 0 m o nt hs of bli n de d treat m e nt i n St u d y B 3 4 6 1 0 2 8.  Gi ve n t he p ositi ve 
res ults of t he B 3 4 6 1 0 2 8 st u d y a n d t he fa v ora ble be nefit t o ris k pr ofile t here was a 
j ustificati o n t o pr o vi de patie nts wit h a n o pti o n f or earl y access t o tafa mi dis.  C o nse q ue ntl y , 
t he B 3 4 6 1 0 4 5 st u dy pr ot oc ol was a m e n de d t o i ncl u de a n a d diti o nal c o h ort of patie nts wit h 
A T T R -C M w h o di d n ot pre vi o usl y  partici pate i n t he B 3 4 6 1 0 2 8 pare nt st u d y ( C o h ort B).  T he 
p ur p ose of t he a d diti o nal c o h ort is t o pr o vi de t hese patie nts ear l y access t o tafa mi dis, u ntil 
l ocal a vaila bility b y prescri pti o n f or t he A T T R -C M i n dicati o n.  A d diti o nall y , a ne w 
f or m ulati o n w hic h is bi oe q ui vale nt t o tafa mi dis me gl u mi ne 8 0 m g  has bee n de vel o pe d a n d is 
pre se nte d as tafa mi dis 6 1 m g (as t he free aci d).  T his f or m ulati o n, w here a vaila ble, will 
re place the tafa mi dis me gl u mi ne 8 0 m g  d ose after pr ot oc ol a me n d me nt 3.
T he c urre nt pr ot oc ol descri bes a l o n g- ter m safet y e xte nsi o n st u d y f or s u bjects dia g n ose d wit h 
A T T R -C M w h o c o m plete d 3 0 m o nt hs of partici pati o n i n S t u d y B 3 4 6 1 0 2 8 ( C o h ort A) a n d 
s u bjects dia g n ose d wit h A T T R -C M w h o ha ve n ot pre vi o usl y  partici pate d i n t he B 3 4 6 1 0 2 8 
( C o h ort B).
1. 3. D ose R ati o n ale
At e nr oll me nt, s u bjects i n C o h ort A were assi g ne d t o 2 0 m g a n d 8 0 m g  tafa mi dis me gl u mi ne 
i n a bli n de d ma n ner.  At e nr oll me nt, s u bjects i n C o h ort B will be assi g ne d t o o pe n la bel 
6 1 m g tafa mi dis ( or 8 0 m g tafa mi dis me gl u mi ne if u na vaila ble).
T he 2 0 m g d ose of tafa mi dis has bee n pre vi o usl y st u die d i n AT T R -P N; it has bee n s h o w n t o 
be effecti ve i n dela y i n g pr o gressi o n of s ym pt o matic A T T R -P N disease a n d is t he a p pr o ve d 
d ose.  B ot h t he 2 0 m g  a n d 8 0 m g d oses of tafa mi dis were st u die d u n der Pr ot oc ol B 3 4 6 1 0 2 8, 
a m ulti nati o nal, m ultice nter, d o u ble -bli n d ra n d o mize d place bo- c o ntr olled P hase 3 cli nical 
trial t o assess t he efficac y, safet y a n d t olera bilit y of tafa mi dis i n s u bject s wit h 
T T R -car di o m y o pat h y ( A T T R -C M) . 
T he rati o nale f or t he 8 0 m g d ose was base d o n res ults fr o m St u d y  B 3 4 6 1 0 4 0, w hic h was a 
P hase 1, ra n d o mize d, d o u ble -bli n d, cr oss o ver, asce n di n g d ose- escalati o n st u d y of tafa mi dis 
d oses greater t ha n 1 2 0 m g  as oral s ol utio n i n healt h y  s u bjects.  Si n gle d oses of tafa mi dis u p 
t o 4 8 0 m g were well t olerate d i n t he st u d y p o p ulati o n of 9 healt h y  a d ult Asia n me n. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
T he T T R pe rce nt sta bilizati o n data fr o m St u d y B 3 4 6 1 0 4 0 ( Fi g ure 1 ) s u g gest t hat a platea u is
ac hie ve d as t he m olar rati o ( M R) of tafa mi dis: T T R plas ma c o nce ntrati o n i ncreases.  Base d 
u p o n t he data a vaila ble pri or t o c o n d ucti n g St u d y B 3 4 6 1 0 4 0, it was be lie ve d t hat e x p os ures 
ac hie ve d f oll o wi n g a tafa mi dis d ose of 2 0 m g o nce dail y ( Q D) were s ufficient t o a p pr oac h 
t he T T R perce nt sta bilizati o n platea u.  T he data fr o m St u d y B 3 4 6 1 0 4 0 s u g gest t hat d oses 
hi g her t ha n 2 0 m g pr o vi de a greater de gree of sta bilizati o n, as meas ure d b y t he urea-base d
T T R sta bilizati o n assa y.  W hile t he l o n g-ter m ris k-be nefit of d oses hi g her t ha n 2 0 m g o nce 
dail y ( Q D) is u n k n o w n, it is reas o na ble t o p ost ulate t hat greater T T R sta bilizati o n has t he 
p ote ntial t o pr o vi de a d diti o nal efficac y.
I n or der t o calc ulate m olar rati os at vari o us tafa mi dis e x p os ures, a T T R c o nce ntrati o n m ust 
b e ass u me d.  Mea n T T R c o nce ntrati o ns o bser ve d at baseli ne i n St u d y  F x- 0 0 5 ( 2 4. 7 m g/ d L) 
a n d i n patie nts wit h V 1 2 2I m utati o ns i n St u d y F x 1 B-2 0 1 ( 1 3. 5 m g / d L) a n d t he Tra nst h yreti n 
A m y l oi d Car diac St u d y ( T R A C S) ( 1 4. 9 m g/ d L) are ass u me d f or t he calc ulati o ns t hat f oll o w: 
a 2 0 m g Q D tafa mi dis d ose at stea d y state pr o d uces a mea n M R i n t he ra n ge of 1. 2 t o 3. 2 
fr o m mea n mi ni m u m c o nce ntrati o n at stea dy state ( C mi n,ss ) t o maxi m u m c o nce ntrati o n at 
stea d y state ( Cma x,ss ), w hic h is bel o w t he platea u re gi o n of t he data de picte d i n Fi g ure 1 .  
Mea n C
mi n,ss t o Cma x,ss f oll o wi n g tafa mi dis d oses of 8 0 m g are e x pecte d t o pr o d uce M R 
val ues of 3. 5 t o 9. 6, w hic h are a p pr oac hi n g or o n t he platea u re gi o n of T T R perce nt 
sta bilizati o n.
Fi g ure 1 .
Sc atter Pl ot of T T R Perce nt St a biliz ati o n vs T af a mi dis: T T R M ol ar R ati o b y 
Tre at me nt i n St u d y B 3 4 6 1 0 4 0
S o urce: B 3 4 6 1 0 4 0 C S R Fi g ure 1 4. 4. 7. 2. 1.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
T T R pe rce nt sta bilizati o n data i n dicate i ncrease d sta bilizati o n at t he 8 0 m g d ose vers us t he 
2 0 m g d os e a n d t he res ults fr o m St u d y F x-0 0 5 s u p p ort t he 2 0 m g d ose i n A T T R -P N.  T he 
2 0 m g d ose will pr o vi de a d diti o nal safet y data i n s u bjects wit h T T R m utati o ns.  T he 8 0 m g 
d ose is a p pr oac hi n g ma xi mal T T R perce nt sta bilizati o n.
Res ults fr o m St u d y B 3 4 6 1 0 5 4 de m o nst rate d t hat tafa mi dis ma y be a d mi nistere d orall y 
wit h o ut re gar d t o f o o d.  I n a d diti o n, stea d y -state e val uati o n of data fr o m St u d y B 3 4 6 1 0 5 6 
de m o nstrate d t he bi oe q ui vale nce of t he 6 1 m g  tafa mi dis s oft gel ca ps ule t o t he 4 x 2 0 m g 
tafa mi dis me gl u mi ne s oft gel ca ps ules. 
I n li g ht of t he si milarit y i n t he cli nical efficac y a n d safety pr ofile of tafa mi dis me gl u mi ne 
2 0 m g a n d 8 0 m g  o bser ve d i n St u d y B 3 4 6 1 0 2 8 a n d bi o mar ke r data t hat s u g gest s o me 
i ncrease d be nefit of t he 8 0 m g d ose c o m pare d t o t he 2 0 m g d ose, tafa mi d is me gl u mi ne 
8 0 m g is t he rec o m me n de d d ose f or patie nts wit h A T T R- C M.  Patie nts w h o are n ot a ble t o 
t olerate t he 8 0 m g  d ose ma y be d o w n-d ose d t o 2 0 m g tafa mi dis me gl u mi ne.
Tafa mi dis, as t he me gl u mi ne salt i n gelati n ca ps ules was use d t o date i n St u dies B 3 4 6 1 0 2 8 
a n d B 3 4 6 1 0 4 5.  T he ne w f or m ulati o n of 6 1 m g tafa mi dis as t he free aci d i n a si n gle gelati n 
ca ps ule is bei n g i ntr o d uce d t o patie nts t o pr o vi de t he hi g her d ose i n a si n gle ca ps ule.  
C o m plete i nf or mati o n f or t his c o m p o u n d ma y  be f o u n d i n t he si n gle refere nce safety 
d oc u me nt ( S R S D), w hic h f or t his st u d y  is t he I n vesti gat or’s Br oc h ure (I B).
Ba n ke d bi os peci me ns will be c ollecte d f or t he p ur p ose of c o n d ucti n g rese arc h; s pecific uses 
are descri be d i n t he Ba n ke d Bi os peci me ns secti o n. C o m pari n g t he de o x yri b o n ucleic aci d 
( D N A), ri b o n ucleic aci d ( R N A), pr otei n, a n d meta b olite variati o n patter ns of s u bjects w h o 
res p o n d well a n d t h ose w h o res p o nd p o orl y t o treat me nt ma y hel p t o better defi ne t he m ost 
a p pr o priate gr o u p of s u bjects i n w hic h t o tar get a gi ve n treat me nt.  C ollecti n g bi os peci me ns 
f or e x pl orat or y p har mac o ge n o mic/ ge n o mic/ bi o mar ker a nalys es a n d retai ni n g t he m i n t he 
Bi os peci me n Ba n ki n g S yste m ( B B S) ma ke it p ossi ble t o better u n dersta n d t he i n vesti gati o nal 
pr o d uct’s mec ha nis m of act i o n a n d t o see k e x pla nati o ns f or differe nces i n, f or e xa m ple, 
e x p os ure, t olera bilit y, safet y, a n d/ or efficac y n ot a ntici pate d pri or t o t he be gi n ni n g of t he 
st u dy.  Ba n ke d bi os peci me ns retai ne d i n t he B B S als o ca n be use d i n researc h o n A T T R -C M.  
Pr o vi di n g t hese bi os peci me ns is a re q uire d st u dy acti vit y f or st u d y sites a n d s u bjects, u nless 
pr o hi bite d b y  l ocal re g ulati o ns or et hics c o m mittee ( E C) decisi o n. 
2. S T U D Y O B J E C TI V E S A N D E N D P OI N T S
2. 1. O bjecti ves
Pri m ar y O bjecti ves:

T o o btai n a d diti o nal, l o n g -ter m, safet y data f or tafa mi dis i n s u b jects wit h 
tra nst h yreti n a myl oi d car di o m y o pat h y ( A T T R -C M). 

T o pr o vi de i n vesti gati o nal pr o d uct, tafa mi dis, t o e nr olle d s u bjects u ntil l o cal 
a vaila bilit y b y prescri pti o n f or t he A T T R-C M i n dicati o n.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
2. 2. E n d p oi nts
Pri m ar y E n d p oi nts
Safet y  as meas ure d b y:

All- ca use m ortalit y.

I nci de nce of treat me nt -e mer ge nt a d verse e ve nts.
Ot her E n d p oi nts

Car di o vasc ular -relate d m ortalit y.

Fre q ue nc y  of all-ca use h o s pitalizati o n.

Fre q ue nc y  of car di o vasc ular-relate d h os pitalizati o n (i ncl u di n g heart fail ure, 
arrh y t h mia, my ocar dial i nfa rcti o n, str o ke a n d ot her car di o vasc ular-relate d e ve nts).

C ha n ge fr o m baseli ne at eac h visit i n Ka nsas Cit y  Car di o m yo pat h y Q uesti o n naire 
O verall S u m mar y sc ore, d o mai n sc ores ( P h y sical li mitati o n, S y m pt o m sta bilit y, 
S y m pt o m fre q ue nc y , S y m pt o m b ur de n, T otal s y m pt o m, Self -efficac y, S ocial 
li mitati o n, a n d Q ualit y of life), a n d Cli nical s u m mar y sc ore.

Ne w Y or k Heart Ass ociati o n classificati o n at eac h visit.

C ha n ge fr o m baseli ne i n B o d y Mass I n de x/ m o difie d B o d y Mass I n de x at eac h visit.

C ha n ge fr o m baseli ne i n N T -pr o B N P c o nce ntrati o n at eac h visit. 

C ha n ge fr o m baseli ne i n Tr o p o ni n I c o nce ntrati o n at eac h visit.

Assess me nt of p h ys ical e xa mi nati o ns, use of c o nc o mita nt me dicati o ns, 
electr ocar di o gra ms ( E C Gs), cli nical la b orat or y  testi n g, vital si g ns at eac h visit.
F or t h ose seri o us a d verse e ve nts ( S A Es) t hat are ha n dle d as disease-relate d e n d p oi nts ( w hic h 
ma y  i ncl u de deat h), a n e xter nal data m o nit ori ng c o m mittee ( E -D M C) will c o n d uct u n bli n de d 
re vie ws o n a re g ular basis t hr o u g h o ut t he trial (Data M o nit ori n g C o m mittee ). 
3. S T U D Y D E SI G N
T his is a P hase 3, o pe n -la bel l o n g-ter m e xte nsi o n safety st u d y desi g ne d t o o btai n a d diti o nal 
safet y data f or tafa mi dis me gl u mi ne 2 0 m g  a n d 8 0 m g ( or tafa mi dis 6 1 m g w here a vaila ble), 
a n d t o c o nti n ue t o pr o vi de e nr olle d s u bjects wit h tafa mi dis f or u p t o 6 0 m o nt hs, or u ntil 
s u bject has access t o tafa mi dis f or A T T R-C M via prescri pti o n, w hic he ver occ urs first.  T he 
st u d y will als o e n d bef ore 6 0 m o nt hs if t he s p o ns or disc o nti n ues t he st u d y .  S u bjects 
wit h dra w n fr o m t he st u d y d ue t o c o m mercial access t o prescri pti o n tafa mi dis i n t heir 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
res pecti ve co u ntries will be c o nsi dere d st u d y  c o m pleters.  T he decisi o n to wit h dra w s u bjects 
f or tra nsiti o n t o c o m mercial tafa mi dis will be ma de b y t he s p o ns or. 
Eli gi bl e st u d y partici pa nts will be e nr olle d i n 2 c o h orts: 

C o h ort A – S u bjects dia g n ose d wit h A T T R -C M w h o c o m plete d 3 0 m o nt hs of 
partici pati o n i n St u d y B 3 4 6 1 0 2 8. 

C o h ort B – S u bjects dia g n ose d wit h A T T R -C M w h o ha ve n ot pre vi o usl y partici pate d 
i n St u d y B 3 4 6 1 0 2 8 ( A p pe n di x 5 ). 
Fi g ure 2 .
Fl o wc h art of St u d y P artici p ati o n
S u bjects i n C o h ort A will be assi g ne d t o o pe n l a bel treat me nt after pr ot oc ol a me n d me nt 3.
4. S U B J E C T S E L E C 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 s u bjects are e nr olle d.  T he f oll o wi n g 
eli gi bilit y criteria are desi g ne d t o select s u bjects f or w h o m partici pati o n i n t he st u d y is 
c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n me dical c o n ditio ns s h o ul d be ta ke n i nt o 
c o nsi derat i o n w he n deci di n g w het her a partic ular s u bject is s uita ble f or t his pr ot oc ol. 
S u bject eli gi bilit y s h o ul d be re vie we d a n d d oc u me nte d b y  a n a p pr o priate me m ber of t he 
i n vesti gat or’s st u dy tea m bef ore s u bjects are i ncl u de d i n t he st u d y .
4. 1. I ncl usi o n Criteri a
4. 1. 1. C o h ort A I ncl usi o n Criteri a
S u bjects i n C o h ort A m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or 
e nr oll me nt i nt o t he st u d y:
1.
Male a n d fe male s u bjects wit h T T R a m y l oi d car di o m yo pat h y w h o ha ve c o m plete d 
3 0 m o nt hs of st u d y  treat me nt o n Pr ot ocol B 3 4 6 1 0 2 8.
2.
E vi de nce of a pers o nall y  si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n dicati n g t hat 
t he s u bject has bee n i nf or me d of all perti ne nt as pects of t he st u d y. 
3.
S u bjects w h o are willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, 
la b orat or y tests, a n d ot her st u d y pr oce d ures.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
4.
Male s u bjects
a ble t o fat her c hil dre n a n d fe male s u bjects of c hil d beari n g p ote ntial a n d
at ris k f or pre g na nc y m ust a gree t o use 2 hi g hl y effecti ve met h o ds of c o ntrace pti o n
t hr o u g h o ut t he st u d y a n d f or at least 2 8 da y s after t he last d ose of assi g ne d treat me nt.
Fe male s u bjects w h o are n ot of c hil d beari n g p ote ntial (ie, meet at least 1 of t he
f oll o wi n g criteria):

Ha ve u n der g o ne a d oc u me nte d h y sterect o m y a n d/ or bilateral o o p h orect o m y ;

Ha ve me dicall y c o nfir me d o varia n fai l ure; or

Ac hie ve d p ost me n o pa usal stat us, defi ne d as f oll o ws: cessati o n of re g ular
me nses 
f or at least 1 2 c o nsec uti ve m o nt hs wit h n o alter nati ve pat h ol o gical or 
p h y si ol o gical ca use; stat us m a y be c o nfir me d b y ha vi n g a ser u m 
f ollicle- sti m ulati n g h or m o ne ( FS H) le vel c o nfir mi n g t he p ost- me n o pa usal state.
All ot her fe male s u bjects (i ncl u di n g fe males wit h t u bal li gati o ns) will be c o nsi dere d
t o be of c hil d beari n g p ote ntial.
4. 1. 2. C o h ort B I ncl usi o n Criteri a
S u bjects i n C o h ort B m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or 
e nr oll me nt i nt o t he st u d y:
1.
Male or fe male s u bject of at least 1 8
ye ars of a ge ( or t he mi ni m u m c o u ntr y s pecific 
a ge of c o nse nt if > 1 8) a n d partici pates at a st u d y  site i n a n eli gi ble c o u ntr y liste d i n 
Pr ot oc ol A p pe n di x 5 . 
2.
E vi de nce of a pers o nall y  si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n dicati n g t hat 
t he s u bject has bee n i nf or me d of all perti ne nt as pects of t he st u d y. 
3.
S u bjects w h o are willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt p la n, 
la b orat or y tests, an d ot her st u d y  pr oce d ures.
4.
A fe male s u bject 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 o ll o wi n g c o n diti o ns a p plies:

Is n ot a W o ma n of C hil d beari n g P ote ntial ( W O C B P) (see defi niti o n 
Secti o n 4. 3. 1 ).
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
failure rate of < 1 % per year) (see Secti o n 4. 3 ) d uri n g t he i nter ve nti o n peri o d a n d 
f or at least 2 8 d a y s after t he last d ose of st u d y i nter ve nti o n, w hic h c orres p o n ds t o 
t he ti me nee de d t o eli mi nate a n y st u d y i nter ve nti o n.  T he i n vesti gat or s h o ul d 
e val uate t he effecti ve ness of t he c o ntrace pti ve met h o d i n relati o ns hi p t o t he first 
d ose of st u d y  i nter ve nti o n.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
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 sex ual acti vit y  t o decrease t he ris k f or i ncl usi o n of a w o ma n wit h a n early 
u n detecte d pre g na nc y . 
5.
D oc u me ntati o n of t he ge netic testi n g f or tra nst h yr eti n a m yl oi d osis (ie, ori gi nal 
la b orat or y res ult, or c o p y).
6.
D oc u me ntati o n of dia g n osis a n d criteria use d (e g, c o n gesti ve heart fail ure a n d 
sci nti gra p hy wit h tracer e g, 9 9 m T C D P D [ 9 9 m T C 3, 3 di p h os p h o n o 1, 2 pr o p a n o 
dic ar b oxylic aci d] , 9 9 m T C P Y P [ Pyr o p h os p h ate] a n d als o 9 9 m T C H M D P 
[ hy dr oxy met hyle ne di p h os p h o n ate] or C o n gesti ve heart fail ure a n d prese nce of 
a m yl oi d de p osits i n bi o ps y tiss ue, e g, f at as pir ate, s aliv ary gl a n d, me di a n nerve 
c o n nective tiss ue s he at h, or c ar di ac [ a myl oi d de m o nstr ate d per a p pr o pri ate st ai n 
s uc h as C o n g o re d or alci a n bl ue st ai n ]).
7.
D oc u me ntati o n t hat pri mar y  (li g ht c hai n) a m yl oi d osis disease has bee n e val uate d a n d 
r ule d o ut (ie, ori gi nal la b orat or y res ult, or c o p y).
8.
E vi de nce of N Y H A c lassificati o n I, II, III, or I V.
4. 2. E xcl usi o n Criteri a
4. 2. 1. C o h ort A E xcl usi o n Criteri a
S u bjects i n C o h ort A wit h a n y  of t he f oll o wi n g c haracteristics/c o n diti o ns will not be i ncl u de d 
i n t he st u d y:
1.
C hr o nic use of difl u nisal, T T R sta bilizer, ta ur o urs o de o x y c h olate, do x y c ycli ne, 
di gitalis, patisira n, calci u m c ha n nel bl oc kers, i n ves ti gati o nal dr u g(s) or ot her 
e x peri me ntal i nter ve nti o ns, ot her t ha n tafa mi dis, i n de pe n de ntl y or as part of a st u d y 
wit hi n 3 0 da y s pri or t o e nr oll me nt or i n oterse n wit hi n 6 m o nt hs pri or t o e nr o ll me nt.
2.
Use of certai n n o n -ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) [Secti o n 5. 8. 1 ].
3.
Li ver a n d/ or heart tra ns pla nt, or i m pla nte d car diac mec ha nical assist de vice.
4.
Pre g na nt fe males ( or pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y i nter val); 
breastfee di n g fe males; male s u bjects wit h part ners c urre ntl y pre g na nt.
5.
Re q uire i nitiati o n of treat me nt wit h cal ci u m c ha n nel bl oc kers.
6.
Uri nar y  rete nti o n re q uiri n g c hr o nic self-cat heterizati o n.
7.
Breac h of c o m pl ia nce wit h treat me nt/si g nifica nt pr ot oc ol vi olati o ns d uri n g c o n d uct of 
B 3 4 6 1 0 2 8 f or w hic h t he s u bject was acc o u nta ble.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
8.
S u bjects w h o are i n vesti gati o nal site sta ff me m bers directly i n v ol ve d i n t he c o n d uct 
of t he st u d y  a n d t heir fa mil y me m bers, site staff mem bers ot her wise s u per vise d b y  t he 
i n vesti gat or, or s u bjects w h o are Pfizer e m pl oye es directl y i n v ol ve d i n t he c o n d uct of 
t he st u d y.
9.
Ot her se vere ac ute or c hr o ni c me dical or ps yc hi atric c o n diti o n or la b orat or y 
a b n or malit y t hat ma y i ncrease t he ris k ass ociated wit h st u d y  partici pati o n or 
i n vesti gati o nal pr o d uct a d mi nistrati o n, or t hat ma y i nterfere wit h t he i nter pretati o n of 
st u d y res ults a n d, i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he s u bject 
i na p pr o priate f or e ntr y i nt o t his st u d y.
4. 2. 2. C o h ort B E xcl usi o n Criteri a
S u bjects i n C o h ort B wit h a n y  of t he f oll o wi n g c haracteristics/c o n diti o ns will n ot be i ncl u de d 
i n t he st u d y:
1.
C hr o nic use of difl u nisal, T T R sta biliz er, ta ur o urs o de o x yc h olate, d o x yc yc li ne, 
di gitalis, patisira n , calci u m c ha n nel bl oc kers, i n vesti gati o nal dr u g(s) or ot her 
e x peri me ntal i nter ve nti o ns, ot her t ha n tafa mi dis, i n de pe n de ntl y or as part of a st u d y 
wit hi n 3 0 da y s pri or t o e nr oll me nt, or i n oterse n wit hi n 6 m o nt hs pri or t o e nr oll me nt.
2.
Use of certai n n o n -steroi dal a nti -i nfla m mat or y dr u gs ( N S AI Ds) [Secti o n 5. 8. 1 ].
3.
Li ver a n d/ or heart tra ns pla nt, or i m pla nte d car diac mec ha nical assist de vice.
4.
Re q uire i nitiati o n of treat me nt wit h calci u m c ha n nel bl oc kers.
5.
Uri nar y  rete nti o n re q uiri n g c hr onic self -cat heterizati o n.
6.
S u bjects wit h heart fail ure t hat i n t he o pi ni o n of t he i n vesti gat or is o n t he basis of 
ische mic heart disease (e g, pri or m y o car dial i nfarcti o n wit h d oc u me nte d hist or y of 
car diac e nz ymes a n d E C G c ha n ges), or u nc orrecte d val v ular di sease a n d n ot 
pri maril y  d ue t o tra nst h yreti n a m yl oi d car di o my o pat h y .
7.
S u bjects w h o are i n vesti gati o nal site staff me m bers directl y i n v ol ve d i n t he c o n d uct 
of t he st u d y a n d t heir fa mil y me m bers, site staff me m bers ot her wise s u per vise d b y t he 
i n vesti gat or, or s u bjects w h o are Pfizer e 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.
8.
Ot her se vere ac ute or c hr o nic me di cal or ps yc hi atric c o n diti o n or la b orat or y 
ab n or malit y  t hat ma y i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or 
i n vesti gati o nal pr od uct a d mi nistrati o n, or t hat ma y  i nterfere wit h t he i nter pretati o n of 
st u d y res ults a n d, i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he s u bject 
i na p pr o priate f or e ntr y i nt o t his st u d y. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
4. 3. Lifest yle G ui deli nes 
All fe male s u bjects w h o are of c hil d beari n g p ote ntial as a p plica ble t o t he st u d y  w h o are, i n 
t he o pi ni o n of t he i n vesti gat or, se x uall y acti ve a n d at ris k f or pre g na nc y wit h t heir part ner(s) 
m ust a gree t o use a hi g hl y  effecti ve met h o d of c o ntrace pti o n c o nsiste ntly a n d c orrectl y f or 
t he d urati o n of the acti ve treat me nt peri o d a n d f or at least 2 8 d a y s after t he last d ose of 
i n vesti gati o nal pr o d uct.  T he i n vesti gat or or his or her desi g nee, i n c o ns ultati o n wit h t he 
s u bject, will c o nfir m t hat t he s u bject has selecte d a n a p pr o priate met h o d of c o ntrace pti on f or 
t he i n di vi d ual s u bject fr o m t he per mitte d list of c o ntrace pti o n met h o ds (see bel o w) a n d will 
c o nfir m t hat t he s u bject has bee n i nstr ucte d i n its c o nsiste nt a n d c orrect use.  At ti me p oi nts 
i n dicate d i n t he Sc he d ule of Acti vitie s, t he i n vesti gat or or desi g nee will i nf or m t he s u bject of 
t he nee d t o use hi g hly effecti ve c o ntrace pti o n c o nsiste nt l y a n d c orrectl y a n d d oc u me nt t he 
c o n versat i o n a n d t he s u bject’s affir mati o n i n t he s u bject’s c hart (s u bjects nee ds t o affir m 
t heir c o nsiste nt a n d c orrect use of at least 1 of t he selecte d met h o ds of c o ntrace pti o n).  I n 
a d diti o n, t he i n vesti gat or or desi g n ee will i nstr uct t he s u bject t o call i m me di atel y if t he 
selecte d c o ntrace pti o n met h o d is disc o nti n ue d or if pre g na nc y is k n o w n or s us pecte d i n t he 
s u bject or t he part ner. 
Hi g hl y effecti ve met h o ds of c o ntrace pti o n are t h ose t hat, al o ne or i n c o m bi nati o n, r es ult i n a 
fail ure rate of less t ha n 1 % per ye ar w he n use d c o nsiste ntl y a n d c orrectl y (ie, perfect use) a n d 
i ncl u de t he f oll o wi n g:
1.
I m pla ntable pr o gest o ge n- o nl y  h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n.
2.
I ntra uteri ne de vice (I U D).
3.
I ntra uteri ne h or m o ne-releasi n g sys te m (I U S).
4.
Bila teral t u bal occl usi o n.
5.
Vasect o mize d part ner:

Vasect o mize d part ner is a hi g hl y effecti ve c o 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 ma n of c hil d beari n g p ote ntial a n d t he 
a bsence of s per m has bee n c o nfir me d.  If n ot, a n a d diti o nal hi g hl y  effecti ve 
met h o d of c o ntrace pti o n s h o ul d be use d.  T he s per mat o ge nesis c y cle is 
a p pr o xi matel y 9 0 d a y s.
6.
C o m bi ne d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n h i biti o n of o v ulati o n:

oral;

i ntra va gi nal;

tra ns der mal;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2

i njecta ble.
7.
Pr o gest o ge n - o nly h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v u lati o n:

Oral;

I njecta ble.
8.
Se x ual a bsti ne nce:

Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y  if defi ned as 
refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d 
wit h t he st u d y  i nter ve nti o n.  T he relia bilit y of se x ual a bsti ne nce nee ds t o be 
e val uate d i n relati o n t o t he d urati o n of t he st u d y a n d t he preferre d a n d us ual 
lifest yle of t he partici pa nt.
4. 3. 1.
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
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 p a usal 
u nless per ma ne ntl y sterile (see bel o w).
If fertilit y is u nclear (e g, a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot 
be c o nfir me d bef o re 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 h e 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 male wit h 1 of t he f oll o wi n g:

D oc u me nte d h y sterect 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 medical 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 p artici pa nt’s me dical rec or ds, me dical e xa mi nati o n, or 
me dical hist or y  i nter vie w.  T he met h o d of d oc u me ntati o n s h o ul d be rec or de d i n t he 
partici pa nt’s me dical re c 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 a ge 6 0 ye ars or ol der or n o me nses f or 
1 2 m o nt hs wit h o ut a n alte r nati ve me dical ca use. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3

A hi g h f ollicle -sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge 
ma y  be use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o ne re place me nt t hera p y  ( H R T). 

Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o 
use o ne of t he n o nestr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds 
if t he y wis h t o c o nti n ue t heir H R T d uri n g t he st u d y.  Ot her wise, t he y m ust 
disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y  
e nr oll me nt.
4. 4. 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 st u d y p ortal.
T o facilitate access t o a p pr o priatel y q ualifie d me dical pers o n nel o n st u d y- relate d me dical 
q uesti o ns or pr o ble ms, s u bjects are pr o vi de d wit h a c o ntact car d.  T he c o ntact car d c o ntai ns, 
at a mi ni m u m, pr ot oc ol a n d i n vesti gati o nal c o m p o u n d i de ntifiers, s u bject st u d y  n u m bers, 
c o ntact i nf or mati o n f or t he i n vesti gati o nal site, a n d c o ntact details f or a c o ntact ce nter i n t he 
e ve nt t hat t he i n vesti gati o nal site staff ca n n ot be reac he d t o pr o vi de a d vice o n a me dical 
q uesti o n or pr o ble m ori gi nati n g fr o m a n ot her healt hcare pr ofessi o nal n ot i n v ol ve d i n t he 
s u bject’s partici pati o n i n t he st u d y. 
T he c o ntact n u m ber ca n als o be use d b y i n vesti gati o nal st aff if t he y are see ki n g a d vice o n 
me dical q uesti o ns or pr o ble ms; h o we ver, it s h o ul d be use d o nl y i n t he e ve nt t hat t he 
esta blis he d c o m m u nicati o n pat h wa y s bet wee n t he i n vesti gati o nal site a n d t he st u d y tea m are 
n ot a vaila ble.  It is t heref ore i nte n de d t o a u g me nt, b ut n ot re place, t he esta blis he d 
c o m m u nicati o n pat h wa ys bet wee n t he i n vesti gati o nal site a n d t he st u d y tea m f or a d vice o n 
me dical q uesti o ns or pr o ble ms t hat ma y  arise d uri n g t he st u d y.  T he c o ntact n u m ber is n ot 
i nte n de d f or use by t he s u bject direc tl y, a n d if a s u bject calls t hat n u m ber, he or s he will be 
directe d bac k t o t he i n vesti gati o nal site.
5. S T U D Y T R E A T M E N T S
F or t he p ur p oses of t his st u d y, a n d per I nter nati o nal C o nfere nce o n Har m o nizati o n (IC H) 
g ui deli nes i n vesti gati o nal pr o d uct is defi ne d as a p har mace utical f or m of a n acti ve i n gre die nt 
or place b o bei n g teste d or use d as a refere nce i n a cli nical trial, i ncl u di n g a pr o d uct wit h a 
mar keti n g a ut h orizati o n w he n use d or asse m ble d (f or m ulate d or pac ka ge d) i n a wa y  differe nt 
fr o m t he a p pr o ve d f or m, or w he n use d f or a n u na p pr o ve d i n dicati o n, or w he n use d t o gai n 
f urt her i nf or mati o n a b o ut a n a p pr o ve d use (I C H E 6 1. 3 3).
5. 1. All oc ati o n t o Tre at me nt
I n vesti gat ors will c o nfir m t he eli gi bilit y of eac h s u bject t o meet i ncl usi o n/e xcl usi o n criteria.  
S u bject eli gi bilit y f or partici pati o n i n t he treat me nt p hase of t he pr ot oc ol will be deter mi ne d
f oll o wi n g t he assess me nts d uri n g t he Scree ni n g visit.  S u bjec ts will be scree ne d f or eli gi bilit y
a n d t h ose, i n t he j u d g me nt of t he i n vesti gat or, w h o meet t he i ncl usi o n crite ria a n d d o n ot meet 
t he e xcl usi o n criteria, will be e nr olle d i nt o t he st u d y. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
Eac h s u bject i n C o h ort A w h o has si g ne d t he i nf or me d c o nse nt d oc u m e nt (I C D) will be 
assi g ne d t he sa me s u bject i de ntificati o n n u m ber fr o m t he pare nt st u d y  B 3 4 6 1 0 2 8 b y a n 
I nteractive Res p o nse Tec h n ol o g y  (I R T) s yste m.  Eac h s u bject i n C o h ort B will be assi g ne d a 
ne w s u bject i d e ntificati o n n u m ber b y t he I nteracti ve Res p o nse Tec h n ol o g y (I R T) s y ste m.
All ocati o n of s u bjects t o treat me nt gr o u ps will pr ocee d t hr o u g h t he use of a n I R T s ys te m 
u nless ot her wise directe d b y  t he S p o ns or t o e ns ure patie nt safety a n d st u d y c o nti n uit y.  T he 
site pers o n nel (st u dy c o or di nat or or s pecifie d de si g nee) will be re q uire d t o e nter or select 
i nf or mati o n i ncl u di n g b ut n ot li mite d t o t he user’s i de ntificati o n (I D) a n d pass w or d, t he 
pr ot oc ol n u m ber, t he s u bject n u m ber a n d t he date of birt h of t he s u bject. T he site pers o n nel 
will t he n be pr o vi de d wit h a treat me nt assi g n me nt a n d dis pe nsa ble u nit ( D U) or c o ntai ner 
n u m ber.  T he I R T S ys te m will pr o vi de a c o nfir mati o n re p ort c o ntai ni n g t he s u bject n u m ber 
a n d D U or c o ntai ner n u m ber assi g ne d.
Cli nic visits will be at 6- m o nt h i nter vals ( M o nt h 6, 1 2, 1 8 etc.).  S u bjects m ust ret ur n f or 
t heir a p p oi nt me nt bef ore t heir st u d y dr u g s u p pl y is e x ha uste d.  S u bjects m ust bri n g all of 
t heir st u d y me dicati o n a n d t heir S u bject Dail y D osi n g Diar y t o eac h cli nic visit.  T he site will 
c ollect all st u d y me dicati o n dis pe nse d at t h e pre vi o us visit a n d dis pe nse a ne w set of st u d y 
me dicati o n a n d a S u bject Dail y  D osi n g Diar y t o t he s u bject.
T he re is a 2 4- h o ur- a-d a y , 3 6 5-d a y s-a-year I R T hel p des k a vaila ble f or a n y q uesti o ns or 
iss ues.  T he st u d y s pecific IR T refere nce ma n ual will pr o vi de t he c o ntact i nf or mati o n a n d 
f urt her details o n t he use of t he IR T s y ste m.
N ote: T he I R T is t he s o urce of t he s u bject n u m ber.  T he I R T s y ste m will pr o vi de t he s u bject 
n u m ber at t he e n d of t he first I R T s u bjec t tra nsacti o n.
5. 1. 1. C o h ort A Tre at me nt Assi g n me nt
T here will be treat me nt assi g n me nt stratificati o n b y T T R ge n ot y pe ( varia nt or wil d -t ype) 
o nl y  f or C o h ort A. 
At e nr oll me nt, s u bjects i n C o h ort A were assi g ne d t o bli n de d acti ve treat me nt i n t his st u d y ; 
tafa mi dis me gl u mi ne 2 0 m g or 8 0 m g  o nce dail y, i n a d diti o n t o sta n dar d of care 
(e g, di uretics) f or u p t o 6 0 m o nt hs base d o n t he f oll o wi n g: 

S u bjects recei vi n g tafa mi dis me gl u mi ne 2 0 m g or 8 0 m g i n St u d y B 3 4 6 1 0 2 8 c o nti n ue 
t he sa me bli n de d treat me nt assi g n me nt.

S u bje cts assi g ne d t o place b o i n St u d y B 3 4 6 1 0 2 8 will be ra n d o mize d ( 1: 2) t o bli n de d 
tafa mi dis me gl u mi ne 2 0 m g or 8 0 m g .  S u bjects assi g ne d t o place b o i n 
St u d y B 3 4 6 1 0 2 8 a n d ra n d o mize d t o tafa mi dis me gl u mi ne 8 0 m g  will be per mitte d 
o ne bli n de d d ose -re d ucti o n t o 2 0 m g f or a d verse e ve nts relate d t o t olera bilit y .
S u bjects i n C o h ort A will be assi g ne d t o o pe n la bel treat me nt after pr ot oc ol a me n d me nt 3.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
S u bjects recei vi n g ta fa mi dis me gl u mi ne 2 0 m g or 8 0 m g will be assi g ne d t o tafa mi dis 6 1 m g, 
o nce dail y, i n a d diti o n t o sta n dar d of care (e g, di uretics), f or u p t o 6 0 m o nt hs.  S u bjects will 
be assi g ne d t o tafa mi dis me gl u mi ne 8 0 m g  i n re gi o ns w here 6 1 m g  tafa mi dis is u na vaila ble.
Fi g ure 3 .
St u d y Tre at me nts
5. 1. 2. C o h ort B Tre at me nt Assi g n me nt
At e nr oll me n t, s u bjects i n C o h ort B will be assi g ne d t o o pe n la bel 6 1 m g  tafa mi dis o nce 
dail y , i n a d diti o n t o sta n dar d of care (e g, di uretics), f or u p t o 6 0 m o nt hs.  O ne d ose re d ucti o n 
t o 2 0 m g tafa mi dis me gl u mi ne will be per mitte d f or a d verse e ve nts relate d t o t olera bilit y .  
S u bjects will be assi g ne d t o 8 0 m g tafa mi dis me gl u mi ne i n re gi o ns w here 6 1 m g tafa mi dis is 
u na vaila ble.
5. 2. Bre a ki n g t he Bli n d
S u bjects i n C o h ort A will b e bli n de d t o treat me nt assi g n me nt at e nr oll me nt i nt o t he st u d y .  
Treat me nt assi g n me nts will re mai n bli n de d t o t he s u bject a n d i n vesti gat or u ntil assi g ne d t o 
o pe n la bel treat me nt as descri be d i n Secti o n 5. 1. 1 . 
T he st u d y  treat me nt assi g n me nt will be s u bject a n d i n vesti gat or bli n de d as t o d ose.  At t he 
i nitiati o n of t he st u d y, t he st u d y site will be i nstr ucte d o n t he met h o d f or brea ki n g t he bli n d. 
T he reas o n f or brea ki n g t he bli n d f or a n i n di vi d ua l s u bject ma y i ncl u de t he f oll o wi n g:
1.
A seri o us, u ne x pecte d/ u nliste d, treat me nt-relate d e ve nt f or reas o ns of s u bject safety;
2.
A n ur ge nt safet y meas ure ta ke n b y t he i n vesti gat or or Pfizer t o pr o tect s u bjects 
a gai nst i m me diate hazar d t o healt h;
3.
A p ote ntiall y  life t hreate ni n g dr u g i nteracti o n;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
4.
Et hical c o nsi derati o ns s uc h as a me dical e mer ge nc y  w here u n dersta n di n g t he 
treat me nt all ocati o n is necessar y t o a de q uatel y ma na ge t he s u bject’s c o n diti o n.  In 
t his case, a n atte m pt s h o ul d be ma de t o c o ntact t he st u d y cli nicia n or a n ot her me m ber 
of t he st u d y  tea m.
W he ne ver p ossi ble, t he i n vesti gat or or s u b- i n vesti gat or s h o ul d c o ns ult wit h a me m ber of t he 
st u d y tea m (e g, t he cli nical trial ma na ger, st u dy cli nicia n or t he me dical m o nit or) pri or t o 
brea ki n g t he bli n d f or a n i n d i vi d ual s u bject.  After re vie wi n g a n d a p pr o vi n g t he 
i n vesti gat or’s re q uest, t he st u d y cli nicia n will pr o vi de writte n a ut h orizati o n (e mail) t o t he 
i n vesti gat or t o brea k t he bli n d.
If u na ble t o c o ntact a me m ber of t he st u d y tea m, t he i n vesti gat or ma y  brea k the bli n d f or a 
gi ve n s u bject e x perie nci n g a seri o us a d verse e ve nt ( S A E) or ot her me dical e mer ge n c y w here 
k n o wle d ge of t he treat me nt assi g n me nt will affect treat me nt decisi o ns.
Brea ki n g t he bli n d will be d o ne electr o nically a n d i nstr ucti o ns will be gi ve n at a trai ni n g 
sessi o n f or t he pr ot oc ol.
W he n t he bli n di n g c o de is br o ke n, t he reas o n m ust be f ull y
d oc u me nte d a n d e ntere d o n t he 
case re p ort f or m ( C R F).  I n di vi d ual s u bjects w h ose bli n d is br o ke n will be disc o nti n ue d fr o m 
t he st u d y as descri be d i n Secti o n 6. 2. 4 .
5. 3. S u bject C o m pli a nce
S u bjects will be i nstr ucte d t o ta ke t he me dicati o n o n a dail y  basis.  T he y will als o be 
i nstr ucte d t o ret ur n all of t heir st u d y me dicati o n t o t he st u d y site, i ncl u di n g use d a n d u n use d 
st u d y me dicati o n, at eac h sc he d ule d st u dy visit s o t hat t he t otal a m o u nt of dr u g ta ke n ca n be 
deter mi ne d a n d u n use d me dicati o n c ollecte d b y site pers o n nel.  St u d y dr u g ca ps ule c o u nt 
will be perf or me d at eac h visit f or all s u bjects or as per l ocal re g ulati o ns.  T he nee d f or 
a d here nce wit h st u d y dr u g a d mi nistrati o n will be rei nf orce d at eac h st u d y visit.
F or t h e p ur p ose of pr o m oti n g d osi n g a d here nce, t he sites will calc ulate t he n u m ber of da y s 
d ose d di vi de d b y  t he n u m ber of da ys partici pati n g in t he st u d y  f or eac h st u d y visit t o pr o vi de 
a meas ure of treat me nt a d here nce.  S u bjects will be c o nsi dere d t o be a d here n t t o t he d osi n g 
re q uire me nts of t he st u d y if t he y ha ve ta ke n t he re q uire d dail y d ose of st u d y me dicati o n per 
da y  o n at least 8 0 % of t he d a y s of st u d y partici pati o n. 
5. 4. I n vesti g ati o n al Pr o d uct S u p plies
C o h ort A bli n de d treat me nt assi g n me nt:
I n or der t o ac hie ve t he pr o per d osa ge a n d mai ntai n t he bli n d i n t he st u d y , ca ps ules will be 
dis pe nse d i n a bli n de d f as hi o n t o ac hie ve a dail y d ose of 4 caps ules.  Eac h d ose of 4 ca ps ules 
will c o nsist of eit her 3 ca ps ules of matc hi n g bli n de d place b o p l us 1 ca ps ule of bli n de d 
tafa mi dis me gl u mi ne 2 0 m g, 2 ca ps ules of matc hi n g bli n de d place b o pl us 2 ca ps ules of 
bli n de d tafa mi dis me gl u mi ne 2 0 m g, or 4 ca ps ules o f bli n de d tafa mi dis me gl u mi ne 2 0 m g .  
(Ta ble 1 ). 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
C o h ort A a n d B o pe n la bel treat me nt assi g n me nt:
After pr ot oc ol a me n d me nt 3, all s u bjects will be assi g ne d t o o pe n la bel treat me nt.  Eac h d ose 
of tafa mi dis 6 1 m g or tafa mi dis me gl u m i ne 2 0 m g c o nsists of 1 ca ps ule.  Eac h d ose of 
tafa mi dis me gl u mi ne 8 0 m g c o nsists of 4 ca ps ules.   (Ta ble 1 ).
T a ble 1 .
I n vesti g ati o n al Pr o d uct S u p plies
D os a ge Le vel ( C o m p o u n d)
A p pe ar a nce
N u m ber of C a ps ules Per D a y ( D ose)
Tafa mi dis me gl u mi ne 2 0 m g 
( P F-0 6 2 9 1 8 2 6 -8 3) - bli n de d
Yell o w, o bl o n g s oft gelati n 
ca ps ules
1 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ule)
3 ( Place b o ca ps ules)
Tafa mi dis me gl u mi ne 8 0 m g 
( P F-0 6 2 9 1 8 2 6 -8 3) - bli n de d
Yell o w, o bl o n g s oft gelati n 
ca ps ules
4 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ules)
Tafa mi dis free aci d 6 1 m g 
( P F 0 6 2 9 1 8 2 6-0 0) - o pe n
Re d dis h br o w n, o bl o n g s oft 
gelati n ca ps ules
1 ( Tafa mi dis free aci d 6 1 m g ca ps ule)
Tafa mi dis me gl u mi ne 2 0 m g 
( P F 0 6 2 9 18 2 6- 8 3) - o pe n
Yell o w, o bl o n g s oft gelati n 
ca ps ules
1 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ule)
Tafa mi dis me gl u mi ne 8 0 m g 
( P F 0 6 2 9 1 8 2 6-8 3) - o pe n
Yell o w, o bl o n g s oft gelati n 
ca ps ules
4 ( Tafa mi dis me gl u mi ne 2 0 m g ca ps ules)
5. 4. 1. D os a ge F or m(s) a n d P ac k a gi n g
C o h ort A Bli n de d D osa ge F or m a n d Pac ka gi n g:
Bli n de d P F - 0 6 2 9 1 8 2 6 (tafa mi dis me gl u mi ne) will be pr o vi de d as s oft gel ca ps ules f or oral 
a d mi nistrati o n (Ta ble 1 ).  T he caps ules will be s u p plie d i n se parate blister car ds a n d la bele d 
acc or di n g t o l ocal re g ulat or y re q uire me nts.
Tafa mi dis me gl u mi ne 2 0 m g i n s oft gel ca ps ules will be pac ka ge d as 8 tri-f ol d 
i n vesti gati o nal pr o d uct wallets i n eac h cart o n, wit h eac h wallet la bele d 1 t hr o u g h 8.  Eac h 
i n vesti gati o nal pr o d uct wallet will be pac ka ge d wit h e n o u g h me dicati o n f or 1 5 da y s of 
d osi n g. 
S u bjects will be dis pe nse d 1 cart o n c o ntai ni n g 8 i n vesti gati o nal pr o d uct wallets.  T his will 
pr o v i de e n o u g h i n vesti gati o nal pr o d uct f or eac h 3 -m o nt h d osi n g peri o d pl us 2 e xtra 
i n vesti gati o nal pr o d uct wallets t o all o w f or fle xi bilit y i n cli nic visit sc he d ulin g (t otal of 
1 2 0 da y s s u p ply). 
S u bjects s h o ul d be i nstr ucte d t o o nl y d ose fr o m 1 i n vesti gati o nal pr o d uct wallet eac h da y.  
S u bjects s h o ul d ta ke 4 ca ps ules o ne ti me per da y wit h water.  S u bjects s h o ul d be i nstr ucte d 
t o c o m plete d osi n g fr o m o ne i n vesti gati onal pr o d uct wallet pri or t o starti n g d osi n g fr o m t he 
ne xt c o nsec uti vel y  n u m bere d i n vesti gati o nal pr o d uct wallet.
C o h ort A & B O pe n La bel D osa ge F or m a n d Pac ka gi n g:
After pr ot oc ol a me n d me nt 3, st u d y  treat me nt will be pr o vi de d as s oft gel ca ps ules f or oral 
ad mi nistrati o n ( Ta ble 1 ).  T he ca ps ules will be s u p plie d i n b ottles a n d la bele d acc or di n g t o 
l ocal re g ulat or y re q uire me nts.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
F or o pe n -la bel treat me nt assi g n me nt, s u bjects will be dis pe nse d 1 cart o n at eac h visit 
c o ntai ni n g eit her:

3 x b ottles of tafa mi dis 6 1 m g ca ps ules ( 4 0 c o u nt per b ottle, 1 2 0 d a y s s u p pl y per 
cart o n); or 

3 x b ottles of tafa mi dis me gl u mi ne 2 0 m g  ca ps ules ( 4 0 c o u nt per b ottle, 1 2 0 da y s 
s u p pl y per cart o n); or 

1 2 x b ottles of tafa mi dis me gl u mi ne 2 0 m g  ca ps ules ( 4 0 c ou nt per b ottle, 1 2 0 da y s 
s u p pl y per cart o n).
5. 4. 2. Pre p ar ati o n a n d Dis pe nsi n g
I n vesti gati o nal pr o d uct will be dis pe nse d at t he Scree ni n g visit ( Da y 0) a n d at e ver y  s pecifie d 
tele p h o ne or cli nic visit t hereafter usi n g a n I RT s yste m.  A q ualifie d staff me m ber will
dis pe nse t he i n vesti gati o nal pr o d uct cart o ns pr o vi de d.
S u bje cts will be gi ve n a s u p pl y (Secti o n 5. 4. 1 ) of tafa mi dis o n Da y 0 f or self -a d mi nistrati o n 
at h o me be gi n ni n g o n Da y 1 (ie, first d o se).  At tele p h o ne visits ( M o nt hs 3, 9, 1 5, 2 1, 2 7, 3 3, 
3 9, 4 5, 5 1, 5 7) s u p plies of I P will be s hi p pe d t o s u bjects fr o m t he cli nical site b y  a 
s pecialize d IP c o urier.  A n y  IP s hi p pe d directl y  t o s u bject f oll o wi n g a tele p h o ne visit will be 
dis pe nse d at t he site per t he pr ocess liste d a b o ve a n d m o nit ore d f or te m perat ure d uri n g 
s hi p pi n g pr ocess t hr o u g h deli ver y.  S u bjects will ret ur n f or cli nic visits e ver y 6 m o nt hs 
( M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4) f or e val uati o n a n d will recei ve a s u p pl y  of I P f or 
self-a d mi nistrati o n at h o me. 
I P will n ot be dis pe nse d if t he pr ot oc ol s pecifie d tele p h o ne visit pr oce d ures ha ve n ot bee n 
perf or me d.  Details of pr oce d ures f or s hi p pi n g b y s pecialize d IP c o urier will be i ncl u de d i n 
t he IP s hi p pi n g refere nce g ui de.  I P will n ot be dis pe nse d at cli nic visits if t he pr ot oc ol 
s pecifie d cli nic visit pr oce d ures ha ve n ot bee n perf or me d.
5. 5. A d mi nistr ati o n
C o h ort A bli n de d treat me nt: S u bjects will be i nstr ucte d t o ta ke 4 ca ps ules per da y of bli n de d 
t hera py fr o m a n i n di vi d ual r o w o n t he dis pe nse d st u d y  me dicati o n wallet a n d t o ta ke t he 
ca ps ules wit h a glass of water.  S u bjects will s w all o w t he st u d y me dicati o n w h ole, a n d will 
n ot ma ni p ulate or c he w t he me dicati o n pri or t o s wall o wi n g. 
C o h ort A & B o pe n la bel treat me nt: S u bjects will be i n structe d t o ta ke 1 ca ps ule per da y 
fr o m b ottle, or 4 ca ps ules per da y f or s u bjects o n tafa mi dis me gl u mi ne 8 0 m g a n d t o ta ke t he 
ca ps ules wit h a glass of water.  S u bjects will s wall o w t he st u d y  me dicati o n w h ole, a n d will 
n ot ma ni p ulate or c he w t he me dicati o n p ri or t o s wall o wi n g.
S u bjects will be i nstr ucte d t o d ose at a c o nsiste nt ti me eac h da y .  S u bjects s h o ul d n ot ta ke a n 
e xtra d ose of me dicati o n i n t he e ve nt t hat a d ose fr o m a pre vi o us da y  is misse d a n d s h o ul d 
res u me d osi n g as i nstr ucte d a b o ve at t he ne xt pla n ne d d osi n g ti me. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
Si milarl y , if m ulti ple d oses fr o m pre vi o us da ys are misse d i n s uccessi o n, t he s u bject s h o ul d 
res u me d osi n g at t he ne xt pla n ne d d osi n g ti me wit h o ut ta ki n g a d diti o nal d oses t o ma ke u p f or 
t h ose d oses t hat were misse d.  I nstr ucti o ns o n dosi n g are pr o vi de d o n t he S u bject Dail y 
D osi n g Diar y . 
O n t he da y  of t he st u d y visit, s u bjects will write t he act ual ti me t hat t he y t o o k t heir 
me dicati o n i n t he S u bject Dail y  D osi n g Diar y a n d t he site staff will rec or d t his d osi n g ti me i n 
t he case re p ort for m ( C R F).  At t he e n d of eac h visit, sites will i nstr uct s u bjects, i n writi n g o n 
t he fr o nt of t he S u bject Dail y  D osi n g Diar y, w he n t o ta ke t heir me dicati o n pri or t o t heir ne xt 
st u d y visit. 
5. 5. 1. D ose -re d ucti o n 
A o ne -ti me d ose re d ucti o n t o 2 0 m g tafa mi dis me gl u mi ne will be per mitte d f or s u bjects after 
s witc hi n g t o 6 1 m g tafa mi dis.
C o h ort A bli n de d d ose re d u cti o n
I n t he e ve nt t hat s u bjects e x perie nce a d verse e ve nts t hat ma y be ass ociate d wit h t he 
t olera bilit y of treat me nt wit h tafa mi dis t hat ma y i m pact d osi n g a dher e nce, t he y s h o ul d ret ur n 
t o t he cli nic wit h t heir me dicati o n.  If t he i n vesti gat or assesses t hat t he t olera bilit y iss ue is 
persiste nt a n d a ntici pate d t o i m pact d osi n g a d here nce a n d t hat t he s u bject’s safet y is n ot 
c o m pr o mise d b y c o nti n ui n g treat me nt, t he n t he s u bject ma y re q uest bli n de d treat me nt 
re-assi g n me nt t o a l o wer d ose.  O nl y  s u bjects assi g ne d t o 8 0 m g  tafa mi dis i n B 3 4 6 1 0 4 5 after 
3 0 m o nt hs of place b o i n St u d y B 3 4 6 1 0 2 8 will be per mitte d o ne bli n de d d ose -re d ucti o n t o 
2 0 m g.
T he site pers o n nel will e nte r t he s u bject’s st u dy- s pecific i de ntificati o n ( S SI D) n u m ber i nt o 
t he IR T s ys te m a n d re q uest bli nde d d ose -re d ucti o n.  T he I R T sys te m will pr o vi de a ne w 
c o ntai ner n u m ber f or bli n de d treat me nt re- assi g n me nt f or t his s u bject. 
If t he s u bject was recei vi n g t he 8 0 m g  d ose i n St u d y B 3 4 6 1 0 4 5 after 3 0 m o nt hs of place b o i n 
St u d y B 3 4 6 1 0 2 8, t he n t he re -assi g n me nt will be t o 2 0 m g.  All ot her s u bjects will be 
mai ntai ne d o n t he pre vi o usl y  assi g ne d d ose b ut will still recei ve a ne w c o ntai ner n u m ber i n 
o r der t o mai ntai n t he bli n d. 
If t olera bilit y iss ues c o nti n ue after t he bli n de d re-assi g n me nt, t he i n vesti gat or has t he o pti o n 
t o disc o nti n ue d osi n g f or t his s u bject a n d t o ter mi nate st u d y partici pati o n.  I n t he e ve nt of 
earl y st u d y disc o nti n uati o n, t he sit e staff will f oll o w-u p o n t he s u bject’s vital 
stat us/tra ns pla nt stat us 6 0 m o nt hs after ra n d o mizati o n i nt o B 3 4 6 1 0 4 5.
C o h ort A & B o pe n l a bel d ose re d ucti o n
I n t he e ve nt t hat s u bjects e x perie nce a d verse e ve nts t hat ma y be ass ociate d wit h t he 
t olera bilit y of treat me nt wit h tafami dis t hat ma y  i m pact d osi n g a d here nce, t he y s h o ul d ret ur n 
t o t he cli nic wit h t heir me dicati o n. If t he i n vesti gat or assesses t hat t he t olera bilit y iss ue is 
persiste nt a n d a ntici pate d t o i m pact d osi n g a d here nce a n d t hat t he s u bject’s saf et y is n ot 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
c o m pr o mise d b y c o nti n ui n g treat me nt, t he n t he s u bject ma y re q uest treat me nt re-assi g n me nt 
t o a l o wer d ose.  All s u bjects will be per mitte d o ne o pe n la bel d ose- re d ucti o n t o 2 0 m g.
T he site pers o n nel will e nter t he s u bject’s st u d y s pecific i de ntif icati o n ( S SI D) n u m ber i nt o 
t he IR T s ys te m a n d re q uest a n o pe n la bel d ose re d ucti o n.  T he IR T s y ste m will pr o vi de a 
ne w c o ntai ner n u m ber f or o pe n la bel treat me nt re -assi g n me nt f or t his s u bject.
If t olera bilit y iss ues c o nti n ue after t he re-assi g n me nt, t he i nvesti gat or has t he o pti o n t o 
disc o nti n ue d osi n g f or t his s u bject a n d t o ter mi nate st u d y  partici pati o n.  I n t he e ve nt of early 
st u d y disc o nti n uati o n, t he site staff will f oll o w u p o n t he s u bject’s vital stat us/tra ns pla nt 
stat us 6 0 m o nt hs after ra n d o mizati o n i nt o B 3 4 6 1 0 4 5.
5. 6. I n vesti g ati o n al Pr o d uct St or a ge
T he i n vesti gat or, or a n a p pr o ve d re prese ntati ve, e g, p har macist, wi ll e ns ure t hat all
i n vesti gati o nal pr o d ucts are st ore d i n a sec ure d area wit h c o ntr olle d access u n der re q uire d
st ora ge c o n diti o ns a n d i n acc or da nce wit h a p plicable re g ulat or y re q uire me nts.  All 
i n vesti gati o nal pr o d ucts s h o ul d be st ore d i n acc or da nce wit h the cli nical s u p pl y la bel.
I n vesti gati o nal pr o d uct s h o ul d be st ore d i n its ori gi nal pac ka ge a n d s h o ul d be pr otecte d fr o m 
li g ht.  Site s yste ms m ust be ca pa ble of meas uri n g a n d d oc u me nti n g (e g, via a l o g), at a 
mi ni m u m, dail y  mi ni m u m a n d ma xi m u m te m perat ures f or all site st ora ge l ocati o ns (as 
a p plica ble, i ncl u di n g fr oze n, refri gerate d a n d/ or r o o m te m perat ure pr o d ucts).  T his s h o ul d be 
ca pt ure d fr o m t he ti me of i n ves ti gati o nal pr o d uct recei pt t hr o u g h o ut t he st u d y.  E ve n f or 
c o nti n u o us m o nit ori n g s yste ms, a l o g or site pr oce d ure t hat e ns ures acti ve dail y  e val uati o n 
f or e xc ursi o ns s h o ul d be a vaila ble.  T he o perati o n of t he te m perat ure m o nit ori n g de vice a n d 
st ora ge u nit (e g, refri gerat or), as a p plica ble, s h o ul d be re g ularl y i ns pecte d t o e ns ure it is 
mai ntai ne d i n w or ki n g or der.
A n y  e xc ursi o ns fr o m t he pr o d uct la bel st ora ge c o n diti o ns s h o ul d be re p orte d u p o n disc o ver y.  
T he site s h o ul d acti vel y p urs ue o p ti o ns f or ret ur ni n g t he pr o d uct t o t he st ora ge c o n diti o ns as 
descri be d i n t he cli nical s u p pl y  la bel, as s o o n as p ossi ble.  De viati o ns fr o m t he st ora ge 
re q uire me nts, i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d re p orte d t o t he s p o ns or.  
O nce a n e xc ur si o n is i de ntifie d, t he i n vesti gati o nal pr o d uct m ust be q uara nti ne d a n d n ot use d 
u ntil t he s p o ns or pr o vi des d oc u me n tati o n of per missi o n t o use t he i n vesti gati o nal pr o d uct.  It 
will n ot be c o nsi dere d a pr ot oc ol de viati o n if t he s p o ns or a p pr o ves t he use of t he 
i n vesti gati o nal pr o d uct after t he te m perat ure e xc ursi o n.  Use of t he i n vesti gati o nal pr o d uct 
pri or t o s p o ns or a p pr o val will be c o nsi dere d a pr ot oc ol de viati o n.
S pecific details re gar di n g i nf or mati o n t he site s h o ul d re p ort f or eac h e xc ursi o n will be 
pr o v i de d t o t he site.  Site staff will i nstr uct s u bjects o n t he pr o per st ora ge re q uire me nts f or 
ta ke h o me i n vesti gati o nal pr o d ucts.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1
5. 7. I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y 
T he i n vesti gati ve site m ust mai ntai n a de q uate rec or ds d oc u me nti n g t he recei pt, use, l oss , or 
ot her dis p osit i o n of t he i n vesti gati o nal pr o d uct s u p plies.  All st u d y dr u gs will be acc o u nte d 
f or usi n g a dr u g acc o u nta bilit y f or m/rec or d.  At eac h sc he d ule d cli nic visit, be gi n ni n g at t he 
M o nt h
6 visit, s u bjects will ret ur n use d a n d u n use d i n vesti gat i o nal pr o d uct a n d site pers o n nel 
will c ollect a n y u n use d me dici ne, deter mi ne d osa ges ta ke n, a n d st ore ret ur ne d dr u g f or 
dis p ositi o n.  See Secti o n 5. 3 f or d oc u me ntati o n of d osi n g c o m plia nce. 
5. 7. 1. Destr ucti o n of I n vest i g ati o n al Pr o d uct S u p plies 
T he s p o ns or or desi g nee will pr o vi de g ui da nce o n t he destr ucti o n of u n use d i n vesti gati o nal 
pr o d uct (e g, at t he site).  If destr ucti o n is a ut h orize d t o ta ke place at t he st u d y  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 nd a n y  special i nstr ucti o ns pr o vi de d b y  
Pfizer, a n d all destr ucti o n m ust be a de q uatel y d oc u me nte d.
5. 8. C o nc o mit a nt Tre at me nt(s)
Treat me nts ta ke n wit hi n 2 8 da y s bef ore t he first d ose of trial me dicati o n i n t his st u d y  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 trial me dicati o n will 
be d oc u me nte d as c o nc o mita nt treat me nts. 
C o nc o mita nt Treat me nt is defi ne d as o n g oi n g or i nitiate d a t a n y ti me o n or after Da y 1 of t he 
st u d y t hr o u g h t he fi nal st u d y visit.  C o nc o mita nt treat me nts i ncl u de a n y s u bsta nce i n geste d, 
i njecte d, a bs or be d, i n hale d, or t hat ot her wise e nters t he b o d y f or a t hera pe utic p ur p ose 
re gar dless of n u m ber of d oses ta ke n.  T his i ncl u des prescri pti o n a n d o ver -t he-c o u nter 
me dici nes, vita mi ns, a n d her bal re me dies.
S u bjec ts ma y use s u p ple me nts a n d me dicati o ns d uri n g t he c o urse of t he st u d y  wit h t he 
e xce pti o n of t h ose liste d i n Secti o n 4. 2 a n d Secti o n 5. 8. 1 .
5. 8. 1. Pr o hi bite d T her a pies
Use of N S AI Ds ot her t ha n t h ose n ote d bel o w was pr o hi bite d d uri n g partici pati o n i n pare nt 
st u d y B 3 4 6 1 0 2 8 a n d is pr o hi bite d d uri n g St u d y B 3 4 6 1 0 4 5.  S o me N S AI Ds, li ke difl u nisal, 
ca n bi n d t o t he t h yr o xi ne bi n di n g sites o n tra nst hyreti n ( Al mei da 2 0 0 4). 1  Per mitte d N S AI Ds 
i ncl u de: acetyl salic ylic aci d, et o d olac, i b u pr ofe n, i n d o met haci n, ket o pr ofe n, na b u met o ne, 
na pr o xe n, ni mes uli de, pir o xica m, a n d s uli n dac.  Use of a n y ot her N S AI Ds re q uire s 
a gree me nt wit h t he S p o ns or’s cli nicia n or me dical m o nit or.
1.
Use of a n y i n vesti gati o nal t hera p y d uri n g t he st u d y is n ot per mitte d.
2.
Use of difl u nisal, i n oterse n, or patisira n d uri n g t he st u d y  is pr o hi bite d. 
3.
Use of ta ur o urs o de o x yc h olate a n d d o x yc ycli ne is n ot per mitte d.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
4.
Di gitalis a n d calci u m c ha n nel bl oc kers (e g, vera pa mil, diltiaze m) are pr o hi bite d 
c o nc o mita nt me dicati o ns beca use t he y  bi n d t o a m yl oi d fi brils a n d m a y  lea d t o 
i ncrease d t o xicit y (Gertz 1 9 8 5 , R u bi n o w 1 9 8 1 , Ra pezzi 2 0 1 0 ).2 ,5 ,4
6. S T U D Y P R O C E D U R E S 
E ver y eff ort s h o ul d be m a de t o e ns ure t hat sc he d ule d visits are c o m plete d acc or di n g t o t he
Sc he d u le of Acti vities o n t he prescri be d da y s a n d 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. T here ma y be circ u msta nces, s uc h as a c o nstrai n t o n tra vel f or 
healt h -relate d reas o ns, i n w hic h a cli nic visit ma y n ot be p ossi ble. I n t hese cases, wit h pri or
disc ussi o n a n d a p pr o val fr o m t he s p o ns or, alter nati ve o pti o ns f or c o m pleti n g t he visit ma y be 
c o nsi dere d. A d diti o nall y, visits s h o ul d be c o m pl ete d as cl ose t o t he sc he d ule d ti mefra me as 
p ossi ble b ut n ot t o e xcee d t he visit wi n d o ws.  Visit wi n d o ws are base d o n tele p h o ne or cli nic 
visit da y s relati ve t o start of st u d y treat me nt ( Da y 1).
6. 1. Scree ni n g Visit 
6. 1. 1. Scree ni n g Visit C o h ort A ( D a y 0)
Scree ni n g V isit ( Da y 0) is t he M o nt h 3 0 E n d of St u d y  visit a n d last da y of treat me nt f or 
St u d y B 3 4 6 1 0 2 8.  S t u d y pr oce d ures a n d assess me nts will be perf or me d o nce per s u bject a n d 
t he pr ot oc ol-s pecifie d data will be re p orte d se paratel y f or eac h st u d y.  S u bjects pr o vi din g 
c o nse nt a n d f ulfilli n g t he i ncl usi o n/e xcl usi o n criteria will be e nr olle d, ra n d o mize d, a n d 
dis pe nse d st u d y  me dicati o n f or St u d y B 3 4 6 1 0 4 5 at t he sa me visit.  S u bjects will be 
i nstr ucte d t o start self-a d mi nistrati o n of tafa mi dis t he f oll o wi n g da y  ( Da y 1). 
If m ore t ha n 3 0 d a y s ha ve ela pse d fr o m t he B 3 4 6 1 0 2 8 E n d of St u d y visit, t he n vital si g ns, a 
bri ef p h ys ical e xa mi nati o n, cli nical la b orat or y tests, c o ntrace pti o n c hec k, c o nc o mita nt 
me dicati o ns, a d verse e ve nt re p orti n g m ust be perf or me d o n Da y 0 pri or t o e n r oll me nt.
Writte n s u bject i nf or me d c o nse nt will be o btai ne d pri or t o a n y st u d y -relate d pr oce d ures.
T he f oll o wi n g pr oce d ures will be c o n d ucte d d uri n g t he Scree ni n g/ Da y 0 visit:

All i ncl usi o n a n d e xcl usi o n criteria will be r e vie we d t o e ns ure eli gi bilit y f or 
partici pati o n i n t his st u d y  [ St u d y B 3 4 6 1 0 4 5 o nly] .

De m o gra p h y ( date of birt h, a ge, ge n der a n d ra ce) [ St u d y B 3 4 6 1 0 4 5 o nly] .

C o m plete me dical hist or y (i ncl u di n g hist or y  of heart fail ure) [ St u d y B 3 4 6 1 0 4 5 o nl y].

F ull p h y sical e xa mi nati o n i ncl u di n g wei g ht a n d h ei g ht meas ure me nts will be 
perf or me d.  If m ore t ha n 3 0 da y s ha ve ela pse d fr o m t he B 3 4 6 1 0 2 8 M o nt h 3 0 E n d of 
St u d y  visit, t he n a brief p h ysical e xa mi nati o n m ust be perf or me d o n Da y 0. 

Meas ure vital si g ns (s ys t olic a n d diast olic bl o o d press ure s u pi ne a n d stan di n g, p ulse 
rate s u pi ne a n d sta n di n g, res pirati o n rate, a n d b o dy te m perat ure).
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3

Si n gle 1 2 -lea d EC G - perf or m E C G pri or t o a n y bl o o d c ollecti o n or bl o o d press ure 
meas ure me nts.

C ollect bl o o d, a n d uri ne sa m ples f or t he f oll o wi n g cli nical la b orat ories.  If m ore t ha n 
3 0 da y s ha ve ela pse d fr o m t he B 3 4 6 1 0 2 8 M o nt h 3 0 E n d of St u d y  visit, t he n a ne w set 
of cli nical la b orat or y  tests m ust be perf or me d pri or t o e nr oll me nt a n d ra n d o mizati o n.

He mat ol o g y ;

Ser u m C he mistr y ;

C oa g ulati o n (I nter nati o nal n or malize d rati o [I N R], Pr ot hr o m bi n ti me [ P T]);

Uri nal y sis;

Uri ne pre g na nc y  test – f or w o me n of c hil d beari n g p ote ntial;

F ollicle -sti m ulati n g h or m o ne ( F S H) test – f or fe male s u bjects of n o n- c hil d beari n g 
p ote ntial w h o ha ve n ot ha d a h y sterect o my, bilateral o o p h orect o m y, or me dicall y 
c o nfir me d o varia n fail ure.  S u bjects w h o alrea d y c o nfir me d me n o pa use wit h a n 
F S H test i n St u d y B 3 4 6 1 0 2 8 d o n ot nee d t o re peat t his test.  T he F S H test is 
a p plica ble o nl y t o s u bjects ne wl y f ulf illi n g t he 1 2 c o nsec uti ve m o nt hs of 
a me n orr hea re q uire d t o ma k e t he dia g n osis of me n o pa use.

C o ntrace pti o n c hec k.

Ne w Y or k Heart Ass ociati o n ( N Y H A) classificat i o n.

A d mi nister Ka nsas Cit y  Car di o m yo pat h y Q uesti o n naire.

D oc u me ntati o n of vital stat us a n d tra ns p la nt or car diac mec ha nical assist de vice 
stat us. 

D oc u me ntati o n of c o nc o mita nt me dicati o ns.

A d verse e ve nt re p orti n g.

Treat me nt all ocati o n/ Ra n d o mizati o n a n d di s pe nse bli n de d i n vesti gati o nal pr o d uct.  
[ St u d y B 3 4 6 1 0 4 5 o nly] .

I nstr ucti o ns t o s u bjects t o self-ad mi nister bli n de d i n vesti gati o nal pr o d uct at h o me at 
t he sa me ti me e ver y da y be gi n ni n g o n Da y 1.  [ St u d y  B 3 4 6 1 0 4 5 o nly] .
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4
6. 1. 2. Scree ni n g Visit C o h ort B ( wit h dise as e d oc u me nt ati o n) ( D a y 0)
S u bjects pr o vi di n g c o nse nt a n d f ulfilli n g t he i ncl usi o n/e xcl usi o n criteri a will be e nr olle d a n d 
dis pe nse d st u d y  me dicati o n f or St u d y B 3 4 6 1 0 4 5 at t he sa me visit.  S u bjects will be 
i nstr ucte d t o start self-a d mi nistrati o n of tafa mi dis t he f oll o wi n g da y ( Da y 1). 
Writte n s u bject i nf or me d c o nse nt will be o btai ne d pri or t o a n y st u d y -relate d pr oce d ures.
T he f oll o wi n g pr oce d ures will be c o n d ucte d d uri n g t he Scree ni n g/ Da y 0 visit:

All i ncl usi o n a n d e xcl usi o n criteria will be re vie we d t o e ns u re eli gi bilit y f or 
partici pati o n i n t he st u d y .

C o m plete De m o gra p h y.

C o m plete me dical hist or y (i ncl u di n g hist or y  of heart fail ure).

F ull p h y sical e xa mi nati o n i ncl u di n g wei g ht a n d hei g ht meas ure me nts will be 
perf or me d. 

Meas ure vital si g ns (s ys t olic a n d diast olic bl o o d press ure s u pi ne a n d sta n di n g, p ulse 
rate s u pi ne a n d sta n di n g, res pirati o n rate, a n d b od y  te m perat ure).

Si n gle 1 2 -lea d E C G - perf or m E C G pri or t o a n y bl o o d c ollecti o n or bl o o d press ure 
meas ure me nts.

C ollect bl o o d, a n d uri ne sa m ples f or t he f oll o wi n g cli nical la b orat ories: 

He mat ol o g y ;

Ser u m C he mistr y ;

C oa g ulati o n (I nter nati o nal n or malize d ra ti o [IN R], Pr ot hr o m bi n ti me [ P T]);

N T -pr o B N P a n d tr o p o ni n I;

U ri nal ysis;

Uri ne pre g na nc y  test – f or w o me n of c hil d beari n g p ote ntial;

F ollicle -sti m ulati n g h or mo ne ( F S H) test – m a y  be use d t o c o nfir m a 
p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o ne 
re place me nt t hera py ( H R T).  Fe males o n H R T an d w h ose me n o pa usal stat us is i n 
d o u bt will be re q uire d t o use o ne of t he n o nestr o ge n h or m o nal h i g hly effecti ve 
c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir H R T d uri n g t he st u dy.  
Ot her wise, t he y  m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost men o pa usal 
stat us bef ore st u dy e nr oll me nt ( Secti o n 4. 3. 1 ).
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5

C ollect ba n ke d bi os peci me n.

C o ntrace pti o n c hec k. 

A d mi nister Ka nsas Cit y  Car di o m yo pat h y Q uesti o n naire.

Ne w Y or k Heart Ass ociati o n ( N Y H A) classificati o n.

C ollect d oc u me ntati o n of t he ge netic testi n g f or tra nst h y reti n a myl oi d osis (ie, ori gi nal 
la b orat or y res ult, or c o p y).  T he ori gi nal la b orat or y res ult, or c o p y will be part of t he 
s o urce d oc u me ntati o n.

C ollect d oc u me ntati o n of dia g n osis a n d criteria use d (e g, c o n gesti ve heart fail ure a n d 
sci nti gra p hy wit h tracer e g, 9 9 m T C D P D [ 9 9 m T C 3, 3 di p h os p h o n o 1, 2 pr o pa n o 
dicar b o x yl ic aci d], 9 9 m T C P Y P [ P yr o p h os p hate] a n d als o 9 9 m T C H M D P 
[ h ydr o x y m et h y le ne di p h os p h o nate] or prese nce of a m yl oi d de p osits i n bi o ps y  tiss ue, 
s uc h as fat as pirate, sali var y gla n d, me dia n ner ve c o n necti ve tiss ue s heat h, or car diac 
[a m yl oi d de m o nstrate d per a p pr o priate stai n s uc h as C o n g o re d or alcia n bl ue stai n]).  
T he ori gi nal la b orat or y  res ult, or c o p y will be part of t he s o urce d oc u me ntati o n.

C ollect d oc u me ntati o n t hat pri mar y  (li g ht c hai n) a m yl oi d osis disease has bee n 
eval uate d a n d r ule d o ut (ie, ori gi nal la b orat or y  res ult, or c o p y).  T he ori gi nal 
la b orat or y res ult, or c o p y will be part of t he s o urce d oc u me ntati o n.

D oc u me ntati o n of vital stat us a n d tra ns pla nt or car diac mec ha nical assist de vice 
stat us. 

D oc u me ntati o n of c o nc o mita nt me dicati o ns.

F or c o u ntries liste d i n A p pe n di x 6 : A d diti o n al s a m ple c ollecti o n pr oce d ures will be 
perf or me d at Scree ni n g ( D ay 0) . See A p pe n dix 7 f or pr oce d ure det ails.

A d verse e ve nt re p orti n g.

Treat me nt all ocati o n a n d dis pe nse bli n de d i n vesti gat i o nal pr o d uct. 

I nstr ucti o ns t o s u bjects t o self-a d mi nister bli n de d i n vesti gati o nal pr o d uct at h o me at 
t he sa me ti me e ver y da y be gi n ni n g o n Da y 1. 
6. 1. 3. Scree ni n g V isit ( D a y -3 0) C o h ort B S u bjects wit h o ut D oc u me nt ati o n of Di a g n osis 
Writte n s u bject i nf or me d c o n se nt will be o btai ne d pri or t o a n y st u d y-relate d pr oce d ures.
T he f oll o wi n g pr oce d ures will be c o n d ucte d d uri n g t he Scree ni n g/ Da y  -3 0 visit:

All i ncl usi o n a n d e xc l usi o n criteria will be re vie we d t o e ns ure eli gi bilit y f or 
partici pati o n i n t he st u d y .
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6

C o m plete De m o gra p h y.

C o m plete Me dical Hist or y  (i ncl u di n g hist or y of heart fail ure).

C ollect sa m ples f or disease dia g n osis: 

Ge n ot y pi n g;

Ser u m a n d uri ne test f or pri mar y  li g ht c hai n a myl oi d osis;

Tiss ue Bi o ps y.

D oc u me ntati o n of vital stat us a n d tra ns pla nt or car diac mec ha nical assist de vice 
stat us. 

D oc u me ntati o n of c o nc o mita nt me dicati o ns.

A d verse e ve nt re p orti n g.
6. 1. 4. S cree ni n g Visit ( D a y 0) C o h ort B ( wit h o ut dise ase d oc u me nt ati o n) 
T he f oll o wi n g pr oce d ures will be c o n d ucte d d uri n g t he Scree ni n g/ Da y 0 visit:
All i ncl usi o n a n d e xcl usi o n criteria will be re vie we d t o e ns ure eli gi bilit y f or partici pati o n i n 
t his st u d y.

F ull p h y sical e xa mi nati o n i ncl u di n g wei g ht a n d hei g ht meas ure me nts will be 
perf or me d. 

Meas ure vital si g ns (s ys t olic a n d diast olic bl o o d press ure s u pi ne a n d sta n di n g, p ulse 
rate s u pi ne a n d sta n di n g, res pirati o n rate, a n d b o dy te m perat ure).

Si n gle 1 2 -lea d E C G perf or m E C G pri or t o a ny bl o o d c ollecti o n or bl o o d press ure 
meas ure me nts.

C ollect bl o o d, a n d uri ne sa m ples f or t he f oll o wi n g cli nical la b orat ories: 

He mat o l o g y;

Ser u m C he mistr y ;

C oa g ulati o n (I nter nati o nal n or malize d rati o [I N R], Pr ot hr o m bi n ti me [ P T]);

N T - pro B N P a n d tr o p o ni n I ;

Uri nal y sis;

Uri ne pre g na nc y  test – f or w o me n of c hil d beari n g p ote ntial;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7

F ollicle -sti m ulati n g h or m o ne ( F S H) test – m a y  be use d t o c o nfir m a 
p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o ne 
re place me nt t hera py ( HR T).  Fe males o n H R T a n d w h ose me n o pa usal s tat us is i n 
d o u bt will be re q uire d t o use o ne of t he n o nestr o ge n h or m o nal hi g hl y effecti ve 
c o ntrace pti o n met h o ds if t he y  wis h t o c o nti n ue t heir H R T d uri n g t he st u dy.  
Ot her wise, t he y  m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal 
stat us bef ore st u d y e nr oll me nt ( Secti o n 4. 3. 1 ). 

C ollect ba n ke d bi os peci me n.

C o ntrace pti o n c hec k.

Ne w Y or k Heart Ass ociati o n ( N Y H A) classific ati o n.

A d mi nister Ka n sas Cit y Car di o m yo pat h y Q uesti o n naire.

D oc u me ntati o n of vital stat us a n d tra ns pla nt or car diac mec ha nical assist de vice 
stat us. 

D oc u me ntati o n of c o nc o mi ta nt me dicati o ns.

F or c o u ntries liste d i n A p pe n di x 6 : A d diti o n al s a m ple c ol lecti o n pr oce d ures will be 
perf or me d at Scree ni n g ( D ay 0) . See A p pe n dix 7 f or pr oce d ure det ails.

A d verse e ve nt re p orti n g.

Treat me nt all ocati o n a n d dis pe nse i n vesti gati o nal pr o d uct. 

I nstr ucti o ns t o s u bjects t o self-a d mi nister bli n de d i n vesti gati o nal pr o d uct at h ome at 
t he sa me ti me e ver y da y be gi n ni n g o n Da y 1.
6. 2. St u d y Peri o d
T he f oll o wi n g c hr o n ol o g y  of acti vities is s u g geste d f or cli nic visits:

E C G – Perf or m E C G pri or t o vital si g n a n d bl o o d s peci me n c ollecti o n.

Vital Si g ns – O bt ai n bl o o d press ure/ p ulse rate pri or t o bl o o d s peci me n c ollecti o n.

Bl o o d sa m ple c ollecti o n f or cli nical la b orat ories. 
All ot her pr oce d ures s h o ul d be o btai ne d after bl o o d s peci me n c ollecti o ns, u nless sa m pli n g is
deter mi ne d b y t he st u d y pers o n nel t o p ote ntia ll y i m pact t he res ults. 
6. 2. 1. D a y 1
S u bjects will self -a d mi nister i n vesti gati o nal pr o d uct at h o me.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8
6. 2. 2. Tele p h o ne Visits ( M o nt hs 3, 9, 1 5, 2 1, 2 7, 3 3, 3 9, 4 5, 5 1, 5 7) 2 Wee ks
T he cli nical site will c o ntact t he s u bject b y tele p h o ne t o i n q uire a b o ut a n y a d verse effec ts a n d 
t heir healt h stat us si nce t he pre vi o us cli nic visit.  Tele p h o ne visit pr oce d ures ma y als o be 
perf or me d at t he st u d y site.

T he site will c o ntact t he s u bject b y  p h o ne at a ti me a gree d wit h t he s u bject t o collect 
t he f oll o wi n g i nf or mati o n si nce t he clinic visit:

D oc u me ntati o n of c o nc o mita nt me dicati o ns;

A d verse e ve nts re p orti n g;

H os pitalizati o n deter mi nati o n.  Sites will deter mi ne w het her t he s u bject has bee n 
h os pitalize d a n d t he reas o n f or h os pitalizati o n;

C o ntrace pti o n c hec k;

D oc u me ntati o n of vital st at us a n d t ra ns pla nt or car diac mec ha nical assist de vice 
stat us.

At t he e n d of t he p h o ne call, t he ne xt cli nic a p p oi nt me nt will be c o nfir me d a n d t he 
s u bject will be re mi n de d t o rec or d a d verse e ve nts a n d me dicatio n use i n t he S u bject 
Dail y  D osi n g Diar y.  T he s u bject will be re mi n de d t o ret ur n t o t he cli nic wit h all 
dis pe nse d st u d y me dicati o n.

St u d y  site will dis pe nse i n vesti gati o nal pr o d uct b y s pecialize d IP c o urier.  T he I P 
c o urier will als o c ollect all pre vi o usl y dis pe nse d ( use d a n d u n use d) i n vesti gati o nal 
pr o d uct fr o m t he s u bject a n d ret ur n t o t he site f or acc o u nta bilit y .

F or c o u ntries liste d i n A p pe n di x 4. 2 : s u bjects will be re q uire d t o ret ur n t o t he st u dy 
site at M o nt h 3. Tele p h o n e visit pr oce d ures will be perf or me d.  T he f ol l o wi n g 
a d diti o n al pr oce d ures will als o be perf or me d at t he M o nt h 3 visit: 

Brief p hysic al ex a mi n ati o n i ncl u di n g wei g ht me as ure me nt;

C ollect all dis pe nse d ( use d a n d u n use d) i nvesti g ati o n al pr o d uct;

Si n gle 1 2 - Le a d E C G - perf or m E C G pri or t o a ny bl o o d c ollect i o n or bl o o d 
press ure me as ure me nts; 

Me as ure vit al si g ns (syst olic a n d di ast olic bl o o d press ure s u pi ne a n d st a n di n g, 
p ulse r ate s u pi ne a n d st a n di n g, res pir ati o n r ate, a n d b o dy te m per at ure);

C ollect bl o o d a n d ur i ne s a m ples f or t he f oll o wi n g cli nic al l a b or at ories:

He m at ol o gy;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
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
Ser u m C he mistry;

C o a g ul ati o n (I N R, P T);

N T - pr o B N P a n d tr o p o ni n I;

Uri n alysis.

Uri ne pre g n a ncy test – f or w o me n of c hil d be ari n g p ote nti al.

A d mi nister K a ns as City C ar di o my o p at hy Q uesti o n n aire.

N Y H A cl assific ati o n.

Rec or d c a ps ule c o u nt f or d osi n g a d here nce.

Dis pe nse bli n de d i nvesti g ati o n al pr o d uct.
6. 2. 3. Cli nic Visits ( M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4) 2 Wee ks
T he f oll o wi n g pr oce d ures will be perf or me d f or all s u b jects at cli nic visits:

Brief p h y sical e xa mi nati o n i ncl u di n g wei g ht meas ureme nt.

C ollect all dis pe nse d ( use d a n d u n use d) i n vesti gati o nal pr o d uct.

Si n gle 1 2 -Lea d E C G - perf or m E C G pri or t o a n y bl o o d c ollecti o n or bl o o d press ure 
meas ure me nts ( T o be perf or me d a n n uall y at M o nt hs 1 2, 2 4, 36, 4 8 or earl y 
disc o nti n uati o n).

Meas ure vital
si g ns (sys t olic a n d diast olic bl o o d press ure s u pi ne a n d sta n di n g, p ulse 
rate s u pi ne a n d sta n di n g, res pirati o n rate, a n d b o dy te m perat ure).

C ollect bl o o d a n d uri ne sa m ples f or t he f oll o wi n g cli nical la b orat orie s: 

He mat ol o g y ;

Ser u m C he mistr y ;

C oa g ulati o n ( I N R, P T);

N T -pr o B N P a n d tr o p o ni n I ;

Uri nal y sis;

Uri ne pre g na nc y  test – f or w o me n of c hil d beari n g p ote ntial.

A d mi nister Ka nsas Cit y  Car di o m yo pat h y Q uesti o n naire.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0

N Y H A classificati o n.

C o ntrace pti o n c hec k.

D oc u me n tati o n of c o nc o mita nt me dicati o ns.

Rec or d ca ps ule c o u nt f or d osi n g a d here nce.

A d verse e ve nt re p orti n g.

H os pitalizati o n deter mi nati o n.  Sites will deter mi ne w het her t he s u bject has bee n 
h os pitalize d a n d t he reas o n f or h os pitaliz ati o n.

D oc u me ntati o n of vital stat us, tra ns pla nt or car diac mec ha nical assist de vice stat us. 

Dis pe nse bli n de d i n vesti gati o nal pr o d uct.

Sc he d ule a date a n d ti me f or t he ne xt tele p h o ne visit.
6. 2. 4. E n d of St u d y Visit ( M o nt h 6 0) 2 wee ks or E arl y St u d y Disc o nti n u a ti o n
T he f oll o wi n g pr oce d ures will be perf or me d f or all s u bjects at t he M o n t h 6 0 visit or at t he 
ti me of Early St u d y Disc o nti n uati o n:

F ull p h y sical e xa mi nati o n i ncl u di n g wei g ht meas ure me nt.

C ollect all dis pe nse d i n vesti gati o nal pr o d uct. 

Si n gle 1 2 -Lea d E C G - perf or m E C Gs pri or t o a n y bl o o d c ollecti o n or bl o o d press ure 
meas ure me nt s.  E C G will be perf or me d o nl y if t he pre vi o us assess me nt occ urre d 
m ore t ha n si x m o nt hs pri or t o t he E n d of St u d y  visit. 

Meas ure vital si g ns (sys t olic a n d diast olic bl o o d press ure s u pi ne a n d sta n di n g, p ulse 
rate s u pi ne a n d sta n di n g, res pirati o n rate, a n d b o d y te m perat ure). 

C o ntrace pti o n c hec k.

C ollect bl o o d a n d uri ne sa m ples f or t he f oll o wi n g: 

He mat ol o g y ;

Ser u m C he mistr y ;

C oa g ulati o n (I N R, P T);

N T -pr o B N P a n d tr o p o ni n I ;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1

Uri nal y sis;

Uri ne pre g na nc y  test – f or w o me n of c hil d beari n g p ote ntial.

Ka nsas Cit y  Car di o m yo pat h y  Q uesti o n naire.

N Y H A classificati o n.

D oc u me ntati o n of c o nc o mita nt me dicati o ns.

Rec or d ca ps ule c o u nt f or d osi n g a d here nce.

A d verse e ve nt re p orti n g.

H os pitalizati o n deter mi nati o n.

D oc u me ntati o n of vi tal stat us, tra ns pla nt or car diac mec ha nical assist de vice stat us.

Sc he d ule date a n d ti me f or t he p ost- st u d y f oll o w-u p visit.
6. 3. P ost -st u d y F oll o w-u p Visit
S u bjects s h o ul d be f oll o we d f or 2 8 da y s after t he last d ose of St u d y Treat me nt t o c ollect a n y
A E/ S A E i n f or mati o n a n d perf or m a c o ntrace pti o n c hec k.  T his p ost -st u d y f oll o w-u p ca n be 
c o n d ucte d at t he st u d y site or b y tele p h o ne.  S u bjects w h o ha ve n ot f oll o we d c o ntrace pti o n 
re q uire me nts as deter mi ne d at t he ti me of t he p ost -st u d y tele p h o ne call will be as ke d t o 
c o nfir m pre g na nc y stat us. 
T he f oll o wi n g i n f or mati o n will be c ollecte d:

A d verse e ve nt re p orti n g (see Secti o n 8 ).

C o ntrace pti o n c hec k. 
6. 4. S u bject Wit h dr a w al a n d Vit al St at us/ Tr a ns pl a nt/ C ar di ac Mec h a nic al Assist De vice 
St at us F oll o w -u p
S u bj ects ma y wit h dra w fr o m t he st u d y at a n y ti me at t heir o w n re q uest, or t he y m a y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or or s p o ns or f or safet y or be ha vi oral 
reas o ns, or t he i na bilit y of t he s u bject t o c o m ply wit h t he pr ot oc ol re q uire d sc he d ule of st u dy 
visits or pr oce d ures at a gi ve n st u d y si te.
A release of Me dical I nf or mati o n F or m will be re q uire d of all s u bjects f or t he p ur p ose of 
access t o me dical rec or ds as well as f or o btai ni n g vital s tat us/tra ns pla nt/car diac mec ha nical 
assist de vice stat us f oll o w -u p wit h t he s u bject’s pri mar y  p h y sicia n or wit h deat h re gistries.  
T he si g ni n g of t his Release of Me dical I nf or mati o n F or m is i n a d diti o n t o t he I nf or me d 
C o nse nt D oc u me nt.  I n s o me cases, site s ma y c o m bi ne t hese t w o f or ms i nt o a si n gle f or m, as 
is t heir sta n dar d practice.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
I n t he sit uati o n w here t he s u bject or t he alter nati ve desi g nate d c o ntact (ie, i n di vi d ual 
i de ntifie d i n t he Release of Me dical I nf or mati o n F or m) ca n n ot be reac he d, atte m pts will be 
ma de t o ascertai n t he vital stat us/tra ns p la nt/car diac mec ha nical assist de vice stat us of t he 
s u bject b y searc hi n g t he a p pr o priate nati o nal or re gi o nal vital stat us re gistr y or ot her rele va nt 
data bases, w here a vaila ble a n d all o wa ble b y l ocal la w.  De pe n di n g o n t he l ocal la w, t his 
searc h will be c on d ucte d b y  t he e nr olli n g p hys icia n or a desi g nee at t he st u d y site.
If a s u bject d oes n ot ret ur n f or a sc he d ule d visit, e ver y eff ort s h o ul d be ma de t o c o ntact t he 
s u bject.  T he site s h o ul d ma ke a mi ni m u m of 3 d oc u me nte d p h o ne calls f oll o we d b y  a 
re gistere d letter i n q uiri n g a b o ut t he reas o n f or lac k of ret ur n f or t he sc he d ule d a p p oi nt me nt.  
I n a ny circ u msta nce, e ver y eff ort s h o ul d be ma de t o d oc u me nt s u bject o utc o me, if p ossi ble, 
i ncl u di n g t he s u bject’s vital stat us/tra ns pla nt/car diac mec ha nical assist de vice stat us t hr o u g h 
6 0 m o nt hs f oll o wi n g t he Scree ni n g visit.  T he i n vesti gat or s h o ul d i n q uire a b o ut t he reas o n 
f or wit h dra wal, re q uest t hat t he s u bject ret ur n f or a fi nal st u d y visit (if a p plica ble) a n d t o 
ret ur n all u n use d i n vesti gati o nal pr o d uct(s), a n d f ol l o w-u p wit h t he s u bject re gar di n g a n y 
u nres ol ve d a d verse e ve nts ( A Es).
If t he s u bject wit h dra ws fr o m t he st u d y, a n d als o wit h dra ws c o nse nt f or discl os ure of f ut ure 
i nf or mati o n, n o f urt her e val uati o ns s h o ul d be perf or me d, a n d n o a d diti o nal data s h o ul d be 
c ollecte d, e xce pt f or ascertai ni n g vital stat us/tra ns pla nt/car diac mec ha nical assist de vice 
stat us at 6 0 m o nt hs after Scree ni n g.  T he s p o ns or ma y  retai n a n d c o nti n ue t o use a n y data 
c ollecte d bef ore s uc h wit h dra w al of c o nse nt.  S u bjects re q uesti n g wit h dra wal s h o ul d be 
i nf or me d t hat wit h dra wal of c o nse nt for f oll o w -u p will je o par dize t he p u blic healt h val ue of 
t he st u d y.  At t he ti me of wit h dra wal, s u bjects will be as ke d a b o ut t he c o ntri b uti o n of 
p ossi ble a d verse e ve nts t o t heir decisi o n t o wit h dra w c o nse nt a n d a n y a d verse e ve nt 
i nf or mati o n elicite d will be d oc u me nte d.  Prefera bl y  t he s u bject s h o ul d wit h dra w c o nse nt i n 
writi n g a n d, if t he s u bject or t he s u bject’s re prese ntati ve ref uses or is p h ysicall y u na vaila ble, 
t he site s h o ul d d oc u me nt a n d si g n t he reas o n f or t he s u bject’s fail ure t o wit h dra w c o nse nt i n 
writi n g.
6. 4. 1. S u bject Wit h dr a w al f or He art or Li ver Tr a ns pl a nt ati o n or I m pl a nt ati o n of 
C ar di ac Mec h a nic al Assist De vice
S u bjects ma y  be o n a tra ns pla nt list at t he ti me of ra n d o mizati o n/e nr oll me nt i n t he st u d y.  
H o we ver, if a s u bject c h o oses t o acce pt a d o n or o r ga n tra ns pla nt d uri n g t he st u d y or 
u n der g oes i m pla ntati o n of a car diac mec ha nical assist de vice, t he y  will st o p ta ki n g bli n de d 
st u d y me dicati o n a n d be disc o nti n ue d fr o m st u d y partici pati o n pri or t o t he tra nspla nt 
o perati o n.  Vital stat us/tra ns pla nt stat us f or t he s u bject will be esta blis he d t hr o u g h 6 0 m o nt hs 
f oll o wi n g t he Scree ni n g visit.  S u bjects w h o disc o nti n ue fr o m t he st u d y d ue t o 
tra ns pla ntati o n or i m pla ntati o n of a car diac mec ha nical assist de vice will be ha n dle d i n t he 
statistical a nal ysis as descri be d i n Secti o n 9. 2. 1 .
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
7. A S S E S S M E N T S
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat t he pr ot oc ol-re q uire d tests a n d pr oce d ures are 
c o m plete d as descri be d.  H o we ver, it is a ntici pate d t hat fr o m ti me t o ti me t here ma y  be 
circ u msta nces o utsi de of 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.  I n t hese cases t he i n vesti gat or will ta ke all ste ps necessar y t o e ns ure t he 
safety a n d well -bei n g of t he s u bject.  W he n a pr ot oc ol -re q uire d test ca n n ot be perf or me d, t he 
i n vesti gat or will d oc u me nt t he reas o n f or t his a n d a n y c orrecti ve a n d pre ve nti ve acti o ns t hat 
he or s he has ta ke n t o e ns u re t hat n or mal pr ocesses are ad here d t o as s o o n as p ossi ble.  T he 
st u d y tea m will be i nf or me d of t hese i nci de nts i n a ti mel y ma n ner.
7. 1. S afet y Assess me nts
7. 1. 1. Me dic al Hist or y
A c o m plete me dical hist or y  is t o be d oc u me nte d f or all s u bjects at t he Scree ni n g visit. T his 
me dical hist or y  will d ocu me nt t he s pecif ic sy m pt o ms t he s u bject re p orts ass ociate d wit h 
A T T R -C M, as well as a n y  a d diti o nal c o-m or bi d c o n diti o ns or s y m pt o ms. 
7. 1. 2. P h ysic al E x a mi n ati o n a n d Hei g ht Me as ure me nts
All s u bjects will u n der g o a f ull p h y sical e xa minati o n at t he Scree ni n g visit a n d t he E n d of 
S t u d y or Earl y Disc o nti n uati o n Visit, i ncl u di n g assess me nt of t he f oll o wi n g b o d y sys te ms:
Ge neral a p peara nce
Ne ur ol o gical
Hea d a n d nec k
Car di o vasc ular
E y es
A b d o me n
Ears
S ki n
N ose
M usc ul os keletal
T hr oat
Res p irat or y
Ge nit o uri nar y
Brief p h ys ical e xa mi nati o ns, i ncl u di n g assess me nt of ge neral a p peara nce, car di o vasc ular, 
res pirat or y, a n d gastr oi ntesti nal s yste ms, are t o be perf or me d at all cli nic visits ( M o nt hs 6, 
1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4).  Brief p hysic a l ex a mi n ati o n a n d wei g ht me as ure me nt will als o
be perf or me d at M o nt h 3 ( C o u ntries liste d i n A p pe n dix 4. 2 ).
Meas ure me nt of hei g ht i n ce nti meters (c m) will be perf or me d at t h e Scree ni n g visit o nl y.
7. 1. 3. Vit al Si g ns
Vital si g ns (i ncl u d i n g b o d y te m perat ure, s yst olic a n d diast olic bl o o d press ure, p ulse rate a n d 
res pirati o n rate) will be assesse d a n d rec or de d at t he Scree ni n g visit, at e ver y cli nic visit, a n d 
at t he E n d of St u d y/ Early Disc o nti n uati o n visit.  Vit al Si g ns will als o be assess e d at 
M o nt h 3 ( C o u ntries liste d i n A p pe n dix 4. 2 ).
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 4
S u pi ne a n d sta n di n g bl o o d press ure will be meas ure d wit h t he s u bject’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.  T he sa me ar m ( prefera bl y t he 
d o mi na nt ar m) will be use d t hr o u g h o ut t he tria l.  T he s u bject s h o ul d be s u pi ne f or at least 
3 mi n utes bef ore t he s u pi ne bl o o d press ure is o btai ne d.  Sta n di n g bl o o d press ure s h o ul d t he n 
be meas ure d a p pr o xi matel y  2 mi n utes after t he s u bject ass u mes t he sta n di n g p ositi o n. 
T he sa me size bl o o d press ure c u ff, w hic h has bee n pr o perly cali brate d, will be use d t o 
meas ure bl o o d press ure at eac h ti me p oi nt.  T he use of a ut o mate d de vic es f or meas uri n g B P 
a n d p ulse rate is acce pta ble, alt h o u g h w he n perf or me d ma n uall y , p ulse rate will be meas ure d 
i n t he brac hial/radial 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, bl o o d press ure 
a n d p ulse rate s h o ul d be o btai ne d pri or t o t he n o mi nal ti me of t he bl o o d c ollecti o n.
7. 1. 4. Electr oc ar di o gr a m
A 1 2 -lea d electr ocar di o gra m ( E C G) will be perf or me d f or all s u bjects at Scree ni n g a n d 
a n n ual visits at M o nt hs 1 2, 2 4, 3 6, 4 8, 6 0 or earl y ter mi nati o n visit.  A 1 2 -le a d E C G will als o 
be perf or me d at M o nt h 3 ( C o u ntries liste d i n A p pe n dix 4. 2 ).  W here p ossi ble, E C Gs will be 
perf or me d pri or t o bl o o d press ure or p ulse meas ure me nts or bl o o d c ollecti o n.  All sc he d ule d 
E C Gs s h o ul d be perf or me d after t he s u bject has reste d q uietl y  f or at least 5 mi n utes i n a 
s u pi ne p ositi o n.
T he f oll o wi n g E C G para meters will be as sesse d: P R, R R, Q R S, Q T, a n d Q Tc ( B a n d F) 
i nter val (c orrected E C G Q T I nter val usi n g t he Bazett’s or Fri dericia’s c orrecti o n), heart rate, 
a n d o verall i nter pretati o n, wit h rec or di n g of a n y a b n or mal fi n di n gs.  T e n- sec o n d r h yt h m 
stri ps will acc o m pa ny eac h E C G.  F or t he Scree ni n g visit, eac h E C G will be rec or de d a n d 
rea d l ocall y b y t he cli nical site, a n d t he cli nical si g nifica nce of E C G fi n di n gs will be assesse d 
b y  t he i n vesti gat or.
I n a d diti o n, f or o verall a nal ysis of t he E C G para meters, eac h E C G will be di gitalize d a n d 
se nt t o a n i n de pe n de nt E C G la b orat or y t hat will c o n d uct a ce ntralize d re vie w of t he res ults 
f or c o nfir mati o n b y a n i n de pe n de nt car di ol o gist.
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 are 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 a n d c o nsiste nt E C G rec or di n gs.  If a 
mac hi ne -rea d Q Tc val ue is pr ol o n ge d, repeat meas ure me nts ma y  n ot be necessar y if a 
q u alifie d p h ysicia n’s i nter pretati o n deter mi nes t hat t he Q Tc val ues are i n t he acce pta ble 
ra n ge. 
Detaile d i nstr ucti o ns f or perf or mi n g E C Gs are pr o vi de d i n a se parate st u d y la b orat or y 
ma n ual ( Ce ntralize d E C G Pr oc e d ure Ma n ual).
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 5
7. 1. 5. Cli nic al L a b or at or y Tests
Bl o o d / uri ne sa m ples f or ser u m c he mistr y, c oa g ulati o n, he mat ol o g y, a n d uri nal ysis will be 
c ollecte d at Scree ni n g, a n d eac h cli nic visit at M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4, a n d 
6 0 ( E n d of St u d y  visit) or Early Ter mi nati o n Visit.  Bl o o d/ uri ne s a m ples will als o be 
c ollecte d at M o nt h 3 ( C o u ntries liste d i n A p pe n dix 4. 2 ).
T he f oll o wi n g cli nical la b orat or y  para meters will be assesse d:
Ser u m C he mistr y
S o di u m
Al ka li ne P h os p hatase
Reti n ol bi n di n g pr otei n
P otassi u m
Gl uc ose
Ga m ma gl ut a m yl tra nsferase
C hl ori de
T otal bilir u bi n
C h olester ol
Bicar b o nate
T otal pr otei n
Uric aci d
Bl o o d Urea Nitr o ge n
Al b u mi n
T h y r oi d-sti m ulati n g h or m o ne
Creati ni ne
Gl o b uli n
T otal t h yr o xi ne ( T 4)
Calci u m
I n or ga nic P h os p h or us
Free T 4
Ala ni ne 
a mi n otra nsferase ( A L T)
As partate 
a mi n otra nsferase ( A S T)
He m at ol o g y
He m o gl o bi n ( H g b)
W hite bl o o d cell c o u nt
L y m p h oc y tes
He mat ocrit
Ne utr o p hils
M o n oc y tes
Re d bl o o d cell c o u nt
L y m p h oc y tes
E osi n o p hils
Mea n c or p usc ular v ol u me
Platelets
Bas o p hils
Mea n c or p usc ular 
he m o gl o b i n
Mea n c or p usc ular 
he m o gl o bi n c o nce ntrati o n
C ar di ac Bi o m ar kers
N T -pr o B N P
Tr o p o ni n I
C o a g ul ati o n (t o be me as ure d i n site’s l oc al l a b or at or y)
Pr ot hr o m bi n ti me ( P T)
I nter nati o nal n or malize d rati o (I N R)
U ri n al ysis
p H
Bl o o d (free H g b)
Pr otei n
Nitrit e
Gl uc ose
Ur o bili n o ge n
Ket o nes
S pecific gra vit y
Bilir u bi n
Le u k oc y te esterase
Uri nal y sis will be a q ualitati ve deter mi nati o n b y di pstic k at t he site.  If t he uri ne di pstic k 
de m o nstrates a p ositi ve bl o o d, pr o tei n, nitrites or le u k oc yte esterase res ult, the s peci me n will 
be se nt t o t he Ce ntral La b orat or y  f or micr osc o pic e val uati o n.  In t he e ve nt t hat a site is 
u na ble t o perf or m a uri ne di pstic k wit h all of t he re q uire d tests, it is acce pta ble f or t he sa m ple 
t o be se nt f or uri nal ys is i ncl u di n g a micr osc o pic e val uati o n i n place of a di pstic k.  T his 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 6
testi n g ca n be perf or me d at eit her t he ce ntral or l ocal la b orat or y.  At mi ni m u m, t his testi n g 
s h o ul d i ncl u de p H, pr otei n, gl uc ose, ket o nes, bilir u bi n, bl o o d (free H g b), nitrite, le u k oc y te 
esterase, ur o bili n o ge n, a n d s pecific gra vit y .  If t he testi n g ret ur ns a n a b n or mal res ult, 
a d diti o nal testi n g s h o ul d be perf or me d as dee me d necessar y  acc or di n g t o t he cli nical 
j u d g me nt of t he i n vesti gat or.
S pecificati o ns f or sa m ple c olle cti o n are pr o vi de d i n t he st u d y la b orat or y ma nual.
7. 2. Pre g n a nc y Testi n g
F or fe male s u bjects of c hil d beari n g p ote ntial, a uri ne pre g na nc y  test, wit h se nsiti vit y of at 
least 2 5 mI U/ m L , will be perf or me d, bef ore i n vesti gati o nal pr o d uct a d mi nistrati o n at t he 
Scre e ni n g visit, at e ver y cli nic visit, a n d at t he E n d of St u d y  or early ter mi nati o n visit. A 
pre g n a ncy test will als o be perf or me d at M o nt h 3 ( C o u ntries liste d i n A p pe n dix 4. 2 ).  A 
ne gati ve pre g na nc y  res ult is re q uire d bef ore t he s u bject ma y recei ve t he i n vesti gati o nal 
pr o d u ct.  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 re peate d at 
all st u d y visits a n d at t he en d of t he st u d y t o c o nfi r m t he s u bject has n ot bec o me pre g na nt 
d uri n g t he st u d y.  Pre g na nc y tests ma y als o be re peate d as per re q uest of i nstit uti o nal re vie w 
b oar ds (I R Bs)/et hics c o m mittees ( E Cs) or if re q uire d b y  l ocal re g ulati o ns. 
I n t he case of a p ositi ve c o nfir me d pre g na nc y, t he s u bject will be wit h dra w n fr o m 
a d mi nistrati o n of i n vesti gati o nal pr o d uct a n d fr o m t he st u d y .
7. 3. C o ntr ace pti o n C hec k
F or fe male s u bjects w h o, i n t he o pi ni o n of t he i n vesti gat or, are bi ol o gicall y ca pa ble of ha vi n g 
c hil dre n a n d are s e x uall y acti ve; at eac h tele p h o ne a n d cli nic visit, disc uss wit h t he s u bject 
t he nee d t o use hi g hly effecti ve c o ntrace pti o n c o nsiste ntl y  a n d c orrectl y, i nstr uct t he s u bject 
t o call i m me diatel y if a selecte d birt h c o ntr ol met h o d is disc o nti n ue d or if pre g nan c y  is 
k n o w n or s us pecte d a n d d oc u me nt s uc h c o n versati o n i n t he case re p ort f or m.  S u bjects will 
be i nstr ucte d t o c o nti n ue use of birt h c o ntr ol f or at least 2 8 d a y s after st u d y partici pati o n.  
S u bjects w h o ha ve n ot f oll o we d c o ntrace pti o n re q uire me nts as de ter mi ne d at t he ti me of t he 
p ost -st u d y tele p h one call will be as ke d t o c o nfir m pre g na nc y  stat us.
7. 4. Ot her Assess me nts
7. 4. 1. Ne w Y or k He art Ass oci ati o n Cl assific ati o n
S u bjects will be e val uate d usi n g t he Ne w Y or k Heart Ass ociati o n ( N Y H A) classificati o n 
(A p pe n di x 3 ) at t he Scree ni n g visit a n d at M o nt h 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4, 6 0 ( or 
Earl y St u d y Disc o nti n uati o n visit).  N Y H A will als o be ev al u ate d at M o nt h 3 ( C o u ntries 
liste d i n A p pe n dix 4. 2 ).
Ne w Y or k Heart Ass ociati o n ( N Y H A) Classificati o n:
Cl a ss I: S u bjects wit h car diac disease b ut wit h o ut res ulti n g li mitati o ns of p h y sical acti vit y.  
Or di nar y  p h ysical acti vit y d oes n ot ca use u n d ue fati g ue, pal pitati o n, d ys p nea, or a n gi nal 
pai n.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 7
Cl ass II: S u bjects wi t h car diac disease res ulti n g i n sli g ht li mitati o n of p h ysical acti vit y.  
T he y  are c o mf orta ble at rest.  Or di nar y p h ysical acti vit y res ults i n fati g ue, pal pitati o n, 
d y s p nea, or a n gi na pai n.
Cl ass III: S u bjects wit h car diac disease res ulti n g i n mar ke d li mita ti o n of p h ysical acti vit y.  
T he y  are c o mf orta ble at rest.  Less t ha n or di nar y p h ysical acti vit y ca uses fati g ue, pal pitati o n, 
d y s p nea, or a n gi nal pai n.
Cl ass I V: S u bjects wit h car diac disease res ulti n g i n i na bilit y  t o carr y o n a n y p h ysical acti vit y 
wit h o ut disc o mf ort.  S y m pt o ms of car diac i ns ufficie nc y or of t he a n gi nal s y n dr o me ma y  be 
prese nt e ve n at rest.  If a n y  p h ysical acti vit y is u n derta ke n, disc o mfort is i ncrease d.
7. 4. 2. K a ns as Cit y C ar di o m y o p at h y Q uesti o n n aire
T he Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire ( K C C Q) ( Gree n 2 0 0 0) 3 is a 2 3-ite m 
s u bject-c o m plete d q uesti o n naire t hat assesses healt h stat us a n d healt h-relate d q ualit y of life 
i n s u bjects wit h heart fail ure.  Ite ms assess t he a bilit y t o perf or m acti vities of dail y  li vi n g, 
fre q ue nc y a n d se verity of s y m pt o ms, t he i m pact of t hese s y m pt o ms , a n d healt h-relate d 
q ualit y  of life.  Res p o nse o pti o ns var y b y q uesti o n.  Sc ori n g yiel ds sc ores f or 8 d o mai ns 
( P h ysical li mitati o n, S ym pt o m sta bilit y , S ym pt o ms fre q ue nc y , S ym pt o m b ur de n, T otal 
s ym pt o m, Self efficac y , S ocial li mitati o n, a n d Q ualit y of life) a n d Cli nical s u m mar y sc ore, as 
well as a n O verall S u m mar y  sc ore.  D o mai n sc ores are tra nsf or me d t o a 0 t o 1 0 0 ra n ge; 
hi g her sc ores i n dicate better healt h stat us.  It ta kes a p pr o xi matel y  4- 6 mi n utes f or a s u bject t o 
c o m plet e t he K C C Q.
S u bjects will c o m ple te t he K C C Q at t he Scree ni n g visit a n d at M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 3 6, 
4 2, 4 8, 5 4, a n d 6 0 ( or Earl y  St u d y Disc o nti n uati o n) as liste d i n t he Sc he d ule of Ac ti vities.  
S u bjects will als o c o m plete K C C Q at M o nt h 3 ( C o u ntries liste d i n A p pe n dix 4. 2 ).
St u d y  sites will be pr o vi de d wit h a n a p pr o ve d tra nslate d versi o n of t he K C C Q.  T he K C C Q 
ca n be f o u n d i n A p pe n di x 2 .
7. 4. 3. B o d y M ass I n de x/ M o difie d B o d y M ass I n de x
Tra nst h y reti n, i n t he m o n o meric f or m, ca n e nter car diac a n d ne ural tiss ues.  As part of t he 
p ol y ne ur o pat h y , T T R ca n ca use se vere gastr oi ntesti nal pr o ble ms res ulti n g i n wasti n g.  A 
mea ns of deter mi ni n g if t here is gastr oi ntesti nal i n v ol ve me nt i n s u bjec ts is t o calc ulate t he 
m o difie d B o d y Mass I n de x ( m B MI).  B o d y M ass I n de x ( B MI) is calc ulate d as wei g ht 
( k g)/[ hei g ht ( meters)]2.  T he mB MI is calc ulate d b y  m ulti pl yi n g B MI by s er u m al b u mi n 
c o nce ntrati o n ( g/ L).
7. 4. 4. T esti n g f or Li g ht C h ai n A m yl oi d
S pecificati o ns f or testi n g sa m ples are pr o vi de d i n t he st u d y la b orat or y ma n ual.  El derly 
s u bjects wit h re d uce d re nal f u ncti o n ma y e x perie nce ele vati ons i n le vels of free ka p pa li g ht 
c hai ns a n d free la m b da li g ht c hai ns wit h n o c ha n ge i n t he ka p pa/la m b da rati o.  S u bjects w it h 
ele vate d ser u m/ uri ne le vels of free ka p pa li g ht c hai n, free la m b da li g ht c hai n a n d a free 
ka p pa/la m b da rati o i n dicati ve of li g ht c hai n a m yl oi d osis ( M G U S) will re q uire c o nfir mat or y  
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
test usi n g mass s pectr o metr y or i m m u n o hist oc he mistr y wit h electr o n micr osc o p y or 
sci nti gra p hy.
7. 4. 5. Bi o ps y D oc u me nt ati o n of A m yl oi d De p ositi o n
F or C o h ort B o nl y.  I n t he e ve nt t hat t here is n o d oc u me ntati o n of pri or bi o ps y a n d 
de m o nstrati o n of T T R a m y l oi d de p ositi o n b y eit her mass s pectr o metr y, 
i m m u n o hist oc he mistr y or sci nti gra p h y [ See Secti o n 4. 1. 2 ], car diac or n o n-car diac tiss ue will 
be bi o psie d a n d teste d b y t he i n vesti gati o nal site as per t he site’s sta n dar d of care a n d 
eval uate d wit h C o n g o re d stai n or alcia n bl ue s tai n.
Stai ne d tis s ue will be vie we d u n der p olarize d li g ht use d t o de m o nstrate a m yl oi d 
c haracteristic ‘a p ple-gree n’ birefri n ge nce.  F or s u bjects wit h o ut i de ntificati o n of a T T R 
varia nt a n d de m o nstrati o n of a m y l oi d de p ositi o n w h o ma y ha ve a dia g n osis of wil d-t ype 
A T T R - C M, a nal ys is will be perf or me d t o c o nfir m t he prec urs or pr otei n basis f or a myl oi d 
de p ositi o n, b y  eit her: mass s pectr o metr y, i m m u n o hist oc he mistr y or sci nti gra p h y [see 
Secti o n 4. 1. 2 ].
7. 4. 6. T T R Ge n ot y pi n g
F or C o h ort B o nl y:  S u bjects wit h a d oc u me nte d pri or ge n oty pi n g a n d t he ori gi nal la b orat or y  
res ult or c o py f or s o urce d oc u me ntati o n will n ot re q uire a d diti o nal ge n ot y p i n g.  S u bjects 
wit h o ut pri or ge n ot y pi n g will re q uire c ollecti o n of a bl o o d sa m ple f or T T R ge n oty p e testi n g.  
T he sa m ple will be se nt t o a refere nce la b orat or y  f or c o m plete ge n o mic se q ue nci n g.
C o m plete i nf or mati o n o n sa m ple c ollecti o n, st ora ge, a n d sa m ple tra ns p ort f or ge n ot y pe 
c o nfirm ati o n are detaile d i n a se parate la b orat or y  man ual.
7. 5. B a n ke d Bi os peci me ns
F or C o h ort B o nl y:  Ba n ke d bi os peci me ns will be c ollecte d fr o m s u bjects f or e x pl orat or y 
researc h relati n g t o t he dr u g res p o nse.  T hese c ollecti o ns are n ot t y picall y ass ociate d wit h a 
p la n ne d assess me nt descri be d i n t he pr ot oc ol .  The y  will be ha n dle d i n a ma n ner t hat pr otects 
eac h s u bject’s pri vac y a n d c o nfi de ntialit y.  Ba n ke d bi os peci me ns will be assi g ne d t he 
s u bject’s st u d y i de ntificati o n c o de (I D) at t he site.  T he data ge nerate d fr o m t hese ba n ke d 
bi os peci me ns will als o be i n de xe d b y  t his I D.  Bi os peci me ns will be ke pt u ntil destr ucti o n i n 
facilities wit h access li mite d t o a ut h orize d pers o n nel, a n d bi os peci me n-deri ve d data will be 
st ore d o n pass w or d-pr otecte d c o m p uter s ys te ms.  T he key bet wee n t he s u bject’s I D a n d t he 
s u bject’s direct pers o nall y i de ntif yi n g i nf or mati o n (e g, na me, a d dress) will be hel d at t he 
st u d y site.  Bi os peci me ns will be use d o nl y f or t he p ur p oses descri be d i n t he pr ot oc ol a n d 
i nf or me d c o nse nt d oc u me nt; a n y ot her uses re q uire a d diti o nal et hical a p pr o val.  U nles s a 
ti me li mitati o n is re q uire d b y l ocal re g ulati o ns or et hical re q uire me nts, bi os peci me ns will be 
st ore d f or ma ny ye ars ( n o ti me li mit) t o all o w f or researc h i n t he f ut ure, i ncl u di n g researc h 
c o n d ucte d d uri n g t he le n gt hy dr u g -de vel o p me nt pr ocess a n d als o p ost mar keti n g researc h.  
S u bjects ma y  wit h dra w t heir c o nse nt f or t he use of t heir ba n ke d bi os peci me ns at a n y ti me b y 
ma ki n g a re q uest t o t he i n vesti gat or; i n t his case, a n y  re mai ni n g bi os peci me ns will be 
destr o ye d, b ut data alrea d y  ge nerate d fr o m t he bi os peci me ns will c o nti n ue t o be a vaila ble t o 
pr otect t he i nte grit y of e xisti n g a nal ys es. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
U nless pr o hi bite d b y  l ocal re g ulati o ns or et hics c o m mittee decisi o n, a 4 -m L bl o o d ge n o mic 
ba n ke d bi os peci me n Pre p D 1 ( di p ota ssi u m e detic aci d [et h yle ne di a mi netetr a acetic aci d] 
[ K2E D T A] w h ole - bl o o d c ollecti o n o pti mize d f or D N A a n al ysis) will be c ollecte d at t he 
ti me s pecifie d i n t he Sc he d ule of Acti vities /St u d y Pr oce d u res secti o n of t he pr ot oc ol t o be 
retai ne d f or p ote ntial p har mac o ge n o mic/ ge n o mic/ bi o mar ker a nalys es relate d t o dr u g 
res p o nse.  F or e xa m ple, p utati ve safety bi o mar kers, dr u g -meta b olizi n g e nz y me ge nes, 
dr u g -tra ns p ort pr otei n ge nes, or ge nes t h o u g ht t o be relate d t o t he mec ha nis m of dr u g acti o n 
ma y  be exa mi ne d.  T he pri mar y  p ur p ose is t o e xa mi ne D N A; h o we ver, t he bi os peci me n ma y 
als o be use d t o st u d y ot her m olec ules (e g, R N A, pr otei ns, a n d meta b olites).
F or c o u ntries liste d i n A p pe n dix 6 , ad diti o n al b a nke d bi o m arker s a m ples ( bl o o d: Pre p R 1
o pti mize d f or R N A ; Pre p B 1 o pti mize d f or pl as m a; uri ne: Pre p M 2) will be c ollecte d at 
Scree ni n g ( D ay 0) f or p ote nti al rese arc h rel ate d t o t he dise ase u n der st u dy. See A p pe n dix 7
f or det ails.
T he ba n ke d bi os peci me n s will be collecte d fr o m s u bjects i n u nless pr o hi bite d b y  l ocal 
re g ulati o ns or I R B/ E C decisi o n.  It is p ossi ble t hat t he use of t hese bi os peci me ns ma y res ult 
i n c o m mercially via ble pr o d ucts.  S u bjects will be a d vise d i n t he i nf or me d c o nse nt d oc u me nt 
t hat th e y will n ot be c o m pe nsate d i n t his e ve nt.
7. 5. 1. A d diti o n al Rese arc h
U nless pr o hi bite d b y  l ocal re g ulati o ns or I R B/ E C decisi o n, s u bjects will be as ke d t o i n dicate 
o n t he c o nse nt f or m w het her t he y  will all o w ba n ke d bi os peci me ns t o als o be use d t o desi g n 
a n d c o n d u ct researc h i n or der t o gai n a f urt her u n dersta n di n g of ot her diseases a n d t o 
a d va nce scie nce, i ncl u di n g de vel o p me nt of ot her me dici nes f or patie nts.
S u bjects nee d n ot pr o vi de a d diti o nal bi os peci me ns f or t he uses descri be d i n t his secti o n; t he 
bi os peci me ns s pecifie d i n t he Ba n ke d Bi os peci me ns secti o n will be use d.  S u bjects ma y still 
partici pate i n t he st u d y if t he y elect n ot t o all o w t heir ba n ke d bi os peci me ns t o be use d f or t he 
a d diti o nal p ur p oses descri be d i n t his secti o n.
7. 6. C ar di a c Bi o m ar ker s N-Ter mi n al Pr o -H or m o ne Br ai n N atri uretic Pe pti de 
(N T -pr o B N P) a n d Tr o p o ni n I
After Pr ot oc ol A me n d me nt 4, bl o o d sa m ple f or car diac bi o mar kers ( N T -pr o B N P a n d 
Tr o p o ni n I) will be c ollecte d at Scree ni n g, a n d eac h cli nic visit at M o nt hs 6, 1 2, 1 8, 2 4, 3 0, 
3 6, 4 2, 4 8, 5 4, a n d 6 0 ( E n d of St u d y  visit) or Earl y Termi nati o n Visit.  S pecificati o ns f or 
sa m ple c ollecti o n ca n be f o u n d i n t he st u d y la b orat or y ma n ual.  N T -pr o B N P a n d Tr o p o ni n I 
will als o be c ollecte d at M o nt h 3 ( C o u ntries liste d i n A p pe n dix 4. 2 ).
8. A D V E R S E E V E N T R E P O R T I N G
8. 1. A d verse E ve nts
All o bser ve d or v ol u nteere d A Es re gar dless of treat me nt gr o u p or s us pecte d ca usal 
relati o ns hi p t o t he i n vesti gati o nal pr o d uct will be re p orte d as descri be d i n t he f oll o wi n g 
secti o ns. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 0
F or all A Es, the i n vesti gat or m ust p urs ue a n d o btai n i nf or mati o n a de q uate b ot h t o deter mi ne 
t he o utc o me of t he A E a n d t o assess w het her it meets t he criteria f or classificati o n as a 
seri o us a d verse e ve nt ( S A E) re q uiri n g i m me diate n otificati o n t o Pfizer or its desi g nate d
re prese ntati ve.  F or all A Es, s ufficie nt i nf or mati o n s h o ul d be o btai ne d b y t he i n vesti gat or t o 
deter mi ne t he ca usalit y  of t he A E.  T he i n vesti gat or is re q uire d t o assess ca usalit y.  
F oll o w -u p b y  t he i n vesti gat or ma y be re q uire d u ntil t he e ve nt or its se q u elae 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.
As part of o n g oi n g safet y re vie ws c o n d ucte d b y t he s p o ns or, a 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 r e p orte d b y t he s p o ns or as a n S A E.  T o assist 
i n t he deter mi nati o n of case seri o us ness, f urt her i nf or mati o n ma y be re q ueste d fr o m t he 
i n vesti gat or t o pr o vi de clarit y a n d u n dersta n di n g of t he e ve nt i n t he c o nte xt of t he cli nical 
st u d y.
8. 2. Re p orti n g Peri o d
F or S A Es, t he ac ti ve re p orti n g peri o d t o Pfizer or its desi g nate d re prese ntati ve be gi ns fr o m 
t he ti me t hat t he s u bject pr o vi des i nf or me d c o nse nt, w hic h is o btai ne d pri or t o t he s u bject’s 
partici pati o n i n t he st u d y , ie, pri or t o 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 i n vesti gati o nal pr o d uct, t hr o u g h a n d i ncl u di n g 2 8 cale n dar da ys after t he last 
a d mi nistrati o n of t he i n vesti gati o nal pr o d uct.  S A Es occ urri n g t o a s u bject after t he acti ve 
re p orti n g peri o d has e n de d s h o ul d be re p orte d t o t he s p o ns or if t he i n vesti gat or bec o mes 
a ware of t he m; at a mi ni m u m, all S A Es t hat t he i n vesti gat or belie ves ha ve at least a 
reas o na ble p ossi bilit y of bei n g relate d t o i n vesti gati o nal pr o d uct are t o be re p orte d t o t he 
s p o ns or.
A Es (seri o us a n d n o n -seri o us) s h o ul d be rec or de d o n t he case re p ort f or m ( C R F) fr o m t he 
ti me t he s u bject has ta ke n at least 1 d ose of i n vesti gati o nal pr o d uct t hr o u g h t he s u bject’s last 
visit. 
8. 3. Defi niti o n of a n A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a cli nical i n vesti gati o n s u bject a d mi nis tere d a 
pr o d uct or me dical de vice; t he e ve nt nee d n ot necessaril y  ha ve a ca usal relati o ns hi p wit h t he 
treat me nt or usa ge.  E xa m ples of A Es i ncl u de b ut are n ot li mite d t o: 

A b n or mal test fi n di n gs;

Cli nicall y  si g nifica nt s y m pt o ms a n d si g ns;

C ha n ge s i n p h ysical e xa mi nati o n fi n di n gs;

H y perse nsiti vit y ;

Pr o gressi o n/ w orse ni n g of u n derl yi n g disease; 

Dr u g a b use;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 1

Dr u g de pe n de nc y .
A d diti o nall y , t he y ma y i ncl u de t he si g ns or sy m pt o ms r es ulti n g fr o m:

Dr u g o ver d ose;

Dr u g wit h dra wal;

Dr u g mis use; 

Dr u g i nterac ti o ns;

E xtr a vasati o n;

E x p os ure d uri n g pre g na nc y  ( E D P);

E x p os ure via breastfee di n g;

Me dicati o n err or;

Occ u pati o nal e x p os ure.
8. 4. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult, i n t his st ud y , fr o m t he a d mi nistrati o n or c o ns u m pti o n of t he 
wr o n g pr o d uct, b y t he w r o n g s u bject, at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h.  
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 C R F, w hic h is a s pecific versi o n of t he A E pa ge, a n d o n t he S A E f or m w he n 
a p pr o priate.  I n t he e ve nt of me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d 
i m me diatel y.
Me dicati o n err ors are re p orta ble irres pecti ve of t he prese nce of a n ass ociate d A E/ S A E, 
i ncl u di n g:

Me dicati o n err ors i n v ol vi n g s u bject e x p os ure t o t he i n vesti gati o nal pr o d uct ;

P ote ntial me dicati o n err ors or uses o 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 partici pati n g s u bject.
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 ca pt ure d o n t he me dicati o n err or versi o n of t he A E pa ge 
a n d, if a p plica ble, a n y ass ociate d A E(s) are ca pt ure d o n a n A E C R F pa ge. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 2
8. 5. A b n or m al Test Fi n di n gs
T he criteria f or deter mi ni n g w het her a n a b n or mal o bjecti ve test fi n di n g s h o ul d be re p orte d as 
a n A E are as f oll o ws:

Test res ult is ass ociate d wit h acc o m pa n yi n g s y m pt o ms; a n d/ or

Test res ult re q 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; 
a n d/ or

Test res ult lea ds t o a c ha n ge i n st u d y  d osi n g or disc o nti n uati o n fr o m t he st u d y, 
si g nificant a d diti o n al c o nc o mita nt dr u g treat me nt, or ot her t hera p y;  a n d/ or

Test res ult is c o nsi dere d t o be a n A E b y t he i n vesti gat or or s p o ns or.
Merel y re peati n g a n a b n or mal test, i n t he a bse nce of a n y of t he a b o ve c o n diti o ns, d oes n ot 
c o nstit ute a n A E.  A n y a b n or mal test re s ult t hat is deter mi ne d t o be a n err or d oes n ot re q uire 
re p orti n g as a n A E.
8. 6. Seri o us A d verse E ve nts
A seri o us a d verse e ve nt is a n y  u nt o war d me dical occ urre nce at a n y d ose t hat:

Res ults i n deat h;

Is life-t hreate ni n g (i m me diate ris k of deat h);

Re q u ires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y (s u bsta ntial disr u pti o n of t he 
a bilit y t o c on d uct n or mal life f u ncti o ns);

Res ults i n c o n ge nital a n o mal y / birt h defect.
Me d ical a n d scie ntific j u d g me nt is e xercise d i n deter mi ni n g w het her a n e ve nt is a n i m p orta nt 
me dical e ve nt.  A n i m p orta nt me dical e ve nt ma y  n ot be i m me diatel y life-t hreate ni n g a n d/ or
res ult i n deat h or h os pitalizati o n.  H o we ver, if it is deter mi ne d t hat t he eve nt ma y  jeo par dize 
t he s u bject or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her A E o utc o mes, t he 
i m p orta nt me dical e ve nt s h o ul d be re p orte d as seri o us.
E xa m ples of s uc h e v e nts are i nte nsi ve treat me nt i n a n e mer ge nc y  r o o m or at h o me f or 
aller gic br onc h os pas m; bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os 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.
8. 6. 1. Pr ot oc ol -S pecifie d Seri o us A d verse E ve nts 
T here are n o pr ot oc ol-s pecifie d S A Es i n t his st u d y.  All S A Es will be re p orte d b y t he 
i n vestigat or as descri be d i n pre vi o us secti o ns, a n d will be ha n dle d as S A Es i n t he safet y 
data base (see t he secti o n o n Seri o us A d verse E ve nt Re p orti n g Re q uire me nts ). 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 3
8. 6. 2. P ote nti al C ases of Dr u g -I n d uce d Li ver I nj ur y 
A b n or mal val u es i n as partate a mi n otra nsferase ( A S T) a n d/ or ala ni ne a mi n otra nsferase ( A L T) 
le vels c o nc urre nt wit h a b n or mal ele vati o ns i n t otal bilir u bi n le vel t hat meet t he criteria 
o utli ne d bel o w i n t he a bse nce of ot her ca uses of li ver i nj ur y  are c o nsi dere d p ote ntial cases of 
dr u g -i n d uce d li ver i nj ur y ( p ote ntial H y’s la w cases) a n d s h o ul d al wa ys be c o nsi dere d 
i m p orta nt me dical e ve nts. 
T he t hres h ol d of la b orat or y  a b n or malities f or a p ote ntial case of dr u g-i n d uce d li ver i nj ur y 
de pe n ds o n t he s u bject’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.  S u bjects w h o 
prese nt wit h t he f oll o wi n g la b orat or y  a b n or malities s h o ul d be e valuate d f urt her t o 
defi niti vel y  deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y val ues:

S u bjects wit h A S T or A L T a n d t otal bilir u bi n 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 or A LT val ues 3 ti mes t he u p per li mit of 
n or mal ( × U L N) c o nc urre nt wit h a t otal bilir u bi n val ue 2 × U L N wit h n o e vi de nce 
of he m ol y sis a n d a n al kali ne p h os p hatase val ue 2 × U L N or n ot a vai la ble;

F or s u bjects wit h pree xisti n g A L T O R A S T O R t otal bilir u bi n val ues a b o ve t he 
U L N, t he f oll o wi n g t hres h ol d va l ues s h o ul d be use d i n t he defi niti o n me nti o ne d 
a b o ve:

F or s u bjects wit h 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 o r 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).
C o nc urre nt wit h

F or s u bjects wit h pree xisti n g val ues of t otal bilir u bi n a b o ve t he n or mal ra n ge: 
T otal bilir u bi n le vel i ncrease d fr o m baseli ne b y a n a m o u nt of at least 1 × U L N or
if t he val ue reac hes 3 × U L N ( w hic he ver is s maller).
T he s u bject s h o ul d ret ur n t o t he i n vesti gati o nal 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 ude la b orat o r 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, la b orat or y  tests s h o ul d i ncl u de 
al b u mi n, creati ne ki nase, t otal bilir u bi n, direct a n d i n direct bilir u bi n, ga m ma -gl uta m y l 
tra nsferase, pr othr o m bi n ti m e ( P T)/i nter nati o nal n or malize d rati o (I N R), a n d al kali ne 
p h os p hatase.  A detaile d hist or y , i ncl udi 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 , recreati o nal dr u g, a n d s u p ple me nt c o ns u m pti o n, fa mil y hist or y, occ u pati o nal 
e x pos ure, se x u al 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 w or k e x p os ure, s h o ul d be c ollecte d.  
F urt her testi n g f or ac ute he patitis A, B, or C i nfecti o n a n d li ver i ma gi n g (eg, biliar y  tract) 
ma y  be warra nte d.  All cases c o nfir me d o n re peat testi n g as meeti n g t he la b orator y  criteria 
defi ne d a b o ve, wit h n o ot her ca use f or L F T a b n or malities i de ntifie d at t he ti me, s h o ul d be 
c o nsi dere d p ote ntial H y’s la w cases irres pecti ve of a vaila bilit y of all t he res ults of t he 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 4
i n vesti gati o ns perf or me d t o deter mi ne eti ol o g y of t he a b n or mal L F Ts.  S uc h p ote ntial H y’s 
la w cases s h o ul d be re p orte d as S A Es.
8. 7. H os pit aliz ati o n
H os pitalizati o n is defi ne d as a n y i nitial a d missi o n (e ve n less t h a n 2 4 h o urs ) i n a h os pital or 
e q ui vale nt healt hcare facilit y or a n y pr ol o n gati o n of a n e xisti n g a d missi o n.  A d missi o n als o 
i ncl u des tra nsfer wit hi n t he h os pital t o a n ac ute/i nte nsi ve care u nit (e g, fr o m t he ps yc hiatric 
wi n g t o a me dical fl o or, me dical fl o o r t o a c or onar y  care u nit, or ne ur ol o gical fl o or t o a 
t u berc ul osis u nit).  A n e mer ge nc y r o o m visit d oes n ot necessaril y c o nstit ute a h os pitalizati o n; 
h o we ver, t he e ve nt lea di n g t o t he e mer ge nc y  r o o m visit s h o ul d be assesse d f or me dical 
i m p orta nce.
H os pital izati o n d oes n ot i ncl u de t he f oll o wi n g:

Re ha bilitati o n facilities;

H os pice facilities;

Res pite care (e g, care gi ver relief);

S kille d n ursi n g facilities;

N ursi n g h o mes;

Sa me -d a y  s ur geries (as o ut patie nt/sa me-d a y /a m b ulat or y pr oce d ures).
H os pitalizati o n or pr o l o n gati o n of h os pitalizati o n i n t he a bse nce of a preci pitati n g, cli nical 
A E is n ot i n itself a n S A E.  E xa m ples i ncl u de: 

A d missi o n f or treat me nt of a pree xisti n g c o n diti o n n ot ass ociate d wit h t he 
de vel o p me nt of a ne w A E or wit h a w orse ni n g of t he pree xisti n g c o n diti o n (e g, f or 
w or k u p of persiste nt pretreat me nt la b orat or y  a b n or malit y);

S ocial a d missi o n (e g, s u bject has n o place t o slee p);

A d mi nistrati ve a d missi o n (e g, f or ye arl y p h ys ical e xa mi nati o n);

Pr ot oc ol -s pecifie d a d missi o n d uri n g a st u dy (e g, f or a pr oce d ure re q uire d b y  t he st u d y 
pr ot oc ol);

O pti o nal a d missi o n n ot ass ociate d wit h a preci pitati n g cli nical A E (e g, f or electi ve 
c os metic s ur ger y);

H os pitalizati o n f or o bser vati o n wit h o ut a me dical A E;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 5

Pre pla n ne d treat me nts or s ur gical pr oce d ures.  T hese s h o u l d be n ote d i n t he baseli ne 
d oc u me ntati o n f or t he e ntire pr ot oc ol a n d/ or f or t he i n di vi d ual s u bject.
Dia g n ostic a n d t hera pe utic n o ni n vasi ve a n d i n vasi ve pr oce d ures, s uc h as s ur ger y , s h o ul d n ot 
be re p orte d as A Es.  H o we ver, t he me dical c o n diti o n f or w hic h t he pr oce d ur e was perf or me d 
s h o ul d be re p orte d if it meets t he defi niti o n of a n A E.  F or e xa m ple, a n ac ute a p pe n dicitis 
t hat be gi ns d uri n g t he A E re p orti n g peri o d s h o ul d be re p orte d as t he A E, a n d t he res ulti n g 
a p pe n dect o m y s h o ul d be rec or de d as treat me nt of t he A E.
8. 8. S e verit y Assess me nt
If re q uire d o n t he A E C R Fs, t he i n vesti gat or will use t he a djecti ves MI L D, M O D E R A T E, 
or S E V E R E t o descri be t he ma xi m u m i nte nsit y  of t he A E.  F or p ur p oses of c o nsiste nc y, 
t hese i nte nsit y gra des are defi ne d as f oll o ws:
MI L D
D oe s n ot i nterfere wit h s u bject's us ual f u ncti o n.
M O D E R A T E
I nterferes t o s o me e xte nt wit h s u bject's us ual f u ncti o n.
S E V E R E
I nterferes si g nifica ntly wit h s u bject's us ual f u ncti o n.
N ote t he disti ncti o n bet wee n t he se verit y a n d t he seri o us ness of a n A E.  A se vere e ve nt is n ot 
necessaril y  a n S A E.  F or e xa m ple, a hea dac he ma y be se vere (i nterferes si g nifica ntl y wit h 
t he s u bject's us ual f u ncti o n) b ut w o ul d n ot be classifie d as seri o us u nless it met o ne of t he 
criteria f or S A Es, liste d a b o ve.
8. 9. C a us alit y Assess me nt
T he i n vesti gat or’s assess me nt of ca usalit y m ust be pr o vi de d f or all A Es (seri o us a n d 
n o n -seri o us); t he i n vesti gat or m ust rec or d t he ca usal relati o ns hi p i n t he C R F, as a p pr o priate, 
a n d re p ort s uc h a n assess me nt i n acc or da nce wit h t he S A E re p orti n g re q uire me nts if 
a p plica ble.  A n i n vesti gat or’s ca usalit y assess me nt is t he deter mi nati o n of w het her t here 
e xists a reas o na ble p ossi bilit y t hat t he i n vesti gati o nal pr o d uct ca use d or c o ntri b ute d t o a n 
A E; ge nerall y  t he facts (e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o nshi p s h o ul d be 
pr o vi de d.  If t he i n vesti gat or d oes n ot k n o w w het her or n ot t he i n vesti gati o nal pr o d uct ca use d 
t he e ve nt, t he n t he e ve nt will be ha n dle d as “relate d t o i n vesti gati o nal pr o d uct” f or re p orti n g 
p ur p oses, as defi ne d b y t he s p o ns or (see Re p orti n g Re q uire me nts ).  If t he i n vesti gat or's 
ca usalit y assess me nt is " u n k n o w n b ut n ot relate d t o i n vesti gati o nal pr o d uct," t his s h o ul d be 
clearl y d oc u me nte d o n st u d y  rec or ds. 
I n a d diti o n, if t he i n vesti gat or deter mi nes t hat an 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, as 
a p pr o priate, a n d re p ort s uc h a n assess me nt i n acc or da nce wit h t he S A E re p orti n g 
re q uire me nts, if a p plica ble.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 6
8. 1 0. E x p os ure D uri n g Pre g n a n c y
F or b ot h u na p pr o ve d/ u nlice nse d pr o d ucts a n d f or mar kete d pr o d ucts, a n e x p os ure d uri n g 
pre g na nc y  occ urs if:
1.
A fe male bec o mes, or is f o u n d t o be, pre g na nt eit her w hile recei vi n g or ha vi n g bee n 
e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he i n vesti gati o nal 
pr o d uct; or t he fe male bec o mes or is f o u n d t o be pre g na nt after disc o nti n ui n g a n d/ or 
bei n g e x p ose d t o t he i n vesti gati o nal pr o d uct; 
A n e xa m ple of e n vir o n me ntal e x p os ure w o ul d be a case i n v ol vi n g direct c o ntact wit h 
a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a n urse re p orts t hat s he is pre g na nt a n d has 
bee n e x p ose d t o c he m ot hera pe utic pr o d ucts).
2.
A male has bee n e x p ose d (e g , beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he 
i n vesti gati o nal pr o d uct pri or t o or ar o u n d t he ti me of c o nce pt i o n a n d/ or is e x p ose d 
d uri n g his part ner’s pre g na nc y . 
If a st u dy s u bject or st u d y s u bject’s part ner bec o mes or is f o u n d t o be pre g na nt d uri n g t he 
st u d y s u bject’s treat me nt wit h t he i n vesti gati o nal pr o d uct, t he i n vesti gat or m ust s u b mit t his 
i nf or mati o n t o t he Pfizer dr u g safet y u nit o n a n 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.  I n a d diti o n, t he i n vesti gat or m ust s u b mit 
i nf or mati o n re gar di n g e n vir o n me ntal e x p os ure t o a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a 
s u bject re p orts t hat s he is pre g na nt a n d has bee n e x p ose d t o a c yt ot o xic pr o d uct b y i n halati o n 
or s pilla ge) usi n g t he E D P s u p ple me ntal f or m.  T his m ust be d o ne irres pecti ve of w het her a n 
A E has occ urre d a n d wit hi n 2 4 h o urs of a ware ness of t he e x p os ure.  T he i nf or mati o n 
s u b mitte d s h o ul d i ncl u de t he a ntici pate d date of deli ver y (see bel o w f or i nf or mati o n relate d 
t o ter mi nati o n of pre g na nc y).
F oll o w -u p is c o n d ucte d t o o btai n ge neral i nf or mati o n o n t he pre g na nc y  a n d its o utc o me f or 
all E D P re p orts wit h a n u n k n o w n o utc o me.  T he i n vesti gat or will f oll o w t he pre g na nc y  u ntil 
c o m pleti o n ( or u ntil pre g na nc y  ter mi nati o n) a n d n otif y Pfizer of t he o utco me as a f oll o w - u p 
t o t he i nitial E D P s u p ple me ntal f or m.  I n t he case of a li ve birt h, t he str uct ural i nte grit y 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 nically p ossi ble, t he str uct ural i nte grit y of t he 
ter mi nate d fet us s h o ul d be assesse d by gr oss vis ual i ns p ecti o n ( u nl ess 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 maly a n d t he fi n di n gs are re p orte d).
If t he o utc o me of t he pre g na nc y meets t he criteria f or a n S A E (ie, ect o pic pre g na nc y , 
s p o nta ne o us a b orti o n, i ntra uteri ne fetal de mise, ne o natal deat h, or c o n ge nital a n o mal y [i n a 
li ve-b or n ba b y, a ter mi 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 uld 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 orted as S A Es f oll o ws: 

S p o nta ne o us a b orti o n i ncl u des miscarria ge a n d misse d a b orti o n;
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 7

Ne o natal deat hs t hat occ ur wit hi n 1 m o nt h of birt h s h o ul d be re p orte d, wit h o ut re gar d 
t o ca usalit y, as S A Es.  I n a d diti o n, i nfa nt deat hs after 1 m o nt h s h o ul d be re p orte d as 
S A Es w he n t he i n vesti gat or assesses t he i nfa nt deat h as relate d or p ossi bl y  relate d t o 
e x p os ure t o t he i n vesti gati o nal pr o d uct. 
A d diti o nal i nf or mat i o n re gar di n g t he E D P ma y be re q ueste d b y t he i n vesti gat or.  F urt her 
f oll o w- u p of birt h o utc o mes will be ha ndle d o n a c ase-b y -case basis (e g, f oll o w- u p o n 
preter m i nfa nts t o i de ntif y de vel o p me ntal dela y s).  In t he case of pater nal e x p os ure, t he 
i n vesti gat or will pr o vi de t he st u d y s u bject wit h t he Pre g na nt Part ner Release of I nf or mati o n 
F or m t o deli ver t o his par t ner.  T he i n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts t hat 
t he s u bject 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. 1 1. Occ u p ati o n al E x p os ure
A n occ u pati o nal e x p os ure occ urs w he n, d uri n g t he perf or ma nce of j o b d uties, a pe rs o n 
( w het her a healt hcare pr ofessi o nal or ot her wise) gets i n u n pla n ne d direct c o ntact wit h t he 
pr o d uct, w hic h ma y  or ma y n ot lea d t o t he occ urre nce of a n A E.
A n occ u pati o nal e x p os ure is re p orte d t o t he dr u g safet y u nit wit hi n 2 4 h o urs of t he 
i nvesti gat or’ s a ware ness, usi n g t he S A E re p ort f or m, re gar dless of w het her t here is a n 
ass ociate d A E/ S A E.  Si nce t he i nf or mati o n d oes n ot pertai n t o a s u bject e nr olle d i n t he st u d y, 
t he i nf or mati o n is n ot re p orte d o n a C R F; h o we ver, a c o p y of t he c o m plete d SA E re p ort f or m 
is mai ntai ne d i n t he i n vesti gat or site file.
8. 1 2. Wit h dr a w al D ue t o A d verse E ve nts ( See Als o t he Secti o n o n S u bject Wit h dr a w al )
Wit h dra wal d ue t o A Es s h o ul d be disti n g uis he d fr o m wit h dra wal d ue t o ot her ca us es, 
acc or din g t o t he defi niti o n of A E n ote d earlier, a n d rec or de d o n t he a p pr o priate A E C R F 
pa ge. 
W he n a s u bject wit h dra ws beca use of a n S A E, t he S A E m ust be re p orte d i n acc or da nce wit h 
t he re p orti n g re q uire me nts defi ne d bel o w.
8. 1 3. Eliciti n g A d verse E ve nt I nf or m ati o n
T h e i n vesti gat or is t o re p ort all directl y  o bser ve d A Es a n d all A Es s p o nta ne o usl y re p orte d by 
t he st u d y s u bject or le gall y acce pta ble re prese ntati ve.  I n a d diti o n, eac h st u d y  s u bject or 
le gall y acce pta ble re prese ntati ve will be q uesti o ne d a b o ut A Es.
8. 1 4. Re p orti n g Re q uire me nts
Eac h A E is t o be assesse d t o deter mi ne if it meets t he criteria f or S A Es.  If a n S A E occ urs, 
e x pe dite d re p orti n g will f oll o w l ocal a n d i nter nati o nal re g ulati o ns, as a p pr o priate.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 8
8. 1 4. 1. Seri o us A d verse E ve nt Re p orti n g Re q uire me nts
If a n SA E occ urs, Pfizer is t o be n otifie d wit hi n 2 4 h o urs of i n vesti gat or a ware ness of t he 
e ve nt. 
I n partic ular, if t he S A E is fatal or life-t hreate ni n g, n otificati o n t o Pfizer m ust be ma de 
i m me diatel y, irres pecti ve of t he e xte nt of a vaila ble A E i nf or mati o n.  This ti me fr a me als o 
a p plies t o a d diti o nal ne w i nf or mati o n (f oll o w- u p) o n pre vi o usl y  f or war de d S A E re p orts as 
well as t o t he i nitial a n d f oll o w- u p re p orti n g of E D P, e x p os ure via breastfee di n g, a n d 
occ u pati o nal e x p os ure cases. 
I n t he rare e ve nt t hat t he i n vesti gat or does n ot bec o me a ware of t he occ urre nce of a n S A E 
i m me diatel y (e g, if a n o ut patie nt st u d y s u bject i nitiall y see ks treat me nt else w here), t he
i n vesti gat or is t o re p ort t he e ve nt wit hi n 2 4 h o urs after lear ni n g of it a n d d oc u me nt t he ti me 
of his or h er first a ware ness of t he A E.
F or all S A Es, t he i n vesti gat or is o bli gate d t o p urs ue a n d pr o vi de i nf or mati o n t o Pfizer i n 
acc or da nce wit h t he ti me frames f or re p orti n g s pecifie d a b o ve.  I n a d diti o n, a n i n vesti gat or 
ma y  be re q ueste d b y Pfizer t o o btai n s pecific a d diti onal f oll o w- u p i nf or mati o n i n a n 
e x pe dite d fas hi o n.  T his i nf or mati o n c ollecte d f or S A Es is m ore detaile d t ha n t hat ca pt ure d 
o n t he A E C R F.   I n ge neral, t his will i ncl u de a descri pti o n of t he A E i n s ufficie nt detail t o 
all o w f or a c o m plete me dica l 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 .  I nf or mati o n o n ot her p ossi ble ca uses of t he e ve nt, s uc h as c o nc o mita nt
me dicati o ns, vacci nes, a n d/ or ill nesses, m ust be pr o vi de d.  I n t he case of a s u bject deat h, a 
s u m mar y of availa ble a u t 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 or its 
desi g nate d re prese ntati ve. 
8. 1 4. 2. N o nseri o us A d verse E ve nt Re p orti n g Re q ui re me nts
All A Es will be re p orte d o n t he A E pa ge(s) of t he C R F.  I t s h o ul d be n ote d t hat t he f or m f or 
c ollecti o n of S A E i nf or mati o n is n ot t he sa me as t he A E C R F.  W here 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.  F or e xa m ple, t he sa me A E 
ter m s h o ul d be use d o n b ot h f or ms.  A Es s h o ul d be re p orte d usi n g c o ncise me dical 
ter mi nol o g y  o n t he C R Fs as well as o n t he f or m f or c ollecti o n of S A E i nf or mati o n.
8. 1 4. 3. S p o ns or’s Re p orti n g Re q uire me nts t o Re g ul at or y A ut h orities
A E re p orti n g, i ncl u di n g s us pecte d u ne x pecte d seri o us a d verse reacti o ns, will be carrie d o ut 
i n acc or da nce wit h a p plica ble l ocal re g ulati o ns.
9. D A T A A N A L Y SI S/ S T A TI S TI C A L M E T H O D S
Detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nalys es of t he data c ollecte d i n t his st u d y  
will be d oc u me nte d i n a statistical a nal y sis pla n ( S A P), w hic h will be mai ntai ne d b y t he 
s p o ns or.  T his d oc ume nt ma y  m odif y  t he pla ns o utli ne d i n t he pr ot oc ol; h owe ver, a n y maj or 
m o dificati o ns of t he pri mar y  e n d p oi nt defi niti o n a n d/ or its a nal ysis will als o be reflecte d i n a 
pr ot oc ol a me n d me nt. 
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 6 9
F or C o h ort A, a nal ys es will be perf or me d usi n g tafa mi dis/tafa mi dis a n d place b o/tafa mi dis 
treat me nt gr o u ps.  S u bjects ra n do mize d t o tafa mi dis i n pare nt st u d y  B 3 4 6 1 0 2 8 a n d c o nti n ue 
o n tafa mi dis i n t he e xte nsi o n st u d y  B 3 4 6 1 0 4 5 will be gr o u pe d as tafa mi dis/tafa mi dis.  
S u bjects ra n d o mize d t o place b o i n st u d y  B 3 4 6 1 0 2 8 a n d ra n d omize d t o ta fa mi dis i n t he 
e xte nsi o n st u d y B 3 4 6 1 0 4 5 will be gr o u pe d as place b o/tafa mi dis. 
F or C o h ort B, si nce s u bjects i n t his c o h ort will all be a d mi nistere d t he sa me d ose, o nl y 
o verall descri pti ve statistics will be pr o vi de d.
9. 1. S a m ple Size Deter mi n ati o n
T h ere is n o for mal sa m ple size calc ulati o n f or t his pr ot oc ol.  S u bjects w h o meet e nr oll me nt 
criteria are eli gi ble; u p t o 2 0 0 0 s u bjects are e x pecte d t o e nr oll i n Pr ot oc ol B 3 4 6 1 0 4 5. 
9. 2. A n al ysis of Ot her E n d p oi nts
9. 2. 1.
M ort alit y ( C ar di o v asc ul ar- rel ate d)
F or C o h ort A, ti me t o cardi o vasc ular -relate d m ortalit y will be calc ulate d fr o m t he first d ose 
of t he ra n d o mize d treat me nt ( St u d y B 3 4 6 1 0 2 8).  Ka pla n -Meier s ur vi val c ur ves f or eac h 
treat me nt gr o u p al o n g wit h me dia n s ur vi val ti mes (if a p plica ble) will be prese nte d.
S u bje cts w h o disc onti n ue f or tra ns pla ntati o n (ie, heart tra ns pla ntati o n a n d c o m bi ne d heart 
a n d li ver tra ns pla ntati o n) or f or i m pla ntati o n of a car diac mec ha nical assist de vice, will be 
ha n dle d i n t he sa me ma n ner as deat h.  Data fr o m s u bjects w h o dr o p o ut f or a liver - o nly 
tra ns pla ntati o n will be ha n dle d i n t he sa me ma n ner as t he data fr o m all ot her ce ns ore d 
s u bjects.
F or C o h ort B, ti me t o car di o vasc ular relate d m ortalit y  will be calc ulate d fr o m t he first d ose 
of treat me nt.  T he Ka pla n Meier s ur vi val c ur ve al o n g w ith me dia n s u r vi val ti me 
(if a p plica ble) will be prese nte d.
9. 2. 2. H os pit aliz ati o n
F or C o h orts A a n d B, t he fre q ue nc y  of h os pitalizati o ns (all-ca use a n d car di o vasc ular-relate d) 
d uri n g t he st u d y will be s u m marize d descri pti vel y.
9. 2. 3. K a ns as Cit y C ar di o m y o p at h y Q uesti o n n a ire
F or C o h ort A, t he Ka nsas Cit y  Car di o m yo pat h y  Q uesti o n naire ( K C C Q, A p pe n di x 2 ) will be 
s u m marize d b y t he f oll o wi n g s u m mar y sc ores calc ulate d usi n g t he g ui deli nes esta blis he d i n 
t he K C C Q Sc ori n g I nstr ucti o n Ma n ual:
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 0
P h y sical li mitati o ns 
Self -efficac y
S y m pt o m sta bilit y  
Q ualit y  of life
S y m pt o m fre q ue nc y  
S ocial li mitati o n
S y m pt o m b ur de n 
O verall s u m mar y  sc ore
T otal s y m pt o m sc ore 
Cli nical s u m mar y sc ore
T he o verall a n d d o mai n sc ores will be e val uate d as a c ha n ge fr o m baseli ne at eac h visit usi n g 
a M M R M wit h a n u nstr uct ure d c o varia nce matri x ( or as a p pr o priate) wit h s u bjects as a 
ra n d o m effect a n d treat me nt, visit, T T R ge n oty pe ( varia nt a n d wil d - t ype), a n d 
visit -b y -treat me nt i nteracti o n, as fi xe d effects a n d baseli ne sc ore as c o variate.  Data will als o 
be s u m marize d b y  eac h sc he d ule d assess me nt.
F or C o h ort B, descri pti ve statistics will be pr o vi de d.
9. 2. 4. Ne w Y or k He art Ass oci ati o n
F or C o h orts A a n d B, s u bjects will be e val uate d usi n g t he Ne w Y or k Heart Ass ociati o n 
( N Y H A) classificati o n (A p pe n di x 3 ).  Descri pti ve statistics will be prese nte d b y cli nic visit 
f or eac h classificati o n: Class I, Class II, Class III, a n d Class I V (see A p pe n di x 3 f or 
defi niti o ns).  T he n u m ber a n d pe rce nta ge of s u bjects w h o i m pr o ve d, w orse ne d, or wit h n o
c ha n ge fr o m baseli ne will als o be prese nte d at eac h visit.
9. 2. 5. B o d y M ass I n de x/ m o difie d B o d y M ass I n de x
F or C o h orts A a n d B, B MI  a n d m B MI val ues at eac h visit a n d c ha n ge fr o m baseli ne will be 
prese nte d i n s u m mar y tables a n d data listi n gs.  Descri pti ve statist ics will be pr o vi de d by visit.
9. 2. 6. C ar di ac Bi o m ar kers N T- pr o B N P a n d Tr o p o ni n I
F or C o h orts A a n d B, descri pti ve statistics f or c ha n ge fr o m baseli ne (i nitiati o n of tafa mi dis) 
i n N T-pr o B N P a n d Tr o p o ni n I c o nce ntrati o n will be s u m marize d. 
9. 3. S afet y A n al ysis
T he safet y assess me nts i n t his st u d y are liste d i n Secti o n 7. 1 .  T he safety a nal ysis p o p ulati o n 
c o nsists of all s u bjects w h o are e nr olle d i n t his st u d y a n d w h o ha ve ta ke n at least o ne d ose of 
st u d y treat me nt.  E xce pt f or all-ca use m ortality ( Secti o n 9. 3. 1 ), all safet y e n d p oi nts i n 
Secti o n 9. 3 will be a nal yze d descri pti v el y f or C o h orts A a n d B. 
9. 3. 1. M ort alit y ( All -c a use)
F or C o h ort A, ti me t o all- ca use m ortalit y  will be calc ulate d fr o m t he first d ose of t he 
ra n d o mize d treat me nt ( St u d y B 3 4 6 1 0 2 8).  Treate d s u bjects fr o m t he pare nt s t u d y B 3 4 6 1 0 2 8 
w h o disc o nti n ue pri or t o t he start of t his st u d y  will als o be i ncl u de d i n t his a nal ysis.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 1
All- ca use m ortalit y wi ll be a nalyz e d usi n g S A S Pr oc Lifetest; p- val ues will be fr o m t he 
l o g-ra n k test.  Ka pla n-Meier s ur vi val c ur ves f or eac h treat me nt g r o u p al o n g wit h me dia n 
s ur vi val ti mes (if a p plica ble) will be prese nte d. 
All- ca use m ortalit y will als o be a nal yz e d usi n g C o x pr o p orti o nal hazar ds m o del wit h 
treat me nt a n d T T R ge n ot y pe ( varia nt a n d wil d-t ype) as fact ors.
S u bjects w h o disc o nti n ue f or tra ns p la ntati o n (ie, heart tra ns pla ntati o n a n d c o m bi ne d heart 
a n d li ver tra ns pla ntati o n) or f or i m pla ntati o n of a car diac mec ha nica l assist de vice, will be 
ha n dle d i n t he sa me ma n ner as deat h.  Data fr o m s u bjects w h o dr o p o ut f or a li ver - o nly 
tra ns pla ntati o n will be ha n dled i n t he sa me ma n ner as t he data fr o m all ot her ce ns ore d 
s u bjects.
F or C o h ort B, ti me t o all -ca use m ortalit y will be calc ulate d fr o m t he first d ose of treat me nt.  
T he Ka pla n Meier s ur vi val c ur ve al o n g wit h me dia n s ur vi val ti me (if a p plica ble) wi ll be 
prese nte d.
9. 3. 2. A d verse E ve nts
All A E data c ollecte d o n t he C R F will be prese nte d i n s u m mar y  ta bles a n d data listi n gs. 
All a d verse e ve nts t hat are o bser ve d fr o m t he ti me of first d osi n g wit h st u d y me dicati o n u ntil 
t he e n d of st u dy partici pati o n will be i ncl u de d i n t he safety a nal ys is.  A d verse e ve nts t hat 
occ urre d d uri n g treat me nt will be re p orte d se paratel y if t he e ve nt occ ur re d pri or t o 
ra n d o mizati o n. 
All a d verse e ve nts will be c o de d acc or di n g t o t he Me dical Dicti o nar y f or Re g ulat or y  
Acti vities ( Me d D R A ) a n d will be s u m marize d b y  treat me nt gr o u p.  T he i nci de nce of 
treat me nt-e mer ge nt a d verse e ve nts will be ta b ulate d b y  treat ment gr o u p a n d b y  sys te m or ga n 
class.  T he i nci de nce of treat me nt -e mer ge nt a d verse e ve nts will be dis pla y e d b y se verity a n d 
attri b uti o n.  I n a d d iti o n, t he i nci de nce of seri o us a d verse e ve nts a n d a d verse e ve nts t hat ca use 
wit h dra wal will be ta b ulate d.  All a d verse e ve nts will be liste d.
9. 3. 3. P h ysic al E x a mi n ati o ns a n d Vit al Si g ns
P h y sical e xa mi nati o ns a n d vital si g ns (l yi n g a n d sta n di n g bl o o d press ure a n d p ulse, 
res pirat or y rate, a n d te m perat ure) will be s u m marize d usi n g descri pti ve statistics.
9. 3. 4. Use of C o nc o mit a nt Me dic ati o ns
All data o n c o nc o mita nt me dicati o n usa ge c ollecte d o n t he C R F will be prese nte d i n 
s u m mar y ta bles a n d i n data listi n gs.
9. 3. 5. C li nic al L a bor at or y Tests
All cli nical la b orat or y  data (ser u m c he mistr y, c oa g ulati o n, he mat ol o g y, a n d uri nal ysis) will 
be s u bjecte d t o cli nical re vie w a n d s u m marize d b y fre q ue nc y  of e ve nts a n d mea n c ha n ges 
fr o m baseli ne.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 2
9. 3. 6. Electr oc ar di o gr a ms
E C G val ues at eac h visit a n d c ha n ge fr o m baseli ne will be prese nte d i n s u m mar y  ta bles a n d 
data listi n gs.  Descri pti ve statistics will be pr o vi de d f or eac h test res ult b y visit.
Ce ntrall y  o ver-rea d E C G varia bles will be s u m marize d b y mea n c ha n ge fr o m baseli ne t o e n d 
of st u d y f or heart rate, P R i nter val, Q R S wi dt h, Q T i nter val, a n d Q Tc B ( Bazett’s c orrecti o n) 
a n d Q Tc F ( Fri dericia’s c o rrecti o n) val ues.  A d diti o nall y, t he i nci de nce of cate g orical 
i ncreases i n Q Tc i nter vals will be pr o vi de d.  Cate g ories f or Q Tc B a n d Q Tc F are 4 5 0 msec, 
4 8 0 msec, a n d 5 0 0 msec.  Cate g ories f or Q Tc B a n d Q Tc F as c ha n ge fr o m baseli ne are: 
3 0 msec i ncrease, 6 0 msec i ncrease, a n d 7 5 msec i ncrease.  Q Tc F is c o nsi dere d t he 
pri mar y  Q Tc val ue as t his c orrecti o n is a ntici pate d t o be m ore a p pr o priate.
9. 4. I nteri m A n al ysis
I nteri m a nalys es ma y be perf or me d if re q uire d t o meet re g ulat or y re q uire me nts a n d as 
re q ueste d by t he Data M o nit ori n g C o m mittee.  I nteri m a nal ys es ma y als o be perf or me d 
d uri n g t he c o urse of t he st u d y  t o all o w f or t he re p orti n g of data t o t he scie ntific c o m m u nit y.
9. 5. D at a M o nit ori n g C o m mittee 
T his st u d y  will use a n e xter nal data m o nit ori n g c o m mittee ( E-D M C ) t hat is i n de pe n de nt fr o m 
Pfizer.  I nf or mati o n re gar di n g t he E - D M C ca n be f o u n d i n t he E xter nal Data M o nit ori n g 
C o m mittee c harter, i ncl u di n g t he me m bers hi p of t he c o m mittee. 
T he E -D M C will be res p o nsi ble f or o n g oi n g m o nit ori n g of t he safet y of s u bjec ts i n t he st u d y 
acc or di n g t o t he c harter.  T he rec o m me n dati o ns ma de b y t he E -D M C t o alter t he c o n d uct of 
t he st u d y will be f or war de d t o Pfizer f or fi nal decisi o n.  Pfizer will f or war d s uc h decisi o ns, 
w hic h ma y  i ncl u de s u m maries of a g gre gate a nal yses of e n dp oi nt e ve nts a n d of safet y data 
t hat are n ot e n d p oi nts, t o re g ulat or y a ut h orities, as a p pr o priate. 
1 0. Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
Pfizer or its a ge n t will c o n d uct peri o dic m o nit ori n g visits d uri n g st u d y c o n d uct t o e ns ure t hat 
t he pr ot oc ol a n d G o o d Cli nical Practices ( G C Ps) are bei n g f oll o we d.  T he m o nit ors ma y  
re vie w s o urce d oc u me nts t o c o nfir m t hat t he data rec or de d o n C R Fs are acc urate.  T he 
i n vestigat or a n d i nstit uti o n will all o w Pfizer m o nit ors/a u dit ors or its a ge nts a n d a p pr o priate 
re g ulat or y aut h orities direct access t o s o urce d oc u me nts t o perf or m t his verificati o n.  T his 
verificati o n ma y  als o occ ur after st u d y c o m pleti o n.
D uri n g st u d y c o n d uct a n d/ or after st u d y c o m pleti o n, t he st u d y  site ma y be s u bject t o re vie w 
b y  t he i nstit uti o nal re vie w b oar d (IR B)/et hics c o m mittee ( E C), a n d/ or t o q ualit y  ass ura nce 
a u dits perf or me d b y Pfizer, or c o m pa nies w or ki n g wit h or o n be half of Pfizer, a n d/ or t o 
i ns pectio n b y  a p pr o priate re g ulat or y a ut h orities.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 3
T he i n vesti gat or(s) will n otif y Pfizer or its a ge nts i m me d iatel y of a n y re g ulat or y i ns pecti o n 
n otificati o n i n relati o n t o t he st u d y .  F urt her m ore, t he i n vesti gat or will c o o perate wit h Pfizer 
or its a ge nt s t o pre pare t he st u d y site f or t he i ns pecti o n a n d will all o w Pfizer or its a ge nt, 
w he ne ver feasi ble, t o be pre se nt d uri n g t he i ns pecti o n.  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 Pfizer or its a ge nt.  Bef ore res p o nse s u b missi o n 
t o t he re g ulat or y a ut h orities, t he i n vesti gat or will pr o vi de Pfizer or its a ge nts wit h a n 
o p p ort u nit y  t o re vie w a n d c o m me nt o n res p o nses t o a n y s uc h fi n di n gs.
It is i m p orta nt t hat t he i n vesti gat or(s) a n d t heir rele va nt pers o n nel are a vaila ble d urin g t he 
m o ni t ori n g visits a n d p ossi ble a u dits or i ns pecti o ns a n d t hat s ufficie nt ti me is de v ote d t o t he 
pr ocess.
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G
1 1. 1. C ase Re p ort F or ms/ Electr o nic D at a Rec or d
As use d i n t his pr ot oc ol, t he ter m C R F s h o ul d be u n derst o o d t o refer t o eit her a pa per f or m or 
a n electr o nic data rec or d or b ot h, de pe n di n g o n t he data c ollecti o n met h o d use d i n t his st u d y.
A C R F is re q uire d a n d s h o ul d be c o m plete d f or eac h i ncl u de d s u bject.  T he c o m plete d 
ori gi nal C R Fs are t he s ole pr o pert y of Pfizer a n d s h o ul d n ot be ma de a vaila ble i n a n y  f or m t o 
t hir d parties, e xce pt f or a ut h orize d re prese ntati ves of Pfizer or a p pr o priate re g ulat or y 
a ut h orities, wit h o ut writte n per missi o n fr o m Pfizer.
T he i n vesti gat or has ulti mate res p o nsi bilit y  f or t he c ollecti o n a n d re p orti n g of all cli nical, 
safety, a n d la b orat or y data e ntere d o n t he C R Fs a n d a n y ot her data c ollecti o n f or ms ( s o urce 
d oc u me nts) a n d e ns uri n g t hat t he y are acc urate, a ut he ntic/ ori gi nal, attri b uta ble, c o m plete, 
c o nsiste nt, le gi ble, ti mel y (c o nte m p ora ne o us), e nd uri n g, a n d a vaila ble w he n re q uire d.  T he 
C R Fs m ust be si g ne d b y t he i n vesti gat or or by a n a ut h orize d staff me m ber t o attest t hat t he 
data c o ntai ne d o n t he C R Fs are tr ue.  A n y c orrecti o ns t o e ntries ma de i n t he C R Fs or s o urce 
d oc u me nts m ust be date d, i niti ale d, a n d ex plai ne d (if necessar y ) a n d s h o ul d n ot o bsc ure t he 
ori gi nal e ntr y . 
I n m ost cases, t he s o urce d oc u me nts are t he h os pital's or t he p hys icia n's s u bject c hart.  I n 
t hese cases, data c ollecte d o n t he C R Fs m ust matc h t he data i n t h ose c harts. 
I n s o me cases, t h e C R F, or part of t he C R F, ma y  als o ser ve as s o urce d oc u me nts.  I n t hese 
cases, a d oc u me nt s h o ul d be a vaila ble at t he i n vesti gati ve site as well as at Pfizer a n d clearl y 
i de ntif y t h ose data t hat will be rec or de d i n t he C R F, a n d f or w hic h t he C R F will sta n d as t he 
s o urce d oc u me nt.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 4
1 1. 2. Rec or d Rete nti o n
T o e na ble e val uati o ns a n d/ or a u dits fr o m re g ulat or y  a uth orities or Pfizer, t he i n vesti gat or 
a grees t o kee p rec or ds, i ncl u di n g t he i de ntit y of all partici pati n g s u bjects (s ufficie nt 
i nf or mati o n t o li n k rec or ds, e g, C R Fs a n d h os pital rec or ds), all ori gi nal si g ne d i nf or me d 
c o nse nt d oc u me nts, c o pies of all C R Fs, s afet y re p orti n g f or ms, s o urce d oc u me nts, a n d 
detaile d rec or ds of treat me nt dis p ositi o n, a n d a de q uate d oc u me ntati o n of rele va nt 
c orres p o n de nce (e g, letters, meeti n g mi n utes, a n d tele p h o ne call re p orts).  T he rec or ds s h o ul d 
be retai ne d b y t he i n vesti gat or ac c or di n g t o t he I C H g ui deli nes, acc or di n g t o l ocal 
re g ulati o ns, or as s pecifie d i n t he cli nical st u d y a gree me nt ( C S A), w hic he ver is l o n ger.
If t he i nvesti gat or bec o mes u na ble f or a n y  reas o n t o c o nti n ue t o retai n st u d y rec or ds f or t he 
re q uire d peri o d (e g, retire me nt, rel ocati o n), Pfizer s h o ul d be pr os pecti vely n otifie d.  T he 
st u d y rec or ds m ust be tra nsferre d t o a desi g nee acce pta ble t o Pfizer, s uc h as an ot her 
i n vesti gat or, a n ot her i nstit uti o n, or a n i n de pe n de nt t hir d part y arra n ge d b y Pfizer.  
I n vesti gat or rec or ds m ust be ke pt f or a mi ni m u m of 1 5 ye ars after c o m pleti o n or 
disc o nti n uati o n of t he st u d y or f or l o n ger if re q uire d b y  a p plica ble l ocal re g ulatio ns.
T he i n vesti gat or m ust o btai n Pfizer's writte n per missi o n bef ore dis p osi n g of a ny rec or ds, 
e ve n if ret e nti o n re q uire me nts ha ve bee n met.
1 2. E T HI C S
1 2. 1. I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee
It is t he res p o nsi bilit y of t he i n vesti gat or t o ha ve pr os pective a p pr o val of t he st u d y  pr ot oc ol, 
pr ot oc ol a me n d me nts, i nf or me d c o nse nt d oc u me nts, a n d ot her rele va nt d oc u m e nts, 
e g, recr uit me nt a d vertise me nts, if a p plica ble, fr o m t he IR B/ E C.  All c orres p o n de nce wit h t he 
I RB/ E C s h o ul d be retai ne d i n t he i n vesti gat or fil e.  C o pies of I R B/ E C a p pr o vals s h o ul d be 
f or war de d t o Pfizer.
T he o nl y  circ u msta nce i n w hic h a n a me n d me nt may be i nitiate d pri or t o I R B/ E C a p pr o val is 
w here t he c ha n ge is necessar y  t o eli mi nate a p pare nt i m me diate hazar ds t o t he s u bjects.  I n 
t hat e ve nt, t he i n vesti gat or m ust n otif y t he I R B/ E C a n d Pfizer i n writi n g i m me diatel y after 
t he i m ple me ntati o n.
1 2. 2. Et hic al C o n d uct of t he St u d y
T he st u d y  will be c o n d ucte d i n acc or da nce wit h le gal a n d re g ulat or y re q uire me nts, as well as 
t he ge neral pri nci ples set f ort h i n t he I nter nati o nal Et hical G ui deli nes f or Bi o me dical 
Researc h I n v ol vi n g H u ma n S u bjects ( C o u ncil f or I nter natio nal Or ga nizati o ns of Me dical 
Scie nces 2 0 0 2), G ui deli nes f or G C P (I C H 1 9 9 6), a n d t he Declarati o n of Helsi n ki ( W orl d 
Me dical Ass ociati o n 1 9 9 6 a n d 2 0 0 8). 
I n a d diti o n, t he st u d y will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol, t he IC H g ui deli ne 
o n G C P, a n d a p plica ble l ocal re g ulat or y re q uire me nts a n d la ws.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 5
1 2. 3. S u bject I nf or m ati o n a n d C o nse nt
All parties will e ns ure pr otecti o n of s u bject pers o nal data a n d will n ot i n cl u de s u bject na mes 
or ot her i de ntifia ble data i n a n y  re p orts, p u blicati o ns, or ot her discl os ures, e xce pt w here 
re q uire d by la w. 
W he n st u d y  data are c o m pile d f or tra nsfer t o Pfizer a n d ot her a ut h orize d parties, s u bject 
na mes, a d dresses, a n d ot h er i de ntifi a ble data will be re place d b y a n u merical c o de base d o n a 
n u m beri n g s ys te m pr o vi de d b y Pfizer i n or der t o de-i de ntif y st u d y s u bjects.  T he st u d y site 
will mai ntai n a c o nfi de ntial li st of s u bjects w h o partici pate d i n t he st u d y, li n ki n g eac h 
s u bject’s n u meri cal c o de t o his or her act ual i de ntit y .  I n case of data tra nsfer, Pfizer will 
mai ntai n hi g h sta n dar ds of c o nfi de ntialit y a n d pr otecti o n of s u bjects’ pers o nal data c o nsiste nt 
wit h a p plica ble pri vac y  la ws.
T he i nf or me d c o nse nt d oc u me nts m ust be i n c o m plia nc e wit h I C H G C P, l ocal re g ulat or y  
re q uire me nts, a n d le gal re q uire me nts, i ncl u di n g a p plica ble pri vac y la ws.
T he i nf or me d c o nse nt d oc u me nts use d d uri n g t he i nf or me d c o nse nt pr ocess m us t be 
re vie we d a n d a p pr o ve d b y t he s p o ns or, a p pr o ve d b y t he I R B/ EC bef ore us e, a n d a vaila ble f or 
i ns pecti o n.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  s u bject ( or his or her le gally acce pta ble 
re prese ntati ve) is f ully i nf or me d a b o ut t he nat ure a n d o bje cti ves of t he st u d y a n d p ossi ble 
ris ks ass ociate d wit h partici pati o n. 
W he n e ver c o nse nt is o btai ne d fr o m a s u bject’s le gall y acce pta ble re prese ntati ve, t he 
s u bject’s asse nt (affir mati ve a gree me nt) m ust s u bse q ue ntl y be o btai ne d w he n t he s u bject has 
t he ca pacit y t o pr o vi de asse nt, as deter mi ne d b y t he IR B/ E C.  If t he i n v esti gat or deter mi nes 
t hat a s u bject’s decisi o nal ca pacity is s o li mite d he/s he ca n n ot reas o na bl y be c o ns ulte d, t he n, 
as per mitte d b y t he I R B/ E C a n d c o nsiste nt wit h l ocal re g ulat or y a n d le gal r e q uire me nts, t he 
s u bject’s asse nt ma y be wai ve d wit h s o urce d oc ume ntati o n o f t he reas o n asse nt was n ot 
o btai ne d.  If t he st u d y s u bject d oes n ot pr o vi de his or her o w n c o nse nt, t he s o urce d oc u me nts 
m ust rec or d w h y t he s u bject di d n ot pr o vi de c o nse nt (e g, mi n or, decisi o nall y  i m paire d a d ult), 
h o w t he i n vesti gat or deter mi n e d t hat t he pers o n si g ni n g t he c o nse nt was t he s u bject’s le gall y 
acce pta ble re prese ntati ve, t he c o nse nt si g ner’s relati o ns hi p t o t he st u d y  s u bject (e g, pare nt, 
s p o use), a n d t hat t he s u bject’s asse nt was o btai ne d, or wai ve d.  If asse nt is o btai ne d ver ball y 
it m ust be d oc u me nte d i n t he s o urce d oc u me nts.
T he i n vesti gat or, or a pers o n desi g nate d b y t he i n vesti gat or, will o btai n writte n i nf or me d 
c o nse nt fr o m eac h s u bject or t he s u bject’s le gall y acc e pta ble re prese ntati ve bef ore a n y 
st u d y-s pecific acti vit y is perf or me d.  T he i n vesti gat or will retai n t he ori gi nal of eac h s u bject's 
si g ne d c o nse nt d oc u me nt.
1 2. 4. S u bject Recr uit me nt
S u bject recr uit me nt eff orts are n ot re q uire d f or t his st u d y  beca use t his is a n e xte nsi o n st u d y.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6
1 2. 5. Re p orti n g of S afet y Iss ues a n d Seri o us Bre ac he s of t he Prot 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) by a n a p plica ble 
c o m pete nt a ut h orit y 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 on of t he be nefits a n d ris ks of t he i n vesti gati o nal 
pr o d uct, Pfizer s h o ul d be i nf or me d i m me diatel y . 
I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety meas ures 
ta ke n by t he i n vesti gat or t o pr otect t he st u d y s u bjects a gai nst a n y  i m me diate hazar d, a n d of 
a n y seri o us breac hes of t his pr ot oc ol or of I C H G C P t hat t he i n vesti gat or bec o mes a ware of.
1 3. D E FI NI TI O N O F E N D O F T RI A L
1 3. 1. E n d of Tri al i n a Me m ber St ate 
E n d of trial i n a Me m ber State of t he E ur o pea n U ni o n is defi ne d as t he ti me a t w hic h it is 
dee me d t hat a s ufficie nt n u m ber of s u bjects ha ve bee n recr uite d a n d c o m pl ete d t he st u d y as 
state d i n t he re g ulat or y a p plicati o n (ie, cli nical trial a p plicati o n [ C T A]) a n d et hics a p plicati o n 
i n t he Me m ber State.  P o or recr uit me nt (recr uiti n g less t ha n t he a ntici pate d n u m ber i n t he 
C T A) b y  a Me m ber State is n ot a reas o n f or pre mat ure ter mi nati o n b ut is c o nsi dere d a 
n or mal c o ncl usi o n t o t he st u d y  i n t hat Me m ber State.
1 3. 2. E n d of Tri al i n All Ot her P artici p ati n g C o u ntries 
E n d of Trial i n all ot her partici pati n g c o u ntries is defi ne d as Last S u bject Last Visit.
1 4. S P O N S O R DI S C O N TI N U A TI O N C R I T E RI A
Pre mat ure ter mi nati o n of t his st u d y  ma y occ ur beca use of a re g ulat or y a ut h orit y decisi o n, 
c ha n ge i n o pi ni o n of t he I R B/ E C, or i n vesti gati o nal pr o d uct safet y  pr o ble ms, or at t he 
discreti o n of Pfizer.  I n a d diti o n, Pfizer retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of 
tafa mi dis at a ny ti me.
If a st u dy is pre mat urel y ter mi nate d or disc o nti n ue d, Pfizer will pr o m ptl y n otif y t he 
i n vesti gat or.  After n otificati o n, t he i nvesti gat or m ust c o ntact all partici pati n g s u bjects a n d 
t he h os pital p har mac y (if a p plica ble) wit hi n 3 0 da y s.  As directe d b y Pfizer, all st u d y 
materials m ust be c ollecte d a n d all C R Fs c o m plete d t o t he greatest e xte nt p ossi ble.
1 5. P U B LI C A TI O N O F S T U D Y R E S U L T S
1 5. 1. C o m m u nic ati o n of Res ults b y Pfizer
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical trial res ults t hr o u g h p osti n g t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E ur o pea n Cli nical Trials 
Data base ( E u dra C T), a n d/ or w w w . pfizer.c o m, a n d ot her p u blic re gistries i n acc or da nce wit h 
a p plica ble l ocal la ws/re g ul ati o ns. 
I n all cases, st u dy res ults are re p orte d b y Pfizer i n a n o bjecti ve, acc urate, bala nce d, a n d 
c o m plete ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y  or t he c o u ntr y i n 
w hic h t he st u d y  was c o n d ucte d.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 7
w w w.cli nicaltrials. g o v
Pfizer p ost s cli nical trial U S Basic Res ults o n w w w.cli nicaltrials. g o v f or Pfizer-s p o ns ore d 
i nter ve nti o nal st u dies c o n d ucte d i n patie nts t hat e val uate t he safety a n d/ or efficac y of a Pfizer 
p r o d uct, re gar dless of t he ge o gra p hical l ocati o n i n w hic h t he st u d y is c o n d ucte d.  U S Basic 
Res ults are s u b mitte d f or p osti n g wit hi n 1 y ear of t he pri mar y c o m pleti o n date f or st u dies i n 
a d ult p o p ulati o ns.
Pri mar y  c o m pleti o n date is defi ne d as t he date t hat t he fi nal s u bject was e xa mi ne d or 
recei ve d a n i nter ve nti o n f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y  o utc o me, 
w het her t he cli nical st u d y c o ncl u de d acc or di n g t o t he pres pecifie d pr ot oc ol or was 
ter mi nate d.
E u dra C T
Pfizer p osts E U Basic Re s ults o n E u dra C T f or all Pfizer-s p o ns ore d i nter ve nti o nal st u dies t hat 
are i n sc o pe of E U re q uire me nts.  E U Basic Res ults are s u b mitte d f or p osti n g wit hi n 1 year 
of t he pri mar y  c o m pleti o n date f or st u dies i n a d ult p o p ulati o ns or wit hi n 6 m o nt hs o f t he 
pri ma r y c o m pleti o n date f or st u dies i n pe diatric p o p ulati o ns.
w w w. pfizer.c o m
Pfiz er p osts P u blic Discl os ure S y n o pses (cli nical st u d y  re p ort s yn o pses i n w hic h a n y  data 
t hat c o ul d be use d t o i de ntif y i n di vi d ual patie nts ha ve bee n re m o ve d) o n w w w. pfizer.c o m f or 
Pf izer-s p o ns ore d i nter ve nti o nal st u dies at t he sa me ti me t he U S Basic Res ults d oc u me nt is 
p oste d t o w w w.cli nicaltrials. g o v.
1 5. 2. P u blic ati o ns b y I n vesti g at ors
Pfizer s u p p orts t he e xercise of aca de mic free d o m a n d has n o o bjecti o n t o p u blicati o n b y  t he 
p ri nci pal i nvesti gat or of t he res ults of t he st u d y  base d o n i nf or mati o n c ollecte d or ge nerate d 
b y  t he pri nci pal i n vesti gat or, w het her or n ot t he res ults are fa v ora ble t o t he Pfizer pr o d uct.  
H o we ver, t o e ns ure a gai nst i na d verte nt discl os ure of c o nfi de ntial i nf or mati o n or u n pr otecte d 
i n ve nti o ns, t he i n vesti gat or will pr o vi de Pfizer a n o p p ort u nit y t o re vie w a n y pr o p ose d 
p u blicati o n or ot her t y pe of discl os ure of t he res ults of t he st u d y (c ollecti vel y, “ P u blicati o n”) 
bef ore it is s u b mitte d or ot her wise discl ose d.
T he i n ve sti gat or will pr o vi de a n y p u blicati o n t o Pfizer at least 3 0 d a y s bef ore it is s u b mitte d 
f or p u blicati o n or ot her wise discl ose d.  If a n y pate nt acti o n is re q uire d t o pr otect i ntellect ual 
pr o pert y ri g hts, t he i n vesti gat or a grees t o dela y  t he disclos ure f or a peri o d n ot t o e xcee d a n 
a d diti o nal 6 0 da y s.
T he i n vesti gat or will, o n re q ue st, re m o ve a n y pre vi o usl y u n discl ose d c o nfi de ntial 
i nf or mati o n bef ore discl os ure, e xce pt f or a ny st u d y - or Pfizer pr o d uct -relate d i nf or mati o n 
necessar y  t o t he a p pr o priate scie ntifi c prese ntati o n or u n dersta n di n g of t he st u d y  res ults.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 8
If t he st u dy is part o f a m ultice nter st u d y, t he i n vesti gat or a grees t hat t he first p u blicati o n is 
t o be a j oi nt p u blicati o n c o veri n g all st u d y sites, a n d t hat a n y s u bse q ue nt p u blicati o ns b y t he 
pri nci p al i n vesti gat or will refere nce t hat pri mar y  p u blicati o n.  H o we ver, if a j oi nt ma n uscri pt 
has n ot bee n s u b mitte d f or p u blicati o n wit hi n 1 2 m o nt hs of c o m pleti o n or ter mi nati o n of t he 
st u d y at all partici pati n g sites, t he i n vesti gat or is free t o p ublis h se par atel y,  s u bject t o t he 
ot her re q uire me nts of t his secti o n.
F or all p u blicati o ns relati n g t o t he st u d y , t he i nstit uti o n will c o m pl y wit h rec o g nize d et hical 
sta n dar ds c o ncer ni n g p u blicati o ns a n d a ut h ors hi p, i ncl u di n g Secti o n II - “ Et hical 
C o nsi dera ti o ns i n t he C o n d uct a n d Re p orti n g of Researc h” of t he U nif or m Re q uire me nts f or 
Ma n uscr i pts S u b mitte d t o Bi o me dical J o ur nals, htt p:// w w w.ic mje. or g/i n de x. ht ml #a ut h ors hi p, 
esta blis he d b y t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors.
P u blicati o n of st u d y res ults is als o pr o vi de d f or i n t he C S A bet wee n Pfizer a n d t he 
i nstit uti o n.  In t his secti o n e ntitle d P u blicati o ns b y  In vesti gat ors , t he defi ne d ter ms s hall ha ve 
t he mea ni n gs gi ve n t o t he m i n t he C S A.
If t here is a ny c o nflic t bet wee n the C S A a n d a n y Attac h me nts t o it, t he ter ms of t he C S A 
c o ntr ol.  If t here is a n y c o nflict bet wee n t his pr ot oc ol a n d t he C S A, t his pr ot oc ol will c o ntr ol 
as t o a n y iss ue re gar di n g treat me nt of st u d y s u bjects, a n d t he C S A will c o ntr ol as t o all ot her 
iss ues.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 7 9
1 6. R E F E R E N C E S 
1.
Al mei da M R, Mace d o B, Car d os o I, et al.  Selecti ve bi n di n g t o tra nst h yr eti n a n d 
tetra mer sta bilizati o n i n ser u m fr o m patie nts wit h fa milial a m yl oi d otic p ol y ne ur o pat hy 
b y  a n i o di nate d difl u nisal deri vati ve.  Bi oc he m. J. 2 0 0 4; 3 8 1: 3 5 1- 5 6.
2.  
Gertz M A , S ki n ner M, C o n n ors L H, et al.  Selecti ve bi n di n g of nife di pi ne t o a m y l oi d 
fi brils. A m J Car di ol. 1 9 8 5; 5 5 ( 1 3 Pt 1): 1 6 4 6.
3.
Gree n C P, P orter C B, Bres na ha n D R, et al.  De vel o p me nt a n d e val uati o n of t he Ka nsas 
Cit y  Car di o m yo pat h y  Q uesti o n naire: a ne w healt h s tat us meas ure f or heart fail ure. J A m 
C oll Car di ol o g y  2 0 0 0; 3 5: 1 2 4 5- 5 5.
4.
Ra pezzi C, et al. Tra nst h y reti n-relate d a myl oi d oses a n d t he heart: a cli nical o ver vie w. 
Nat Re v Car di ol 2 0 1 0; 7: 3 9 8- 4 0 8.
5. 
R u bi n o w A, S ki n ner M, a n d C o he n A S.  Di g o xi n se nsiti vi t y i n a myl o i d 
car di o my o pat h y. Circ ulati o n 1 9 8 1; 6 3: 1 2 8 5 - 8 8.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 0
A p pe n di x 1. A b bre vi ati o ns 
T his is a list of a b bre vi ati o ns t h at m a y be use d i n t he pr ot oc ol. 
A b bre vi ati o n
Ter m
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
B B S
Bi os peci me n Ba n ki n g S y ste m
B MI
B o d y Mass I n de x
C R F
case re p ort f or m
C S A
cli nical st u d y a gree me nt
C T A
cli nical trial a p plicati o n
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
D AI
d osa ge a n d a d mi nistrati o n i nstr ucti o ns
D M C
data m o nit ori n g c o m mittee
D N A
d e o x yri b o n uc leic aci d
D U
dis pe nsa ble u nit
E C
et hics c o m mittee
E C G
electr ocar di o gra m
E D M C
e xter nal data m o nit ori n g c o m mittee 
E D P
e x p os ure d uri n g pre g na nc y
E D T A
e detic aci d (et h yl e ne dia mi netetraacetic aci d)
E u dra C T
E ur o pea n Cli nical Trials Data base
F D A
F o o d a n d Dr u g A d mi nistrati o n ( U nite d States)
F S H
f ollicle-sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
H F p E F
h eart fail ure wit h preser ve d ejecti o n fracti o n
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 nfere nce o n Har m o nisati o n
I D
i de ntificati o n
I ND
i n vesti gati o nal ne w dr u g a p plicati o n
I N R
i nter nati o nal n or malize d rati o
I RB
i nstit uti o nal re vie w b oar d
I R C
i nter nal re vie w c o m mittee
I R T
i nteracti ve res p o nse tec h n ol o g y
I UD
i ntra uteri ne de vice
I U S
i ntra uteri ne sy ste m
I V R
interacti ve v oice res p o nse
K 2E D T A
di p otassi u m et h y le ne dia mi netetraacetic aci d
K C C Q
Ka nsas Cit y  Car di o m yo pat h y  Q uesti o n naire
L F T
li ver f u ncti o n test
m B MI
M o difie d B o d y Mass I n de x
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 1
A b bre vi ati o n
Ter m
M G U S
M o n ocl o nal ga m m o pat h y of u n deter mi ne d si g nifica nce
M R
M ol ar rati o
N / A
n ot a p plica ble
N S AI D
n o n -ster oi dal a nti-i nfla m mat or y dr u g
N T -pr o B N P
N -ter mi nal pr o-h or m o ne brai n natri uretic pe pti de
N Y H A
Ne w Y or k Heart Ass ociati o n
P T
pr ot hr o m bi n ti me
Q Tc ( B a n d F)
C orrecte d E C G Q T I nter val usi n g t he Bazett’s or Fri der icia’s 
c orrecti o n
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
SI B
s uici dal i deati o n a n d be ha vi or
S O P
sta n dar d o perati n g pr oce d ure
S P C
s u m mar y of pr o d uct c haracteristics
S R S D
si n gle refere nce safety d oc u me nt
S SI D
st u d y-s pecific i de ntificati o n n u m ber
T T R
tra nst h yreti n
A T T R -P N
tra nst h yreti n p ol yne ur o pat h y
T T R -C M or 
A T T R -C M
tra nst h yreti n car di o m yo pat h y
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 pac ka ge i nsert
W O C B P
W o ma n of C hil d Beari n g P ote ntial
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 2
A p pe n di x 2. K a ns as Cit y C ar d i o m y o p at h y Q uesti o n n aire
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 3
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 4
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 5
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 6
A p pe n di x 3. Ne w Y or k He art Ass oci ati o n Cl assific ati o n
A d o pte d fr o m: D ol gi n M, e dit or.  N o me nclat ure a n d Criteria f or Dia g n osis of Diseases of t he Heart a n d Great Vessels.  T he 
Criteria C o m mittee of t he Ne w Y or k Heart Ass ociati o n.  9t h e d. B ost o n: Little Br o w n & C o, 1 9 9 4: 2 5 3 – 2 5 6.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 7
A p pe n di x 4. C o u ntr y -s pecific Pr ot oc ol Re q uire me nts
A p pe n di x 4. 1. St u d y D ur ati o n
Fra nce a n d Ger ma n y o nl y: T he B 3 4 6 1 0 4 5 st u d y will e n d 2 4 m o nt hs after t he i nitial pr ot oc ol 
a p pr o val date b y t he l ocal C o m pete nt A ut h orit y .  C o nti n uati o n after t he i nitial pr ot oc ol 
a p pr o val peri o d will de pe n d o n re vie w of t he fi nal Cli nical St u d y  Re p ort f or pare nt st u d y 
B 3 4 6 1 0 2 8 b y t he l ocal C o m pete nt A ut h orit y.
A p pe n di x 4. 2. St u d y Pr oce d ures
Fra nce a n d Ger ma n y o nl y: S u bjects are re q uire d t o ret ur n t o t he st u d y  site f or a d diti o nal 
pr oce d ures at M o nt h 3.
Ja pa n o nl y: Per l ocal c ust o m, st u d y sites t o c o ntact all e nr olled s u bjects b y t ele p h o ne at 
2 wee ks ( ± 1 wee k) a n d 1 m o nt h ( ± 1 wee k) after i nitiati o n of tafa mi dis 6 1 m g t o c hec k f or 
a d verse e ve nts/ m o n it or safety.
A p pe n di x 4. 3. Fr a nce C o ntr at U ni q ue
T his i nf or mati o n relates t o re q uire me nts f or G C P Trai ni n g, I n vesti gati o nal P r o d uct, a n d
I ns pecti o ns i n Fra nce.  T he f oll o wi n g s u p ple me ntar y te xt s h o ul d be rea d i n c o nj u ncti o n wit h 
t his pr ot oc ol: 

G C P Trai ni n g: Pri or t o e n r oll me nt of a ny s u bjects, t he i n vesti gat or a n d a n y 
s u b-i n vesti gat ors will c o m plete t he Pfizer-pr o vi de d G o o d Cli nical Pract ice trai ni n g 
c o urse (“ Pfizer G C P Trai ni n g”) or trai ni n g dee me d e q ui vale nt b y  Pfizer.  A n y 
i n vesti gat ors w h o later j oi n t he St u d y will c o m plete t he Pfizer G C P Trai ni n g or 
e q ui vale nt bef ore perf or mi n g St u d y -relate d d uties.  F or st u dies of a p plica ble d urati o n, 
t he i n vesti gat or a n d s u b-i n vesti gat ors will c o m plete Pfizer G C P Trai ni n g or 
e q ui vale nt e ver y t hree ye ars d uri n g t he ter m of t he St u d y,  or m ore ofte n if t here are 
si g nifica nt c ha n ges t o t he IC H G C P g ui deli nes or c o urse materials. 

I n vesti gati o nal Pr o d uct: N o s u bjects or t hir d -part y  p a yers will be c har ge d f or 
i n vesti gati o nal pr o d uct. 

I ns pecti o ns: T he i n vesti gat or(s) will n otif y Pfizer or its ser vice pr o vi der 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 herm ore, t he 
in vesti gat or will c o o perate wit h Pfizer or its ser vice pr o vi der t o pre pare t he st u d y  site 
f or t he i ns pecti o n a n d will all o w Pfizer or its ser vice pr o vi der (if n ot pr o hi bite d b y 
la w) t o be prese nt d uri n g t he i ns pecti o n.  T he st u d y site a n d i n vestigat or will 
pr o m ptl y  res ol ve a ny discre pa ncies t hat are i de ntifie d bet wee n t he st u d y data a n d t he 
s u bject's me dical rec or ds.  T he i n vesti gat or will pr o m ptl y pr o vi de c o pies of t he 
i ns pecti o n fi n di n gs t o Pfizer or its ser vice pr o vi der.  Bef ore res p o nse s u b missi o n t o 
t he re g ulat or y a ut h orities, t he i n vesti gat or will pr o vi de Pfizer or its ser vice pr o vi der 
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 resp o nses t o a n y  s uc h fi n di n gs.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 8
A p pe n di x 5. C o u ntries P artici p ati n g i n C o h ort B
O nl y  st u d y sites i n t he f oll o wi n g c o u ntries may s cree n/e n r oll s u bjects i n C o h ort B:

A ustralia;

Ar ge nti na;

Bel gi u m;

Ca na da;

Czec h Re p u blic;

Fra nce;

H o n g K o n g;

Ja pa n;

Net herla n ds;

S pai n;

S we de n;

Tai wa n;

U nite d States.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 8 9
A p pe n di x 6. C o u ntries t h at will P artici p ate i n A p pe n di x 7 f or N e wl y E nr olli n g S u bjects
O nl y  st u d y sites i n c o u ntries liste d bel o w ma y partici pate i n t he ser u m, plas ma, a n d uri ne 
bi o mar ker sa m ple c ollecti o n detaile d i n A p pe n di x 7 . 

A ustralia ;

Fra nce ;

S pai n .
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 9 0
A p pe n di x 7. A d diti o n al S a m ple a n d B a n ke d Bi os peci me n C ollecti o n f or N e wl y E nr olle d 
S u bject s i n C o u ntries L iste d i n A p pe n di x 6
O bjecti ve s:

C ollecti o n of bl o o d a n d uri ne sa m ples t o s u p p ort i de ntificati o n a n d c haracterizati o n 
of bi o m ar kers of tra nst h yreti n a m yl oi d osis.

C ollecti o n of a d diti o nal ba n ke d bi o mar ker sa m ples t o s u p p ort e x pl orat or y researc h 
relati n g t o dr u g res p o nse a n d ot her disease s.
Visit I de ntifier
Scree ni n g
P o p ulati o n
C o h ort B
( wit h o ut disease 
d oc u me ntati o n)
C o h ort B 
( wit h disease 
d oc u me ntati o n)
Visit Wi n d o w
Da y  -3 0
Da y  0
Da y  0
I nf or me d C o nse nt f or C o u ntr y-s pecific Sa m ple a n d 
B a n ke d Bi os peci me n C ollecti o n
X
X
C o u ntr y -s pecific Sa m ple a n d Ba n ke d Bi os peci me n 
C ollecti o n
C ollect bl o o d f or bi o mar kers a n d ba n ke d bi os peci me ns a
X
X
C ollect uri ne f or bi o mar kers a n d ba n ke d bi os peci me ns a
X
X
Rec or d e n d -Diast olic i nter ve ntric ular se ptal wall 
t hic k ness ( m m)a, b
X
X
Rec or d left ve ntric ular p osteri or w all t hic k ness ( m m) a, b
X
X
Rec or d left ve ntric ular ejecti o n fracti o n ( %) a, b
X
X
a.
O nl y f or ne wl y e nr olli n g s u bjects i n c o u ntries liste d i n A p pe n di x 6 .
b.
C ollect t his data fr o m me dical hist or y o nl y if a n ec h ocar di o gra p h perf or me d i n last 1 2 m o nt hs pri or t o e nr oll me nt is 
a vaila ble. T his ma y be o mitte d if u na vaila ble. Data ca n be e ntere d at a s u bse q ue nt st u d y visit.
At t he Scree ni n g visit ( Da y 0), bl o o d a n d uri ne sa m ples will be c ollecte d fr o m ne wl y 
e nr ol le d s u bjects i n t he c o u ntries i de ntifie d i n A p pe n di x 6 .  T hese s u bjects will ha ve 
c o nfir me d dia g n osis of A T T R -C M b ut ha ve ne ver ta ke n tafa mi dis.  T hese sa m ples will be 
use d t o s u p p ort i de ntificati o n a n d c haracterizati o n of ser u m, plas ma , or uri nar y bi o mar k ers of
tra nst h yr eti n a myl oi d osis. Res ults of t hese a nal ys es will be re p orte d else w here.
I de ntifie d bi o mar kers will be f urt her c haracterize d a n d vali date d usi n g sa m ples fr o m ot her 
st u dies i n patie nts wit h h eart fail ure wit h preser ve d ejecti o n fracti o n ( H F p E F), or i ma gi n g
evi de nce c o nsiste nt wit h or s u g gesti ve of H F p E F or A T T R -C M w h o ha ve bee n 
c o m pre he nsi vel y e val uate d f or A T T R-C M.   
At t he Scree ni n g visit ( Da y 0) t he f oll o wi n g pr oce d ures will be c o n d ucte d:

A d diti o nal I nf or me d c o nse nt f or sa m pl e c ollecti o n .
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)

Tafa mi dis me gl u mi ne ( P F -0 6 2 9 1 8 2 6)
B 3 4 6 1 0 4 5
Fi nal Pr ot oc ol A me n d me nt 5 , 2 4 Ja n uar y 2 0 2 0
P FI Z E R C O N FI D E N TI A L
Pa ge 9 1

C ollect bl o o d a n d uri ne sa m ples f or t he f oll o wi n g:

A T T R bi o mar ker i de ntificati o n:

4 5 m L  bl o o d ( 7. 5 m L  i n eac h of 6 t u bes) i ncl u di n g 2 K 2-E D T A plas ma 
sa m ples, 2 lit hi u m he pari n plas ma sa m ples, a n d 2 ser u m sa m ple t u bes;

1 0 m L  uri ne.

Ba n ke d Bi os peci me ns:

2. 5 m L  w h ole bl o o d P re p R 1 o pti mize d f or R N A;

1 0 m L  w h ole bl o o d Pre p B 1 o pti mize d f or plas ma;

1 0 m L  uri ne ( Pre p M 2).

C ollect t he f oll o wi n g ec h ocar di o gra p hy para meters fr o m patie nt me dical rec or ds
fr o m t he pre vi o us 1 2 m o nt hs pri or t o e nr o ll me nt, if a vaila ble.  O nl y t he m ost re ce nt 
ec h ocar di o gra p h s h o ul d be use d if t here are m ulti ple res ults fr o m t he pre vi o us 
1 2 m o nt hs.   

E n d -Diast olic i nter ve ntric ular se ptal wall t hic k ness ( m m) ;

Left ve ntric ular p os teri or wall t hic k ness ( m m);

Left ve ntric ula r ejecti o n fracti o n ( %).
Ba n ke d Bi os p eci me ns will be c ollecte d as l ocal re g ulati o ns a n d I R Bs/ E Cs all o w. 
Ba n ke d Bi os peci me ns ma y  be use d f or e x pl orat or y researc h relati n g t o t he dr u g res p o nse, t he 
disease u n der s t u d y a n d ot her diseases as descri be d i n Secti o ns 7. 5 a n d 7. 5. 1 .  Ge nes a n d 
ot her a nal yt es (e g, pr otei ns, R N A, n o n dr u g meta b olites) ma y  be st u die d usi n g t he ba n ke d 
sa m ples.
Detaile d i nstr ucti o ns o n c ollecti o n, p r ocessi n g, st ora ge, s hi p me nt 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 i n t he st u d y la b orat or y  ma n ual.
0 9 0 1 7 7 e 1 9 2 a d a c 7 4\ A p pr o v e d\ A p pr o v e d O n: 2 8- J a n- 2 0 2 0 1 2: 2 3 ( G M T)