Conditions: Transthyretin (TTR) Amyloid Cardiomyopathy
Keywords: amyloidosis amyloid transthyretin TTR ATTR-CM
Allocation: NA | Intervention model: PARALLEL
Enrollment: 1733
Healthy volunteers: no

Brief summary:
Open label study to evaluate tafamidis for the treatment of transthyretin cardiomyopathy

Detailed description:
Global Phase 3, open label long term extension safety study designed to obtain additional safety data for tafamidis meglumine 20 mg and 80 mg (or tafamidis 61 mg where available), and to continue to provide enrolled subjects with tafamidis for up to 60 months, or until subject has access to tafamidis for ATTR CM via prescription, whichever occurs first.

Arms:
arm 1: Active treatment - 61 mg or if not available, tafamidis meglumine 80 mg

Interventions: intervention 1: Tafamidis
Intervention descriptions: intervention 1: Soft gel capsules administered once a day for 60 months

Protocol document:
Prot_000.pdf: 
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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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
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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
Pa ge 4 9

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)

SAP_001.pdf: 
Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
PFIZER CONFIDENTIAL
Page 1
TMF Doc ID: 98.03
Protocol B3461045
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)
Statistical Analysis Plan 
(SAP)
Author:
 
Version:
5
Date:
11-Mar-2021
090177e1967e7e9c\Approved\Approved On: 11-Mar-2021 17:53 (GMT)
PPD


Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
PFIZER CONFIDENTIAL
Page 2
TMF Doc ID: 98.03
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................9
2.1. Study Objectives .......................................................................................................9
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoint(s) ................................................................................................10
3.2. Secondary Endpoint(s) ............................................................................................10
3.3. Other Endpoints.......................................................................................................11
3.4. Baseline Variables...................................................................................................11
3.5. Safety Endpoints .....................................................................................................12
3.5.1. Adverse Events...........................................................................................12
4. ANALYSIS SETS ...............................................................................................................12
4.1. Full Analysis Set .....................................................................................................12
4.2. Per Protocol Analysis Set........................................................................................12
4.3. Safety Analysis Set..................................................................................................12
4.4. Other Analysis Sets .................................................................................................12
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................13
5.2. General Methods .....................................................................................................13
5.3. Methods to Manage Missing Data ..........................................................................13
6. ANALYSES AND SUMMARIES ......................................................................................13
6.1. Primary Endpoint(s) ................................................................................................13
6.1.1. All-cause Mortality.....................................................................................13
6.2. Other Endpoint(s)....................................................................................................14
6.2.1. Cardiovascular-related Mortality................................................................14
6.2.2. Hospitalization............................................................................................14
6.2.3. Kansas City Cardiomyopathy Questionnaire..............................................14
6.2.4. New York Heart Association......................................................................15
090177e1967e7e9c\Approved\Approved On: 11-Mar-2021 17:53 (GMT)


Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
PFIZER CONFIDENTIAL
Page 3
TMF Doc ID: 98.03
6.2.5. Body Mass Index/modified Body Mass Index ...........................................15
6.2.6. NT-proBNP and Troponin I........................................................................15
6.3. Subset Analyses.......................................................................................................16
6.4. Baseline and Other Summaries and Analyses.........................................................16
6.5. Safety Summaries (including other endpoints) .......................................................16
6.5.1. Adverse Events...........................................................................................16
6.5.2. Laboratory Data..........................................................................................17
6.5.3. Electrocardiogram.......................................................................................17
6.5.4. Physical Examinations and Vital Signs ......................................................17
7. INTERIM ANALYSES.......................................................................................................17
7.1. Introduction .............................................................................................................17
7.2. Interim Analyses and Summaries............................................................................17
8. REFERENCES ....................................................................................................................18
9. APPENDICES .....................................................................................................................19
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................5
Table 2.
Summary of Definition for Baseline Values ............................................11
LIST OF FIGURES
Figure 1.
Flowchart of Study Participation..............................................................10
APPENDICES
Appendix 1. SUMMARY OF ANALYSES............................................................................19
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................20
Appendix 2. STATISTICAL METHODOLOGY DETAILS..................................................21
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Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
PFIZER CONFIDENTIAL
Page 4
TMF Doc ID: 98.03
1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for Study B3461045 is based on the protocol global 
amendment 4 dated 09 August 2019 and United States specific PACL dated November 26, 
2019.  
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
Changes are captured in 
the summary of changes 
table (Table 1)
Amendment to make minor corrections to the SAP
3
Amended to reflect the 
protocol amendment 3. 
Changes are captured in 
summary of major 
changes table (Table 1)
Amended to reflect the protocol amendment 3 
4
Amended to reflect the
protocol amendment 4.
Changes are captured in 
summary of major 
changes table (Table 1)
Amended to reflect the protocol amendment 4
5
Added analyses of select 
endpoints excluding data 
from site 1121 (all 
subjects) to address a
potential quality event
identified at the site.
Amended to add analyses to address a potential 
quality event identified at site 1121
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Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
PFIZER CONFIDENTIAL
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TMF Doc ID: 98.03
Table 1.
Summary of Major Changes in SAP Amendments
Amendment 1 (Version 2)
Section of the SAP
Summary of Change
Rationale
3.3. Other Endpoints
Updated KCCQ related domain 
and summary scores
Updated to be consistent with the 
developers’ names for the KCCQ 
domain and summary scores
3.4. Baseline Variables
Updated “Day 0”, the screening 
visit as the baseline for all 
endpoints in study B3461045, 
except for mortality- based and 
KCCQ endpoints
Updated to accurately reflect “Day 0” 
as baseline vs “Day 1”
4.4. Other Analysis Sets
Added definition of “Combined 
Mortality Analysis Set” 
Will be used to conduct mortality 
based analyses on combined mortality 
data across studies B3461028 and its 
extension B3461045
6.1.1. All-cause Mortality
Clarified that analysis will be 
done using “Combined Mortality 
Analysis Set”
Updated to clarify the analysis set to 
be used in all-cause mortality analysis 
6.1.1. All-cause Mortality
Added sensitivity analysis 
treating subjects with heart 
transplantation or cardiac 
mechanical assist device as 
censored subjects 
Added sensitivity analysis of the 
all-cause mortality analysis
6.1.1. All-cause Mortality
Clarified the “Placebo/Tafamidis” 
as the comparator arm in the “by 
–dose” analysis of mortality 
based endpoints
Subjects that received placebo in the 
parent and were never enrolled in the 
extension study cannot be included in 
“placebo/20mg” or “placebo/80 mg” 
group. The pooled “Placebo/Tafmidis” 
group will be used as the comparator 
arm in the “by-dose” analysis of 
mortality based endpoints
6.2. Other Endpoint(s)
Updated to clarify how data 
collected as part of the 
country-specific amendment 
(Amendment 1) will be handled. 
Updated to clarify how data at 
Month 3 collected as part of 
country-specific amendment will be 
handled.
6.2.3. Kansas City 
Cardiomyopathy 
Questionnaire
Updated KCCQ related domain 
and summary scores
Updated to be consistent with the 
developers’ names for the KCCQ 
domain and summary scores
Appendix 1. SUMMARY OF 
ANALYSES
Updated KCCQ related domain 
and summary scores
Updated to be consistent with the 
developers’ names for the KCCQ 
domain and summary scores
090177e1967e7e9c\Approved\Approved On: 11-Mar-2021 17:53 (GMT)


Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
PFIZER CONFIDENTIAL
Page 6
TMF Doc ID: 98.03
Amendment 2 (Version 3)
Section of the SAP
Summary of Change
Rationale
2.1. Study Objectives
Updated objective to reflect 
addition of Cohort B and to be
consistent with protocol 
amendment
Updated objective to be consistent 
with protocol amendment
2.2. Study Design
Updated study design section  to 
reflect the addition of Cohort B, 
transition of all subjects to open 
label 61 mg dose (where 
available), and to update the 
study flow chart to be consistent
with protocol amendment 
Updated study design section to be 
consistent with protocol amendment
3.4. Baseline Variables
Updated to add definition of 
baseline values for Cohort B
Updated to add definition of baseline 
values for Cohort B
3.5.1 Adverse Events
Updated definition of 
treatment-emergent adverse event
Updated the definition to add more 
clarity
4.3. Safety Analysis Set
Updated to reflect addition of 
Cohort B and removed reference 
to mortality related analyses
Updated to reflect addition of 
Cohort B. Sentence referencing 
mortality based analyses was removed 
after adding more text to Section 4.4 
“Other Analysis Sets” clarifying the 
subjects who will be used in analyzing 
mortality related analyses
4.4. Other Analysis Sets
Updated to clarify the definition 
of “Combined Mortality”
Analysis Set”, and indicate this 
analysis set will only be used for 
time to event analyses of 
Cohort A
Updated to clarify the definition of 
“Combined Mortality” Analysis Set”, 
and indicate this analysis set will only 
be used for time to event analyses of 
Cohort A
5. GENERAL 
METHODOLOGY AND 
CONVENTIONS
Updated to clarify the  timing of 
the final analysis with respect to 
subjects that withdraw from the 
study due to commercial access 
to prescription
Updated to clarify the  timing of the 
final analysis
5.1. Hypotheses and Decision 
Rules
Updated to reflect addition of 
Cohort B and added clarity on the 
type I error rate to be used and 
rationale for not having 
multiplicity adjustment
Updated to reflect addition of 
Cohort B and added clarity on the type 
I error rate to be used and rationale for 
not having multiplicity adjustment
5.2. General Methods
Updated to clarify that all 
summaries for Cohort A will be 
presented using 
“Tafamidis/Tafamidis” and 
“Placebo/Tafamidis” and “by 
dose” summaries are removed 
Since all Cohort A subjects will be on 
61 mg free acid soft gel capsule, 
analyses by dose are not relevant and 
therefore removed
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Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
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Page 7
TMF Doc ID: 98.03
Section of the SAP
Summary of Change
Rationale
6.1.1. All-cause Mortality
Updated to reflect the addition of 
Cohort B and removed “by dose” 
analyses for Cohort A subjects
Updated to reflect the addition of 
Cohort B and all subjects in Cohort A 
moving to the 61 mg free acid 
formulation
Sections 6.2.1. 
Cardiovascular-related 
mortality,
6.2.2. Hospitalization, 6.2.3. 
Kansas City Cardiomyopathy 
Questionnaire, 
6.2.4. New York Heart 
Association, 
6.2.5. Body Mass 
Index/modified Body Mass 
Index, 
6.3. Subset Analyses, 
6.4. Baseline and Other 
Summaries and Analyses, 6.5. 
Safety Summaries (including 
other endpoints)
Updated to reflect the addition of 
Cohort B and indicate descriptive 
summaries will be provided 
separately for Cohorts A and B 
Updated to reflect the addition of 
Cohort B
Section 6.2.3
Added center and subject-within-
center as random effect to the 
repeated measures model
Added center random effect to align 
the model description with the SAS 
code in the appendix and also the 
model used in study B3461028
Section 6.3, and Appendix 1 
Summary of Analyses
Removed references to “pooled 
treatment group”
“pooled treatment group” was used in 
the prior versions of the SAP referring 
to “Tafamidis/Tafmidis” and 
“Placebo/Tafamidis”groups and was
used to distinguish these groups from 
“by dose” analyses treatment groups. 
The “by dose” analyses are removed in 
this amendment and therefore the 
references to “pooled treatment group” 
are also removed
Appendix 1. SUMMARY OF 
ANALYSES
Updated to reflect addition of 
Cohort B and removed “by dose” 
summaries
Updated to reflect addition of Cohort
B and removed “by dose” summaries
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Amendment 3 (Version 4)
Section of the SAP
Summary of Change
Rationale
3.3. Other Endpoints
Updated to reflect the addition of 
NT-proBNP and Troponin I
Updated to be consistent with protocol 
amendment 4
3.4. Baseline Variables
Updated to specify the definition 
of baseline for NT-proBNP and
Troponin I
Updated to specify the definition of 
baseline for NT-proBNP and 
Troponin I
5.3. Methods to Manage 
Missing Data
Clarify that missing data from 
Cohort A subjects who ended 
participation in the study and 
returned subsequently will not be 
imputed
Updated to reflect the protocol
administrative letter (PACL) issued on 
November 26, 2019 allowing Cohort A 
subjects who ended participation to 
return to the study
6.2.3. Kansas City 
Cardiomyopathy 
Questionnaire
Clarified the treatment groups to 
be used in the analysis of KCCQ 
related endpoints
Updated to clarify the treatment 
groups to be analyzed
6.2.6. NT-proBNP and 
Troponin I
Specific analyses for the 2 
endpoints (NT-proBNP and 
Troponin -I) added in protocol 
amendment 4
Updated to be consistent with protocol 
amendment 4
6.5.1. Adverse Events
Clarify how adverse events from 
Cohort A subjects who ended 
participation in the study and 
returned subsequently will be
handled
Updated to reflect the protocol
administrative letter (PACL) issued on 
November 26, 2019 allowing Cohort A 
subjects who ended participation to 
return to the study.
Section 9. APPENDICES
Summary of analyses table in 
Appendix 1 and definition and 
use of visit windows in reporting
in Appendix 1.1. updated to 
reflect the addition of 
NT-proBNP and Troponin I
Updated to be consistent with protocol 
amendment 4
Amendment 4 (Version 5)
Section of the SAP
Summary of Change
Rationale
Various Sections listed below.
2.1. Study Objectives
3.3. Other Endpoints
3.4. Baseline Variables
4.4. Other Analysis Sets
6.2.1. Cardiovascular-related 
mortality
Removed extra spaces and/or 
updated text to correct typos
Removed extra spaces and/or updated 
text to correct typos
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Section of the SAP
Summary of Change
Rationale
6.3. Subset Analyses 
6.4. Baseline and Other
Summaries and Analyses
6.5.1. Adverse Events
Appendix 1.1. Definition and 
Use of Visit Windows in 
Reporting
6.5.2. Laboratory Data
Added analyses of laboratory data 
excluding site 1121
Updated to address a potential quality 
issue at site 1121
6.5.4. Physical Examinations 
and Vital Signs
Added analyses of vital signs data 
excluding site 1121
Updated to address a potential quality 
issue at site 1121
Appendix 1.1. Definition and 
Use of Visit Windows in 
Reporting
Added a paragraph describing 
calculation of visit windows for 
KCCQ, NT-proBNP, Troponin I
endpoints
KCCQ, NT-proBNP, Troponin I
analyses will combine data from 
B3461028. Clarification was provided 
on how visit windows will be
re-calculated for all study visits from 
B3461045
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study B3461045. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
Primary Objectives:

To obtain additional, long-term, safety data for tafamidis in subjects with
transthyretin amyloid cardiomyopathy (ATTR-CM). 

To provide investigational product, tafamidis, to enrolled subjects until local
availability by prescription for the ATTR-CM indication.
2.2. Study Design
This is a Phase 3, open-label long-term extension safety study designed to obtain additional 
safety data for tafamidis meglumine 20 mg and 80 mg (or tafamidis 61 mg where available), 
and to continue to provide enrolled subjects with tafamidis for up to 60 months, or until 
subject has access to tafamidis for ATTR-CM via prescription, whichever occurs first. The 
study will also end before 60 months if the sponsor discontinues the study. Subjects 
withdrawn from the study due to commercial access to prescription tafamidis in their 
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respective countries will be considered study completers. The decision to withdraw subjects 
for transition to commercial tafamidis will be made by the sponsor. 
Eligible study participants will be enrolled in 2 Cohorts: 

Cohort A – Subjects diagnosed with ATTR-CM who completed 30 months of 
participation in Study B3461028. 

Cohort B – Subjects diagnosed with ATTR-CM who have not previously participated 
in Study B3461028.
Figure 1.
Flowchart of Study Participation
Cohort A subjects receiving tafamidis meglumine 20 mg or 80 mg will be assigned to 
tafamidis 61 mg, once daily, in addition to standard of care (eg, diuretics), for up to 
60 months. Subjects will be assigned to tafamidis meglumine 80 mg in regions where 61 mg 
tafamidis is unavailable.
At enrollment, subjects in Cohort B will be assigned to open label 61 mg tafamidis once 
daily, in addition to standard of care (eg, diuretics), for up to 60 months. One dose reduction 
to 20 mg tafamidis meglumine will be permitted for adverse events related to tolerability. 
Subjects will be assigned to 80 mg tafamidis meglumine in regions where 61 mg tafamidis is 
unavailable.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Safety as measured by:

All-cause mortality.

Incidence of treatment-emergent adverse events.
3.2. Secondary Endpoint(s)
Not Applicable.
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3.3. Other Endpoints

Cardiovascular-related mortality.

Frequency of all-cause hospitalization.

Frequency of cardiovascular-related hospitalization (including heart failure, 
arrhythmia, myocardial infarction, stroke and other cardiovascular-related events).

Change from baseline at each visit in Kansas City Cardiomyopathy Questionnaire 
Overall Score and domain scores (Physical limitation, Symptom stability, Symptom
frequency, Symptom burden, Total symptom, Self-efficacy, Social limitation, and 
Quality of life) and Clinical summary score.

New York Heart Association classification at each visit.

Change from baseline in Body Mass Index/modified Body Mass Index at each visit.

Change from baseline in N-terminal pro-hormone brain natriuretic peptide 
(NT-proBNP) concentration at each visit.

Change from baseline in Troponin I concentration at each visit.

Assessment of physical examinations, use of concomitant medications, 
electrocardiograms (ECGs), clinical laboratory testing, vital signs at each visit.
3.4. Baseline Variables
Cohort A Subjects: In the analyses of Cohort A subjects, for all endpoints except for
all-cause and cardiovascular-related mortality,KCCQ, NT-proBNP, and Troponin I, Day 0 of 
the subjects participation in Study B3461045 will be used as baseline.
For time to event endpoints, ie, all-cause mortality and cardiovascular related mortality, the
data from Study B3461028 will be included in the time to event analysis. Therefore, the 
baseline for Study B3461028 will be used as the start time in the time to event analyses.
Table 2.
Summary of Definition for Baseline Values
Endpoints
Baseline Definition
All endpoints except for mortality, KCCQ, 
NT-proBNP, Troponin I
Last observation prior to the subject receiving 
B3461045 study treatment.
All-cause and cardiovascular-related 
mortality,KCCQ (overall and domain scores), 
NT-proBNP, Troponin I
Study day corresponding to baseline measurement in 
the preceding double-blind study B3461028 will be 
used as the start time in all the mortality based 
analysis and as baseline for the KCCQ based 
endpoints (overall, domain, and clinical summary
scores), NT-proBNP, Troponin I
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Cohort B Subjects: In all the analyses of Cohort B subjects, Day 0 of the subjects 
participation in Study B3461045 will be used as baseline.
3.5. Safety Endpoints
3.5.1. Adverse Events
An adverse event is considered treatment emergent in study B3461045 if:

The event occurs during the “effective duration of treatment” (defined in 
Section 6.5.1) in Study B3461045 and was not seen prior to the start of treatment in 
the study B3461045, or

The event was observed prior to the start of study B3461045 but increased in severity 
during treatment in Study B3461045.
4. ANALYSIS SETS
4.1. Full Analysis Set
Not Applicable.
4.2. Per Protocol Analysis Set 
Not Applicable.
4.3. Safety Analysis Set
The safety analysis population consists of all subjects (Cohorts A and B) who are enrolled in 
this study and who have taken at least one dose of study treatment.  
4.4. Other Analysis Sets
The “Combined Mortality Analysis Set” will include all subjects in the ITT-Analysis Set 
from B3461028. Mortality analyses in study B3461045 for Cohort A subjects will combine 
data from subjects in study B3461028, including subjects who died, discontinued in 
B3461028, or didn’t enroll into B3461045 (ie, ITT Analysis Set from B3461028) with 
mortality data through participation in the B3461045 study. This analysis set will be referred 
to as “Combined Mortality Analysis Set”.
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis will be performed when all the subjects enrolled into the the study either 
discontinue (including deaths), or complete the study (60 months), or withdraws from the 
study due to commercial access to prescription tafamidis. Note that subjects withdrawn from 
the study due to commercial access to prescription tafamidis in their respective countries will 
be considered study completers. The study will also end before 60 months if the sponsor 
discontinues the study. Interim analyses may also be performed during the course of the 
study to allow for the reporting of data to the scientific community.
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5.1. Hypotheses and Decision Rules
The primary objective of the study is to obtain additional, long term, safety data for tafamidis 
in subjects with transthyretin cardiomyopathy (ATTR-CM) and to provide investigational 
product, tafamidis, to ATTR-CM subjects who complete 30 months of blinded treatment on 
protocol B3461028 (Cohort A) and to Subjects diagnosed with ATTR-CM who have not 
previously participated in Study B3461028 (Cohort B). Therefore, only limited hypothesis 
testing ie, mortality and change from baseline in KCCQ for Cohort A subjects will be 
performed. All hypothesis testing will be conducted using two-sided tests with alpha = 0.05 
level of significance. Since the primary objective of the study is to collect safety information, 
no multiplicity adjustment will be done. No hypothesis testing will be done on Cohort B 
subjects.
5.2. General Methods 
For Cohort A, analyses will be performed using tafamidis/tafamidis and placebo/tafamidis 
treatment groups. Subjects randomized to tafamidis in parent study B3461028 and continue 
on tafamidis in the extension study B3461045 will be grouped as tafamidis/tafamidis. 
Subjects randomized to placebo in study B3461028 and randomized to tafamidis in the 
extension study B3461045 will be grouped as placebo/tafamidis. 
For Cohort B, since subjects in this Cohort will all be administered the same dose, only 
overall descriptive statistics will be provided.
5.3. Methods to Manage Missing Data
Other than standard approaches for missing dates for adverse events, no data imputation will 
be performed in the study. Missing data from Cohort A subjects who ended participation in 
B3461045 study without achieving the completion criteria of sustainable access to tafamidis 
by prescription, and allowed to return to the study and continue participation until they reach 
protocol defined study completion will not be imputed. Adverse events reported in the CRF 
that occurred between the time a subject ended the participation and subsequently returned
will be evaluated for treatment-emergence in the same manner as adverse events that 
occurred during the study participation. 
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. All-cause Mortality
For Cohort A subjects, time to all-cause mortality will be calculated from Day 1 of the Study
B3461028 based on the “Combined Mortality Analysis Set” as defined in Section 4.4. 
All-cause mortality will be analyzed using SAS Proc Lifetest; p-values will be from the 
log-rank test. Kaplan-Meier survival curves for each treatment group along with median 
survival times (if applicable) will be presented comparing tafamidis/tafamidis group with 
placebo/tafamidis group.
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All-cause mortality will also be analyzed using Cox proportional hazards model with 
treatment, NYHA baseline classification, and TTR genotype (variant and wild-type) as 
factors. Subjects who discontinue for transplantation (ie, heart transplantation and combined 
heart and liver transplantation) or for implantation of a cardiac mechanical assist device, will 
be handled in the same manner as death. Data from subjects who drop out for a liver-only
transplantation will be handled in the same manner as the data from all other censored 
subjects.
To examine the potential effect of including heart transplantation or cardiac mechanical assist 
device as “deaths” in the all-cause mortality analysis, a sensitivity analysis will be performed 
treating all transplantation or cardiac mechanical assist device in the same manner as any 
other censored observation.  
For Cohort B, since subjects in this Cohort will all be administered the same dose, only 
overall descriptive statistics will be provided. Kaplan-Meier survival curve along with 
median survival time (if applicable) will be presented.
6.2. Other Endpoint(s)
As a general rule, data from endpoints that are collected at “Month 3” either in France or 
Germany as part of the country-specific protocol amendment will be included in study 
listings and will be summarized descriptively at that time point but will not be included in 
any inferential analyses. Data at Month 3 from one or two countries will be limited and could 
lead to convergence issues for the models used in the inferential analyses. 
6.2.1. Cardiovascular-related Mortality
For both Cohort A and B, cardiovascular-related mortality will be analyzed separately similar 
to all-cause mortality detailed in Section 6.1.1. Cardiovascular relatedness will be based on 
an evaluation and clinical judgment of the MedDRA preferred terms. 
6.2.2. Hospitalization
The frequency (annualized rate) of all-cause and cardiovascular-related hospitalizations 
during the study will be summarized descriptively separately for Cohort A and B.
Cardiovascular relatedness will be based on an evaluation and clinical judgment of the 
MedDRA preferred terms.
6.2.3. Kansas City Cardiomyopathy Questionnaire
The KCCQ will be summarized by the following summary scores calculated using the 
guidelines established in the KCCQ scoring instructions from the developer:
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Physical limitations 
Self-efficacy
Symptom stability 
Quality of life
Symptom frequency 
Social limitation
Symptom burden 
Overall summary score
Total symptom score 
Clinical summary score
For Cohort A, the overall, domain, and clinical summary scores will be evaluated as a change 
from baseline at each visit using a MMRM (repeated measures mixed model) with an
unstructured covariance matrix (or as appropriate) with center and subject-within-center as a 
random effects and treatment (tafamidis/tafamidis and placebo/tafamidis), visit, TTR 
genotype (variant and wild- type), and visit-by-treatment interaction, as fixed effects and 
baseline score as covariate. Data will also be summarized by each scheduled assessment.
As defined in Section 3.4, the baseline for Study B3461028 will be used as the baseline for 
all KCCQ based analyses. All visits from Study B3461028 will also be included in the 
repeated measures model described above.
For Cohort B, descriptive statistics for change from baseline at each post-baseline visit will 
be provided.
6.2.4. New York Heart Association
For Cohorts A and B, subjects will be evaluated using the New York Heart Association 
(NYHA) classification. Descriptive statistics (frequency) will be presented by clinic visit for 
each classification: Class I, Class II, Class III, and Class IV. The number and percentage of
subjects who improved, worsened, or with no change from baseline will also be presented at 
each visit via a shift table.
6.2.5. Body Mass Index/modified Body Mass Index
For Cohorts A and B, BMI and mBMI values at each visit and change from baseline will be 
presented in summary tables and data listings. Descriptive statistics will be provided by visit.
6.2.6. NT-proBNP and Troponin I
For Cohort A, as defined in Section 3.4, the baseline for Study B3461028 will be used as the 
baseline for all NT-proBNP and Troponin I based analyses. Change from baseline for all 
visits, including the visits from Study B3461028 will be summarized descriptively for 
NT-proBNP and Troponin I by treatment group (tafamidis/tafamidis and placebo/tafamidis).
For Cohort B, descriptive statistics for change from baseline at each post-baseline visit will 
be provided for NT-proBNP and Troponin I.
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6.3. Subset Analyses 
All Cohort A and Cohort B analyses will be repeated by genotype (wild type and variant)
separately.
6.4. Baseline and Other Summaries and Analyses
Subjects disposition, demographics, treatment exposure, and concomitant medications will be 
summarized descriptively for both Cohort A and Cohort B separately.
6.5. Safety Summaries (including other endpoints)
All safety endpoints listed in this section will be analyzed descriptively for Cohorts A and B 
separately.
6.5.1. Adverse Events
All AE data collected on the CRF will be presented in summary tables and data listings. 
All adverse events that are observed from the time of first dosing with study medication until 
the treatment end date will be included in the safety analysis. Adverse events that occurred 
during treatment will be reported separately if the event occurred prior to randomization.
The effective duration of treatment is determined by the lag time. Any event occurring within 
the lag time, whether this occurs during a break in treatment or at the end of treatment, is 
attributed to the corresponding treatment period. A lag of 28 days will be used for this study. 
Treatment emergence is defined in Section 3.5.1.
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by treatment group. The incidence of 
treatment-emergent adverse events will be tabulated by treatment group and by system organ
class. The incidence of treatment-emergent adverse events will be displayed by severity and 
attribution. In addition, the incidence of serious adverse events and adverse events that cause 
withdrawal will be tabulated. All adverse events will be listed. All subjects in both Cohort A
and B will be permitted one open label dose-reduction to 20 mg. All adverse events that led 
to temporary dose discontinuation or dose reduction will be summarized.
For Cohort A subjects who ended participation in B3461045 study without achieving the 
completion criteria of sustainable access to tafamidis by prescription, and allowed to return to 
the study and continue participation until they reach protocol defined study completion, 
adverse events that occurred between the time a subject ended the participation and 
subsequently returned will be collected and evaluated for treatment-emergence in the same
manner as adverse events that occurred during the study participation. 
Given that in B3461045 all subjects will be receiving active treatment, 3-tier analysis will not 
be performed on the adverse events. 
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6.5.2. Laboratory Data
All clinical laboratory data (serum chemistry, coagulation, hematology, and urinalysis) will 
be subjected to clinical review and summarized by frequency of events and mean changes 
from baseline.
There was a Quality Event investigation (PR 2163545) concerning repeated data for the 
assessment of respiratory rate and urine dipstick at site 1121. The investigation could not
confirm whether the repeated data was fraudulent or due to human error. To evaluate the 
impact of these findings on the overall interpretation of the endpoints potentially impacted, 
the laboratory analyses specified above will be repeated by excluding all subject data from
this site 1121. Overall results will be compared to summaries generated by excluding the site 
to assess if there was a meaningful impact on the clinical interpretation. 
6.5.3. Electrocardiogram
ECG values at each visit and change from baseline will be presented in summary tables and 
data listings. Descriptive statistics will be provided for each test result by visit.
Centrally over-read ECG variables will be summarized by mean change from baseline to end 
of study for heart rate, PR interval, QRS width, QT interval, and QTcB (Bazett’s correction) 
and QTcF (Fridericia’s correction) values. Additionally, the incidence of categorical 
increases in QTc intervals will be provided. Categories for QTcB and QTcF are ≥450 msec, 
≥480 msec, and ≥500 msec. Categories for QTcB and QTcF as change from baseline are: 
≥30 msec increase, ≥60 msec increase, and 75 msec increase. QTcF is considered the 
primary QTc value as this correction is anticipated to be more appropriate.
6.5.4. Physical Examinations and Vital Signs
Physical examinations and vital signs (lying and standing blood pressure and pulse, 
respiratory rate, and temperature) will be summarized using descriptive statistics.
To assess the impact of the findings in the Quality Event investigation  described in 
Section 6.5.2, vital signs summaries will also be generated by excluding all subject data from
site 1121. Overall results of vital signs will be compared to summaries generated by 
excluding the site to assess if there was a meaningful impact on the clinical interpretation.
7. INTERIM ANALYSES
7.1. Introduction
Interim analyses may be performed if required to meet regulatory requirements and as 
requested by the Data Monitoring Committee. Interim analyses may also be performed 
during the course of the study to allow for the reporting of data to the scientific community.
7.2. Interim Analyses and Summaries
Interim analyses will include either all the analyses or a subset of the summaries described in 
Sections 5 and 6.
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8. REFERENCES
Not Applicable.
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9. APPENDICES 
Appendix 1. SUMMARY OF ANALYSES
Summary of Proposed Analyses
End Point or Assessment
Overall 
## 
Wild-type 
vs 
Variant 
All cause mortality.#
x
x
Cardiovascular related mortality.#
x
x
Frequency of all cause hospitalization.
x
x
Frequency of cardiovascular related hospitalization 
(including heart failure, arrhythmia, myocardial
infarction, stroke and other cardiovascular related 
events).
x
x
Change from baseline at each visit in Kansas City 
Cardiomyopathy Questionnaire Overall Score,  
domain scores (Physical limitation, Symptom 
stability, Symptom frequency, Symptom burden, 
Total symptom, Self efficacy, Social limitation, 
and Quality of life) and clinical summary score #
x
x
New York Heart Association classification at each 
visit.
x
x
Change from baseline in Body Mass 
Index/modified Body Mass Index at each visit.
x
x
Change from baseline in NT-proBNP at each 
visit #
x
x
Change from baseline in Troponin I at each visit.#
x
x
Assessment of physical examinations, use of 
concomitant medications, electrocardiograms 
(ECGs), clinical laboratory testing, vital signs at 
each visit.
x
x
# Cohort A Analysis will include data from B3461028.
## Overall implies that it is not subgroup analysis. For Cohort A, summaries are provided by 
“Tafamidis/Tafamidis” and “Placebo/Tafamidis” groups. For Cohort B, summaries are provided by “Tafamidis” 
group.
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Appendix 1.1. Definition and Use of Visit Windows in Reporting
For the purpose of this study, Day 1 is defined as the first dose day under this protocol 
(except for mortality-based endpoints,KCCQ, NT-proBNP, and Troponin I).
The following describes the clinical visit windows allowed within the protocol:
Clinic Visits (Months 6, 12, 18, 24, 30, 36, 42, 48, 54) ±2 weeks
End of Study Visit (Month 60) ±2 weeks or Early Study Discontinuation
However, in order to maximize the use of all available data, the visit windows for each visit 
are expanded as follows:
Clinic Visits (Months 6, 12, 18, 24, 30, 36, 42, 48, 54) ±3 months 
All nominal visits (months 6, 12, 18, 24, 30, 36, 42, 48, 54) will use the data as collected 
from that visit. Early termination visits will never replace an existing visit. If the visit 
covered by the windowing rules above is already populated with an existing nominal visit, 
then the early termination visit should be mapped forward to the next 6 month visit.
Data from endpoints that are collected at “Month 3” either in France or Germany as part of 
the country-specific protocol amendment will be summarized descriptively as 
‘Month 3- Unscheduled’ and will not be subject to the windowing rules described above.
Analyses of KCCQ, NT-proBNP, Troponin I will combine data from B3461028 study. For 
these endpoints, visits for B3461045 will be evaluated as “30 Months” plus the visit window
calculated using the B3461045 windowing rules specified above.
090177e1967e7e9c\Approved\Approved On: 11-Mar-2021 17:53 (GMT)


Protocol B3461045 (PF-06291826) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
PFIZER CONFIDENTIAL
Page 21
TMF Doc ID: 98.03
Appendix 2. STATISTICAL METHODOLOGY DETAILS 
Sample SAS code for time to event analysis is given below. 
PROC LIFETEST DATA=xxx PLOTS=(s) graphics;
TIME dur *status(0);
STRATA trt;
RUN;
PROC PHREG DATA=xxx;
MODEL dur*status(0)=trt genotype NYHAbase/ ties=EXACT;
RUN;
Sample SAS code to fit the mixed model repeated measures is given below.  The response 
variable Y is the change from baseline at the study visits. 
PROC MIXED DATA=xxx METHOD=REML EMPIRICAL;
CLASS pid center trt visit genotype;
MODEL y= ybase trt visit genotype trt *visit;
RANDOM int/SUBJECT=center; 
REPEATED visit /SUBJECT= pid (center) r type=UN;
RUN;
090177e1967e7e9c\Approved\Approved On: 11-Mar-2021 17:53 (GMT)