Clinical trial NCT00925002
Conditions: ATTR-PN
Sponsor: Pfizer
Start date: 2009-08-05; Completion date: 2020-07-08
Enrollment: 93 participants; Allocation: NA; Intervention model: 

Brief summary:
This is a Phase 3, open-label study designed to obtain additional long-term safety and efficacy data for oral tafamidis (20 mg soft gelatin capsule) administered once daily (QD). In addition, this study continued to provide tafamidis to Val30Met subjects who had completed Protocol Fx-006 (a 1-year, open-label extension study to Protocol Fx-005 which was a randomized, double-blind, placebo-controlled, 18-month study to evaluate the safety and efficacy of tafamidis) or non-Val30Met subjects who had completed Protocol Fx1A-201 (a Phase 2, open-label study to evaluate TTR stabilization, safety, and tolerability of tafamidis) for up to 10 years or until subjects had access to tafamidis for ATTR-PN via prescription. Upon regulatory approval for the treatment of ATTR-PN in their respective country and access to prescription tafamidis, subjects may have been withdrawn from the study. Such subjects were considered study completers.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Tafamidis
Intervention descriptions: intervention 1: 20 mg oral Fx-1006A daily

Protocol documents:
Prot_000.pdf: 
Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 1
A wholly-owned subsidiary of Pfizer, Inc.
OPEN-LABEL SAFETY AND EFFICACY EVALUATION OF FX-1006A IN 
SUBJECTS WITH TRANSTHYRETIN (TTR) AMYLOIDOSIS
Compound:
Fx-1006A/PF-06291826
Compound Name (if applicable):
Tafamidis
US IND Number (if applicable):
74,866
European Clinical Trial Database 
(EudraCT) Number (if applicable):
2009-011535-12
Protocol Number:
Fx1A-303/B3461023
Phase:
3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing,
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
The name, title, address and telephone number(s) of the sponsor's medical expert for the trial 
is documented in the study contact list located in the coordinator’s manual.


Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 2
Document History
Document
Version Date
Summary of Changes
Amendment 2
05 June 2012
1.
Protocol:  extension of study duration to up to 10 years 
or until subject has access to tafamidis for TTR-FAP via 
prescription.  Upon regulatory approval for the treatment 
of TTR-FAP in their respective country and access to 
prescription tafamidis, subjects may be withdrawn from
the study.  The decision to withdraw subjects in a 
country will be done in consultation between the 
investigator and the sponsor.
2.
Protocol – change in nomenclature for abbreviation of 
TTR-CM and TTR-FAP from ATTR-CM and 
ATTR-PN.
3.
Protocol – change of term “patient” to “subject”.
4.
Protocol number – changed from Fx1A-303 to 
Fx1A-303/B3461023.
5.
Renumbering of sections to align with standard Pfizer 
protocols:
Original section number
New section number
3.1
1.2
3.2
1.2.1
3.3.1
1.2.3
3.3.2
1.2.4
3.4
1.2.2
4
2.1
5.1
3
5.2
3.1
5.3
3.2
6.2
4.1
6.3
4.2
6.4
6.3
7.1
5.2.1
7.2
5.2.2
7.3
5.1
7.4
5.2.3
7.5
Removed
7.6
5.2.1
7.7
5.3
7.8
5.2.4
8, 8.1, 8.2, 8.3
6.1
8.4
6
8.5
7.3
8.6
7.2
8.7
7.6
8.8.1
5.4.1
8.8.2
5.4.2
8.9
7 (7.1– 7.7)
9 (9.1-9.12)
8 (8.1-8.12)
10 (10.1- 10.10)
9 (9.1-9.11)


Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 3
6.
Section 1.1: Indication - Indication has been added
7.
Section 1.2.4: Clinical Experience - update of Clinical 
experience to reflect most current IB
8.
Section 2.2: Endpoints - section added
9.
Section 3: Study design - abbreviated
10. Section 4.1: Inclusion Criteria – Inclusion of evidence of 
a signed informed consent document added
11. Section 4.2: Exclusion Criteria – added exclusion 
criteria 
•
Males with partners of childbearing potential not 
using highly effective contraception or not agreeing 
to continue highly effective contraception for at 
least 3 months after last dose of investigational 
product
12. Section 4.3.1: Contraception – added section to increase 
clarity
13. Section 5.3: Drug Storage and Drug Accountability –
updated to reflect most recent information on drug 
storage.
14. Section 6: Study Procedures –
Addition of possibility for alternative options for study 
visits added
15. Sections 6.1, 6.2 added to increase clarity of required 
assessments and procedures to be performed at each 
telephone and clinic visit
16. Section 7.4: Assessments – electrocardiograms – ECGs 
added to protocol to be performed every 12 months.
17. Section 8 – Adverse Event Reporting – updated to 
reflect most updated requirements from Pfizer.
18. Section 9.10 – ECG analysis – added section
19. Section 9.11 – Interim analysis – added section
20. Sections 10, 11, 12, 13, 14, 15 – replace sections 11 and 
12 from FoldRx protocol to reflect Pfizer requirements.
21. Appendix 4.  Updated to remove Fold Rx and replace 
with Pfizer.


Tafa mi dis me gl u mi ne
F x 1 A -3 0 3/ B 3 4 6 1 0 2 3
Fi nal Pr ot oc ol A me n d me nt 2 , 0 5 J u ne 2 0 1 2
P FI Z E R C O N FI D E N TI A L
Pa ge 4
A me n d me nt 
1. 1
2 7 J u ne 2 0 1 1
1.
C o m pa n y  na me u p date
2.
Tra nsfer of p har mac o vi gila nce fr o m I C O N t o 
Pfizer, I nc. ( E xce pti o n: Ar ge nti na)
3.
T he c o m p o u n d “ F x -1 0 0 6 A” (researc h n u m ber) is 
“tafa mi dis me glu mi ne” ( 2 0 m g s oft gelati n 
ca ps ule), t hereafter referre d t o as si m pl y , 
“tafa mi dis”
4.
Na me of c he mical c o m p o u n d c ha n ge: Fr o m: 
[ N-met h y l 
D- ( 2, 3, 4, 5, 6-pe nta h y dr o x y -h e x y l)-a m m o ni u m; 
2- ( 3, 5-dic hl or o -p he n yl )-be nz o xaz ole - 6-car b o x yl ate
] 
T o: [ d -gl ucit ol, 1 -de o x y- 1-( met h y la mi n o)-, 
2- ( 3, 5-dic hl or o p he n y l)-6- be nz o xaz olecar b o x y late 
( 1: 1)]
5.
Me dical M o nit or c ha n ge d fr o m 
 
6.
F ol d R x Pr ot oc ol A p pr o val F or m: U p date d pr ot oc ol 
versi o n a n d release date
U p date d Si g nat ories f or Re g ulat or y / Q A a nd 
Bi ostatistics.
7.
S y n o psis ( Secti o n 2 ), Secti o ns 5. 1, 6. 4, 8. 1 0, 8. 1 1, 
1 0. 7. 5, A p pe n di x 1 : A d de d te xt relati n g t o 
assess me nt of a m b ulat or y stat us: patie nt a m b ulati o n 
will be deter mi ne d b y t he I n vesti gat or at e ver y  
6- m o nt h cli nic visit a n d d uri n g eac h 3 -m o nt h 
tele p h o ne f oll o w-u p (i n bet wee n cli nic visits), a n d 
at t he e n d of st u d y visit.
8.
S y n o psis ( Secti o n 2 ), Secti o ns 3. 4, 5. 1, 8. 5, 8. 1 1, 
1 0. 6, A p pe n di x 1: A d de d te xt relati n g t o cli nical 
la b orat or y testi n g t hat will i n v ol ve bl o o d sa m ples 
ta ke n at Baseli ne, e ver y 6-m o nt h cli nic visit, a n d at 
t he e n d of st u dy visit.
9.
 
 
 
 
Q ualifie d patie nts will be as ke d t o pr o vi de writte n 
i nf or me d c o nse nt.
 
P P D
C CI


Tafa mi dis me gl u mi ne
F x 1 A -3 0 3/ B 3 4 6 1 0 2 3
Fi nal Pr ot oc ol A me n d me nt 2 , 0 5 J u ne 2 0 1 2
P FI Z E R C O N FI D E N TI A L
Pa ge 5
1 0. Secti o n 3. 3: U p date d N o n- Cli nical a n d Cli nical 
s u m mar y i nf or mati o n.
1 1. N E W - Secti o ns 3. 3. 1 a n d 3. 3. 2: Create d ne w 
s u b-hea di n gs f or N o n -Cli nical a n d Cli nical 
S u m maries, res pecti vel y,  i n Secti o n 3. 3.
1 2. Secti o n 7. 7: U p date d st ora ge c o n diti o ns f or 
i n vesti gati o nal pr o d uct.
1 3. Secti o ns 8. 1 0, 1 0. 7. 5, 1 4: T w o ne w refere nces 
a d de d f or t he assess me nt of a m b ulati o n usi n g t he 
m o difie d P ol y ne ur o pat h y Disa bilit y  ( m P N D) 
sc ori n g sys te m.
1 4. Secti o n 9 ( A d verse E ve nts): E ntire Secti o n 9 
u p date d per ne w pr oce d ures ( Pfizer).
S A E Re p orti n g i nf or mati o n u p date d fr o m I C O N 
(e xce pti o n Ar ge nti na) t o Pfizer, Inc.
1 5. A p pe n di x 1 ( Sc h e d ule of E ve nts): U p date d per 
Pr ot oc ol A me n d me nt.
Visit wi n d o ws a d de d.
 
 
 
Ori gi nal 
pr ot oc ol
1 9 J u ne 2 0 0 9
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, IR B/ E R B, etc.  
 
C CI


Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 6
PROTOCOL SUMMARY
Indication:
Tafamidis is being developed for the treatment of transthyretin amyloidosis, specifically 
targeting TTR amyloid polyneuropathy and cardiomyopathy
Study Objectives:
•
To obtain additional, long-term, open-label safety and efficacy data for tafamidis in 
subjects with transthyretin (TTR) familial amyloid polyneuropathy (TTR-FAP);
•
To continue to provide the investigational product tafamidis to subjects with 
TTR-FAP who have completed Protocol Fx-006 or Protocol Fx1A-201.
Study Population:
Male and female subjects with TTR-FAP who have not undergone liver transplantation and 
who have completed Protocol Fx-006 (EudraCT 2008-001262-87) or Protocol Fx1A-201 
(EudraCT 2007-006791-12).  Up to 110 subjects are anticipated.
Test Product, Dose, and Mode of Administration:
Tafamidis 20 mg soft gelatin capsule once daily (at the same time each day).
Duration of Treatment: Up to 10 years or until subject has access to tafamidis for 
TTR-FAP via prescription.  Upon regulatory approval for the treatment of TTR-FAP in 
their respective country and access to prescription tafamidis, subjects may be withdrawn 
from the study.  Such subjects are considered study completers. The decision to withdraw 
subjects in a country will be done in consultation between the investigator and the sponsor.
Clinical Endpoints:
Safety
The incidence of treatment-emergent adverse events (TEAEs), physical examinations,  
clinical laboratory testing, ECGs, use of concomitant medications, and vital signs.
Efficacy
•
The Neuropathy Impairment Score (NIS);
•
The Total Quality of Life (TQOL) score as measured using the Norfolk Quality of 
Life for diabetic neuropathy (QOL-DN) questionnaire;
•
The Karnofsky Performance Scale Index;
•
Assessment of subject ambulation.
Inclusion Criteria:
•
Evidence of a personally signed and dated informed consent document indicating 
that the subject (or a legal representative) has been informed of all pertinent aspects 
of the study.
•
Subject has successfully completed either Protocol Fx-006 or Fx-1A-2011.
•
If female, subject is post-menopausal, surgically sterilized, or willing to use an 
acceptable method of birth control (ie, hormonal contraceptive, intra-uterine device, 
diaphragm with spermicide, condom with spermicide) throughout the study and for 
3 months from the end of the study.  (A condom alone is not considered an 
acceptable method of birth control).


Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 7
•
Male or female subjects with TTR-FAP who have not undergone liver or heart 
transplantation at time of enrollment and who have successfully completed Protocol 
Fx-006 or Protocol Fx1A-201.
Exclusion Criteria:
•
Subject has not successfully completed either Protocol Fx-006 or Fx1A-201.
•
Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 3 to 4 times/month.  The following NSAIDs are 
allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethacin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac.
•
If female, subject is pregnant or breast feeding.
•
Clinically significant medical condition that, in the opinion of the investigator, 
would place the subject at an increased risk to participate in the study.
•
An ALT and AST value >3X ULN that in the medical judgment of the investigator 
is due to reduced liver function or active liver disease.
•
The subject has received a liver or heart transplant at time of enrollment.
•
Sexually active males with partners of childbearing potential not using highly 
effective contraception or not agreeing to continue highly effective contraception 
for at least 3 months after last dose of investigational product.
Study Design:
This is a Phase 3, open-label study designed to obtain additional, long-term, open-label 
safety and efficacy data for tafamidis and to continue to provide subjects with 20 mg oral 
tafamidis (soft gel capsule) who have completed either Protocol Fx-006 (a 1-year, 
open-label extension study to Protocol Fx-005 which is a randomized, double-blind, 
placebo-controlled, 18-month study to evaluate the safety and efficacy of tafamidis) or 
Protocol Fx1A-201 (a Phase 2, open-label study to evaluate TTR stabilization as well as 
the safety and tolerability of tafamidis) up to 10 years or until subject has access to 
tafamidis for TTR-FAP via prescription.  Upon regulatory approval for the treatment of 
TTR-FAP in their respective country and access to prescription tafamidis, subjects may be 
withdrawn from the study.  The decision to withdraw subjects in a country will be done in 
consultation between the investigator and the sponsor.
Subjects who successfully complete Protocol Fx-006 or Fx1A-201 will report to the 
clinical unit on Day 0 (Baseline) to sign the informed consent form and determine their 
eligibility for Protocol Fx1A-303/B3461023.  In addition, on Day 0 (Baseline), subjects 
will have their entrance criteria reviewed, medical history and demography for all subjects 
will be obtained.  Relevant end of study assessments from Protocols Fx1A-201 and Fx-006 
will serve as Baseline assessments for Protocol Fx1A-303/B3461023 if these examinations 
were performed within 30 days of Day 0 (Baseline).  For any subject successfully 
completing Protocol Fx-006, the Karnofsky Performance Scale Index will be assessed and 
the cranial nerve and upper limb components of the NIS will be performed and combined 
with the NIS-LL data from the end of study visit from Protocol Fx-006.


Tafa mi dis me gl u mi ne
F x 1 A -3 0 3/ B 3 4 6 1 0 2 3
Fi nal Pr ot oc ol A me n d me nt 2 , 0 5 J u ne 2 0 1 2
P FI Z E R C O N FI D E N TI A L
Pa ge 8
If t here is m ore t ha n 3 0 da ys bet wee n t he fi nal st u d y visit of F x- 0 0 6 or F x 1 A-2 0 1 a n d Da y  
0 ( Baseli ne) of F x 1 A -3 0 3/ B 3 4 6 1 0 2 3 , all Da y 0 st u d y pr oce d ures will be perf or me d (ie, n o 
data fr o m t he fi nal st u d y  visits fr o m t he pre vi o us st u dies will be utilize d).
Eli gi ble s u bject s will be gi n o nce-dail y d osi n g wit h 2 0 m g tafa mi dis at h o me o n Da y 1 (ie, 
first d ose) a n d will ret ur n t o t he cli nical u nit f or st u d y visits e ver y 6 m o nt hs.
A d verse e ve nts ( A Es) a n d c o nc o mita nt me dica ti o n use will be c ollecte d at eac h 6-m o nt h 
visit t o t he cli nical u nit a n d, if fe male, a uri ne pre g na nc y  test will be perf or me d.  Cli nical 
la b orat or y testi n g will als o occ ur at e ver y 6-m o nt h visit a n d s u bject a m b ulati o n stat us will 
be deter mi ne d b y t he I n vesti gat or at t hese visits. E C Gs will be o btai ne d a n n uall y .
A tele p h o ne call will be ma de at 3 -m o nt h i nter vals bet wee n cli nic visits t o assess safet y, 
t he use of c o nc o mita nt me dicati o ns, pre g na nc y, a n d t o assess s u bject a m b ulat or y.
F or t he e val uati o n of eff icac y, t he NIS, N orf ol k Q O L -D N, a n d Kar n ofs k y  Perf or ma nce 
Scale I n de x will be perf or me d o n a n a n n ual basis (ie, e ver y  ot her 6-m o nt h visit).
 
 
A n e n d of st u d y visit t o assess safet y a n d efficac y  will occ ur u p o n s u bject wit h dra wal (f or 
a n y reas o n), pr o gra m disc o nti n uati o n b y t he S p o ns or, or u p o n c o m pleti o n of t he st u d y .
St atistic al Met h o ds:
Descri pti ve statistics will be use d f or t his o pe n -la bel st u d y; t he l o n g-ter m effect of 
tafa mi dis o n cli nical o utc o mes as meas ure d b y NI S, NIS- L L, N orf ol k Q O L -D N, a n d 
s u bject a m b ulati o n will be e x pl ore d.  All de m o gra p hic, cli nical la b orat or y , c o nc o mita nt 
me dicati o ns, vital si g ns/ p h y sical e xa mi nati o ns, E C Gs a n d A E data c ollecte d will be 
prese nte d i n d ata listi n gs. A n i nteri m a nalys es will 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 safety a n d efficac y  data t o t he scie ntific c o m m u nit y 
t hr o u g h prese ntati o n at scie ntific a n d pr ofessi o nal meeti n gs .
 
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Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 9
SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to Study Procedures (Section 6) and Assessments (Section 7) for detailed information 
on each procedure and assessment required for compliance with the protocol.   
Procedure/Evaluation
End of study visit 
from Fx-006 or 
Fx1A-201 and/or
Day 0 
(Baseline)a
Open-label Investigational Product
End of 
study 
visitg
Day 
1
Telephone 
contact 
(every 
3 months 
between 
clinic visits)
Clinic visits
(every 6 
months
other than 
12 month
visits)
Clinic visits
(every 12 
months)
Visit windows:
±1 
week
±1 week
±2 weeks
±2 weeks
±2 
weeks
Informed consent
X
Inclusion/exclusion 
criteria
X
Demographics
X
Medical history
X
Physical examination
Xb
Xb
X
Blood sample for 
laboratory testingc
X
X
X
Assessment of 
ambulatory status 
(mPND)
X
X
X
X
Urine test for 
pregnancyd
X
X
X
X
Pregnancy 
determinationd
X
Enrollment
X
Dispense tafamidise
X
X
X
X
First dose of tafamidis
X
Tafamidis compliance 
and accountability 
X
X
X
NISf
X
X
X
Norfolk QOL-DNf
X
X
X
Karnofsky 
Performance Scale 
Indexf
X
X
X
ECG
X
X
Adverse events
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X


Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 10
a  Relevant data from the end of study visits from Protocols Fx-006 and Fx1A-201 will be used for Day 0 
(Baseline) if evaluations were performed within 30 days of Day 0. 
b The end of study physical examination (including weight and vital signs) from Protocols Fx-006 and 
Fx1A-201 will serve as Day 0 (Baseline) for Protocol Fx1A-303/B3461023 if these examinations were 
performed within 30 days of Day 0.  An abbreviated physical examination (including weight and vital 
signs) will be conducted at every other 6-month visit.  For blood pressure and pulse, measurements will 
be taken lying and standing. 
c Laboratory tests listed in Section 7.3.
d Subjects with a positive result will be excluded or discontinued. Urine pregnancy test will be done at all 
clinic visits, subjects will be asked about potential pregnancies on phone contacts.
e If determined to be eligible, subjects will be given a 3-month supply of investigational product on Day 0 
(Baseline) for self-administration at home beginning on Day 1 (i.e., first dose).  Subjects will return to 
the clinical unit every 6 months and will receive a 3-month supply of investigational product at each 
visit for self-administration at home.  At 3-month intervals between clinic visits, 3-month supplies of 
investigational product will be mailed directly to subjects from the clinical site.
f For subjects who successfully completed Protocol Fx1A-201, the NIS, Norfolk QOL-DN, and Karnofsky 
scores from the end of study visit of Protocol Fx1A-201 will serve as Day 0 (Baseline) assessments for 
Protocol Fx1A-303/B3461023 if these procedures were performed within 30 days of Day 0.  For 
subjects who successfully completed Protocol Fx-006, the Norfolk QOL-DN from the end of study visit 
from Protocol Fx-006 will serve as Day 0 (Baseline) if it was performed within 30 days of Day 0.  In 
addition, the cranial nerve and upper limb components of the NIS will be performed on Day 0 
(Baseline) and combined with the NIS-LL data from the end of study visit from Protocol Fx-006 and the 
Karnofsky Performance Scale Index will be assessed on Day 0 (Baseline) of Protocol 
Fx1A-303/B3461023.


Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 11
TABLE OF CONTENTS
LIST OF TABLES.........................................................................................................................14
1. INTRODUCTION .....................................................................................................................18
1.1. Indication.......................................................................................................................18
1.2. Background and Rationale ............................................................................................18
1.2.1. Tafamidis for the Treatment of TTR-FAP........................................................19
1.2.2. Study Rationale.................................................................................................19
1.2.3. Non-Clinical Experience of Tafamidis.............................................................20
1.2.4. Tafamidis (Fx-1006A) Clinical Experience .....................................................23
2. STUDY OBJECTIVES AND ENDPOINTS.............................................................................25
2.1. Objectives......................................................................................................................25
2.2. Endpoints.......................................................................................................................25
3. STUDY DESIGN.......................................................................................................................25
3.1. Rationale for Study Design and Control Group............................................................26
3.2. Study Duration and Dates .............................................................................................26
4. SUBJECT SELECTION............................................................................................................26
4.1. Inclusion Criteria...........................................................................................................26
4.2. Exclusion Criteria..........................................................................................................27
4.3. Life Style Guidelines.....................................................................................................27
4.3.1. Contraception....................................................................................................27
5. STUDY TREATMENTS...........................................................................................................28
5.1. Allocation to Treatment ................................................................................................28
5.2. Drug Supplies................................................................................................................28
5.2.1. Formulation and Packaging..............................................................................28
5.2.2. Preparation and Dispensing..............................................................................28
5.2.3. Administration..................................................................................................29
5.2.4. Compliance.......................................................................................................29
5.3. Drug Storage and Drug Accountability.........................................................................30
5.4. Concomitant Medication(s)...........................................................................................30
5.4.1. Allowed Medications........................................................................................30
5.4.2. Medication Restrictions....................................................................................30


Tafamidis meglumine
Fx1A-303/B3461023
Final Protocol Amendment 2, 05 June 2012
PFIZER CONFIDENTIAL
Page 12
6. STUDY PROCEDURES ...........................................................................................................31
6.1. Screening/Baseline Assessment ....................................................................................31
6.2. Study Period ..................................................................................................................32
6.2.1. Months 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, 99, 
105, 111, 117................................................................................................32
6.2.2. Months 6, 18, 30, 42, 54, 66, 78, 90, 102, 114.................................................33
6.2.3. Months 12, 24, 36, 48, 60, 72, 84, 96, 108.......................................................33
6.2.4. End of Study Visit ............................................................................................34
6.3. Subject Withdrawal.......................................................................................................35
7. ASSESSMENTS........................................................................................................................36
7.1. Efficacy Assessments....................................................................................................36
7.2. Pregnancy......................................................................................................................37
7.3. Clinical Laboratory Tests..............................................................................................38
7.4. Electrocardiograms........................................................................................................39
7.5. Physical Examinations and Vital Signs.........................................................................39
7.6. Adverse Events..............................................................................................................39
7.7. Concomitant Medications .............................................................................................39
8. ADVERSE EVENT REPORTING............................................................................................39
8.1. Adverse Events..............................................................................................................39
8.2. Reporting Period ...........................................................................................................40
8.3. Definition of an Adverse Event.....................................................................................40
8.4. Abnormal Test Findings................................................................................................41
8.5. Serious Adverse Events.................................................................................................41
8.5.1. Potential Cases of Drug-Induced Liver Injury..................................................42
8.6. Hospitalization ..............................................................................................................43
8.7. Severity Assessment......................................................................................................44
8.8. Causality Assessment....................................................................................................44
8.9. Exposure During Pregnancy..........................................................................................45
8.10. Withdrawal Due to Adverse Events (See Also Section 6.3).......................................46
8.11. Eliciting Adverse Event Information ..........................................................................46
8.12. Reporting Requirements..............................................................................................46
8.12.1. Serious Adverse Event Reporting Requirements ...........................................47


Tafa mi dis me gl u mi ne
F x 1 A -3 0 3/ B 3 4 6 1 0 2 3
Fi nal Pr ot oc ol A me n d me nt 2 , 0 5 J u ne 2 0 1 2
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
8. 1 2. 2. N o n -Seri o us A d verse E ve nt Re p orti n g R e q uire me nts ................................... 4 7
8. 1 2. 3. S p o ns or Re p orti n g Re q uire me nts t o Re g ulat or y  A ut h orities......................... 4 7
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..................................................................... 4 7
9. 1. Sa m ple Size Deter mi nati o n ........................................................................................... 4 8
9. 2. Efficac y  A nalys is .......................................................................................................... 4 8
9. 2. 1. A n al ysis of Pri mar y E n d p oi nt .......................................................................... 4 8
9. 2. 2. NI S -L L .............................................................................................................. 4 8
9. 2. 3. NI S 4 8
9. 2. 4. N orf ol k Q O L- D N .............................................................................................4 8
9. 2. 5. Kar n ofs k y Perf or ma nce Scale I n de x ................................................................ 4 9
9. 2. 6. A m b ulat or y  Stat us............................................................................................ 4 9
9. 4. De m o gra p hics a n d Baseli ne C haracteristics ................................................................. 4 9
9. 5. P h y sical E xa mi nati o n a n d Vital Si g ns .......................................................................... 4 9
9. 6. Cli nical L a b orat or y Testi n g .......................................................................................... 4 9
9. 7. A d verse E ve nts .............................................................................................................. 4 9
9. 8. C o nc o mita nt Me dicati o n ...............................................................................................4 9
9. 9. Pre g na nc y ...................................................................................................................... 5 0
9. 1 0. E C Gs ........................................................................................................................... 5 0
9. 1 1. I nteri m A nal ys is.......................................................................................................... 5 0
9. 1 2. Data M o nit ori n g C o m mittee ....................................................................................... 5 0
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 ....................................................... 5 0
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 ...................................................................5 0
1 1. 1. Case Re p ort F or ms/ Electr o nic Data Rec or d ...............................................................5 0
1 1. 2. Rec or d Rete nti o n ......................................................................................................... 5 1
1 2. E T HI C S ....................................................................................................................................5 2
1 2. 1. I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee (I E C) .................. 5 2
1 2. 2. Et hical C o n d uct of t he St u d y ...................................................................................... 5 2
1 2. 3. S u bject I nf or mati o n a n d C o nse nt ................................................................................ 5 2
1 2. 4. 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 ............................................................................................................................. 5 3
1 3. D E FI NI TI O N O F E N D O F T RI A L ......................................................................................... 5 3
 
C CI


Tafa mi dis me gl u mi ne
F x 1 A -3 0 3/ B 3 4 6 1 0 2 3
Fi nal Pr ot oc ol A me n d me nt 2 , 0 5 J u ne 2 0 1 2
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
1 3. 1. E n d of Trial i n a Me m ber State................................................................................... 5 3
1 3. 2. E n d of Trial i n all Partici pati n g C o u ntries .................................................................. 5 3
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 ...................................................................... 5 3
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 ................................................................................ 5 3
1 5. 1. C o m m u nicati o n of Res ults b y  Pfizer .......................................................................... 5 4
1 5. 2. P u blicati o ns b y  In vesti gat ors ...................................................................................... 5 4
1 6. R E F E R E N C E S ........................................................................................................................ 5 6
LI S T O F T A B L E S
Ta ble 1.
M ost C o m m o n ( ≥5 % i n Tafa mi dis Treat me nt Gr o u p) Treat me nt -E mer ge nt 
A d verse E ve nts Re p orte d at a Hi g her I nci de nce f or Tafa mi dis T ha n 
Place b o – T T R -F A P Patie nts i n St u d y  F x- 0 0 5........................................................... 2 4
A P P E N DI C E S
 
C CI


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ABBREVIATIONS
Abbreviation
Definition
ADL
activities of daily living
ADME
absorption, distribution, metabolism, excretion
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATTR
TTR amyloidosis
TTR-CM
TTR with cardiomyopathy
TTR-FAP
TTR with polyneuropathy
AUC
area under the concentration-time curve
BLQ
below the limit of quantification
bpm
beats per minute
C
Celsius
Cl
clearance
cm
centimeter
CMAP
compound muscle action potential amplitude
Cmax
maximum plasma concentration
CRF
case report form
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation; conduction velocity
dL
deciliter
DML
distal motor latency
DN
diabetic neuropathy
DPN
diabetic polyneuropathy
EC
ethics committee
ECG
electrocardiogram
FAP
familial amyloid polyneuropathy
FDA
Food and Drug Administration
GCP
good clinical practice
Glu89Gln
glutamic acid replaced by glutamine at position 89
Gly47Ala
glycine replaced by alanine at position 47
Gly47Glu
glycine replaced by glutamic acid at position 47
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HPMC
hydroxypropyl methylcellulose
HRDB
heart rate response to deep breathing
ICH
International Conference on Harmonisation
Ile107Met
isoleucine replaced by methionine at position 107
Ile84Thr
isoleucine replaced by threonine at position 84
Ile107Val
isoleucine replaced by valine at position 107


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Abbreviation
Definition
IND
investigational new drug
INR
international normalized ratio
IRB
institutional review board
ITT
intent-to-treat
K EDTA
potassium edetic acid
kg
kilogram
Leu55Arg
leucine replaced by arginine at position 55
Leu58His
leucine replaced by histidine at position 58
LFTs
Liver function tests
LLN
lower limit of normal
LLQ
lower limit of quantification
Lys70Asn
lysine replaced by asparagine at position 70
mBMI
modified body mass index
mPND
Modified polyneuropathy disability
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
μg
microgram
μM
micromolar
mL
milliliter
NCI
National Cancer Institute
NCS
nerve conduction studies
NIS
Neuropathy Impairment Score
NIS-LL
Neuropathy Impairment Score – Lower Limb
nM
nanomolar
NOAEL
no observable adverse effect level
NSAID
non-steroidal anti-inflammatory drug
NYHA
New York Heart Association
OTC
over-the-counter
PK
pharmacokinetic
PT
prothrombin time or preferred term
SRSD
Single reference safety document
QOL
quality of life
SAE
serious adverse event
Ser77Phe
serine replaced by phenylalanine at position 77
Ser77Tyr
serine replaced by tyrosine at position 77
SF-36
Short-form 36
SOC
system organ class
t1/2
half-life
T4
thyroxine
Thr49Ala
threonine replaced by alanine at position 49
Thr60Ala
threonine replaced by alanine at position 60
Tmax
time to maximum plasma concentration
TPGS
d-alpha-tocopherol polyethylene glycol 1000 succinate


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Abbreviation
Definition
TQOL
total quality of life
TSH
thyroid-stimulating hormone
TTR
transthyretin
Tyr114Cys
tyrosine replaced by cysteine at position 114
ULN
upper limit of normal
Val30Ala
valine replaced by alanine at position 30
V30M
valine replaced by methionine at position 30
WBC
white blood cell


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1. INTRODUCTION
1.1. Indication
Tafamidis is being developed for the treatment of transthyretin amyloidosis, specifically 
targeting ATTR polyneuropathy and cardiomyopathy.  This protocol will be specific for the 
ATTR polyneuropathy (TTR-FAP) indication.
Marketing authorization for TTR-FAP was granted in the European Union on 16 November 
2011 for the indication of treatment of transthyretin amyloidosis in adult patients with stage 1 
symptomatic polyneuropathy to delay neurologic impairment.
1.2. Background and Rationale
Transthyretin amyloidosis is a disease induced by accumulation of insoluble fibrillar protein 
as amyloid, in the tissues in amounts sufficient to impair normal function.  The major 
phenotypic presentations are a sensorimotor and autonomic neuropathy (ATTR with 
polyneuropathy, or TTR-FAP) and restrictive cardiomyopathy (ATTR with cardiomyopathy, 
or TTR-CM).  Transthyretin, a 127-amino acid, 55 kDa protein, primarily synthesized in the 
liver, is a secreted protein present in the blood and cerebrospinal fluid and is a carrier of 
thyroxine and retinol-binding protein-retinol (vitamin A) complex.1, 2  In its native state, TTR 
exists as a homotetramer with two C2 symmetric funnel-shaped thyroxine binding sites 
located at the central dimer-dimer interface.
Natural amino acid sequence (wild-type) TTR and mutated variants of TTR can be involved 
in amyloid disease.  However, mutated TTR species are more prone to accelerated 
fibrillogenesis, the most important risk factor for TTR amyloidosis.1, 2  There are more than 
80 TTR point mutations that have been associated with TTR amyloidosis.3  All 
disease-associated mutations characterized thus far destabilize the TTR tetramer and many 
influence the velocity of rate-limiting tetramer dissociation.4  An amyloidogenic mutation or 
aging can lead to tetramer dissociation into an alternatively folded monomeric amyloidogenic 
intermediate.  This intermediate self-assembles into profilaments, filaments, and, under 
certain conditions, amyloid fibrils.4, 5 In fact, the rate determining step for TTR amyloid 
formation is tetramer dissociation.6
V30M is the most common mutation associated with TTR-FAP, with major foci of patients 
in Portugal, Sweden and Japan. The disease usually begins in the third or fourth decade, but 
the onset of symptoms may be later, particularly in Sweden.  Initial symptoms include 
decrease in temperature and pain sensation in the lower extremities; autonomic dysfunction, 
including orthostatic hypotension, gastrointestinal motility disorders, impotence, and urinary 
retention/incontinence.  As the disease progresses to involve larger myelinated fibers, muscle 
weakness, loss of reflexes, and the impairment of position and vibratory sensations can 
occur.  At this stage, involvement of upper extremities becomes apparent.  Although 
penetrance varies greatly among geographic and ethnic foci, the outcome of TTR-FAP is 
invariably progressive and fatal.7, 8  The length of survival for patients with TTR-FAP is 
severely shortened.  After a mean interval of 10 years from initial symptom, patients usually 


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die from progressive and relentless worsening of the neuropathy, secondary infections, 
cachexia or sudden death.7  The only currently available disease-modifying treatment option 
is liver transplant.
1.2.1. Tafamidis for the Treatment of TTR-FAP
Pfizer, Inc. is currently investigating tafamidis meglumine (Fx-1006A) for the treatment of 
TTR-FAP.  Tafamidis meglumine, d-glucitol, 1-deoxy-1-(methylamino)-, 
2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate (1:1), is the meglumine salt form of 
tafamidis (Fx-1006), 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, a novel, small 
molecule stabilizer of transthyretin.  Specifically, tafamidis exhibits non-cooperative binding 
(ie, dissociation constants of 2 nM [Kd1] and 154 nM [Kd2], respectively) to the two thyroxine 
binding sites on the native tetrameric form of TTR and thereby prevents its dissociation into 
monomers.  At low pH, fibril formation of wild-type TTR and the most prevalent 
amyloidogenic variants, V30M and V122I, is potently inhibited by tafamidis.  No fibril 
formation is observed for wild-type, V30M, and V122I variants at a 2:1 tafamidis: TTR 
stoichiometry.  Under urea denaturating conditions, only 33% of TTR tetramer dissociates 
after incubation for 72 hours with equimolar quantity of tafamidis, when negligible tetramer 
dissociation is observed at a 2:1 tafamidis:TTR stoichiometry.  Based on these data, it 
appears that a 1:1 tafamidis:TTR stoichiometry should be sufficient to stabilize TTR.  The 
normal range of TTR level is between 18 and 38 mg/dL, corresponding to 3.2 to 6.8 μM of 
TTR.  Therefore, plasma level of 3.6 to 7.2 μM (~1-2 μg/mL) of tafamidis should stabilize 
TTR levels at least to the upper limit of the normal range.
In vitro addition of tafamidis and tafamidis meglumine to human plasma stabilizes wild-type, 
V30M, and V122I tetrameric TTR under strong urea denaturing conditions for at least 
4 days.  Under these same conditions most of the TTR is denatured in 2 days in the absence 
of stabilizer.  Stabilization is observed at tafamidis concentrations between 3.6 and 7.2 μM 
for TTR plasma levels ranging from low [15.5 mg/dL (2.8 λM)] to high [28 mg/dL (5 μM)], 
confirming the effective therapeutic plasma level range between 3.6 and 7.2 μM 
(corresponding to ~1-2 μg/mL concentration of tafamidis in plasma).  Ex-vivo results with 
plasma samples from initial Phase 1 clinical testing confirm this hypothesis and indicate that 
drug plasma levels between 0.7 to 1.7 μg/mL stabilize plasma TTR (when TTR plasma levels 
are between 16 and 36 mg/dL) after once a day dosing with tafamidis meglumine.  Based on 
Phase 1 results, this drug level range would be achieved at steady-state after once-daily 
20 mg (soft gel capsule), the tafamidis meglumine dose chosen for clinical evaluation.
Refer to the tafamidis (Fx-1006A) Investigator Brochure for further information.
1.2.2. Study Rationale
This current study is being conducted to obtain additional safety and efficacy data and to 
provide continued dosing of tafamidis for up to 10 years, or until subject has access to 
tafamidis for TTR-FAP via prescription, to patients with TTR-FAP who have not undergone 
liver or heart transplantation and who have completed either Protocol Fx-006 (EudraCT 


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2008-001262-87) or Protocol Fx1A-201 (EudraCT 2007-006791-12), as described above.  
Upon regulatory approval for the treatment of TTR-FAP in their respective country and 
access to prescription tafamidis, subjects may be withdrawn from the study.  The decision to 
withdraw subjects in a country will be done in consultation between the investigator and the 
sponsor (see Section 6.3).  Subjects will continue to receive once-daily 20 mg tafamidis.  
Safety will be assessed via the incidence of treatment-emergent AEs, the use of concomitant 
medications, and by results from clinical laboratory testing, physical examinations, ECGs, 
and vital signs.
Prior to enrollment in this current study, subjects who complete Protocol Fx-006 will have 
received study medication for a total of 30 months (18 months of double-blinded treatment in 
Protocol Fx-005 plus 12 months of open-label treatment in Protocol Fx-006); subjects who 
complete Protocol Fx1A-201 will have received open-label tafamidis for 12 months.
1.2.3. Non-Clinical Experience of Tafamidis
Nonclinical pharmacology, pharmacokinetic (absorption, distribution, metabolism, and 
excretion; ADME), and toxicology studies conducted both in vitro and in vivo in the mouse, 
rat, rabbit, and dog have been completed.  In vitro nonclinical studies have confirmed that the 
pharmacological activity of tafamidis is consistent with its high affinity binding to the two 
thyroxine binding sites of TTR in a non-cooperative manner and the resulting stabilization of 
TTR (wild type and amyloidogenic variants) by preventing dissociation of tetramers into 
monomers.
The general safety pharmacology profile of tafamidis demonstrated minimal nonselective 
binding to enzymes or ion channels, with no potential for anti-inflammatory activity.
Tafamidis had minimal effects on either the central nervous system or cardiopulmonary 
physiology parameters in dogs. Tafamidis did not demonstrate the potential for QT 
prolongation. QTc shortening, observed at doses of 100 and 300 mg/kg, was associated with 
total plasma concentrations that exceeded 90 μg/mL. However, mean human steady-state 
maximum concentration (Cmax) values following the daily therapeutic dose of 20 mg in 
elderly and nonelderly subjects were 2.8 and 2.3 μg/mL respectively. Given the 30 to 
40-fold difference in exposures, it is felt that the nonclinical observations have little 
relevance to the clinical profile of tafamidis.
Predictable pharmacokinetic behavior of tafamidis was demonstrated following oral 
administration in the nonclinical species. Tafamidis was absorbed following oral 
administration with an absolute bioavailability >90% and exhibited dose proportional 
increases in Cmax and AUC at dose up to 30 mg/kg, but further increases in the administered 
dose provided less than proportional increases in systemic exposure, indicating saturation in 
the drug absorption. Terminal plasma half life is about 40 hours following a single 
administration. Drug accumulation has been confirmed in repeated dose studies.


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Tafamidis is readily absorbed through the intestinal wall upon administration and is bound to 
a high extent to plasma proteins (>97%), essentially TTR and albumin. Tafamidis distributes 
widely in tissues (maternal and fetal), crosses the placental barrier to an extent of less than 
5% of the initial dose, and ~ 30% of the dam’s dose transferred into the milk.
Tafamidis demonstrated a high degree of metabolic stability and its limited biotransformation 
resulted in the formation of a monoglucuronide (acylglucuronide) as the primary metabolite 
in most of the nonclinical species and humans, while a monooxidative product was only 
detected in the mouse and rabbit.  In rats, tafamidis is cleared primarily via biliary excretion 
and fecal elimination with some enterohepatic circulation, with a smaller contribution by the 
urine.   A human ADME study suggests similar pathways are operative in humans.
Tafamidis meglumine has been evaluated in vitro to assess protein binding, induction and 
inhibition of cytochrome P450 enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5), and 
inhibition of transporter protein P glycoprotein (P gp), with results suggesting very low 
likelihood for clinical drug-drug interactions.  No significant CYP 450 inhibition was 
observed.  A series of nonclinical toxicity studies were conducted in mice, rats, and dogs to 
assess the safety of tafamidis. The absence of acute toxicity following a single dose of 
tafamidis up to 600 mg/kg in dogs is indicative of a low risk for overdose. Tafamidis was 
well tolerated following repeated daily oral administration up to 26 weeks in rats and 
39 weeks in dogs. The NOAEL was determined to be 30 mg/kg/day in the rat and 
45 mg/kg/day in dog. When doses were increased above the NOAELs, rodents had a drug 
accumulation in their stomachs while dogs vomited. Other signs of toxicity accompanied 
these obvious signs, including decreased food intake, modified feces, stress related signs, 
increase in liver weight and in liver enzyme levels, lymphoid depletion, and kidney lesions in 
rodents. 
Tafamidis was nongenotoxic in a battery of in vitro studies, although a slight increase in 
frequency of polyploid cells was observed at 100 and 200 μg/mL in the presence of 
S9 activation but not without metabolic activation in the in vitro chromosome aberration 
assay using human peripheral lymphocytes. Polyploidy is not considered to be a reliable 
surrogate marker for aneugenicity.  The lack of risk for aneuploidy induction with tafamidis 
was further evidenced by the lack of micronucleus induction in the bone marrow of 
Sprague-Dawley rats at the doses producing Cmax and AUC values significantly exceeding 
the predicted clinical exposures (~ 72X over the Cmax and ~ 67X over the steady state 
AUC(0-24) observed in humans, based on exposure in a 4-week rat study). The evaluation of 
the carcinogenic potential in hemizygous Tg.rasH2 mice did not demonstrate an increase in 
the incidence of neoplasia.
Tafamidis did not demonstrate any effects on fertility, general reproductive performance and 
early embryo-fetal development in the rat and the maternal and paternal NOEL for 
reproductive toxicity was determined to be greater than 30 mg/kg/day. Developmental 
toxicity was evident in the rat by reduced fetal weights in the 30 and 45 mg/kg/day maternal 
dosage groups (developmental NOAEL = 15 mg/kg). Developmental toxicity in the rabbit 
was demonstrated by increased post-implantation loss, reduced fetal body weight and 
associated skeletal variations, and malformation at 8 mg/kg and skelatal variations at 


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2 mg/kg/day. The NOEL for developmental toxicity in rabbits was 0.5 mg/kg/day.
Tafamidis-related toxicity in the developmental and perinatal/postnatal reproduction toxicity 
study in rats resulted in a NOAEL for reproductive toxicity and for viability and growth of 
the F1 generation of 5 mg/kg/day. Women of child-bearing potential should take measures 
to prevent pregnancy while being treated with tafamidis.
Non-clinical data indicate that there is a large safety margin above the anticipated human 
efficacious plasma concentration and those concentrations associated with toxicity in rats or 
dogs. Emesis was the most common form of clinical intolerance in the dog. Owing to the 
dosing strategy, the immediate emetic activity led to apparent aspiration of gastric contents 
and/or drug, leading to moribundity and subsequent euthanasia. The gastric impaction and 
subsequent delayed gastric emptying, presumably followed by circulatory distress, shock and 
multiorgan failure, in rats was caused by a supraclinical dosing regimen and is not a relevant 
risk to human subjects. While the exact mechanism(s) for the toxicities observed following 
the oral administration of tafamidis has not been elucidated, there is an ample therapeutic 
margin to permit safe exposure to humans and there was no toxicity identified that would 
preclude human use, such as undetectable lesions or irreversible damage.
No target organs of tafamidis-related toxicity were identified in the repeated dose toxicity 
studies conducted in rats or dogs (26 weeks and 39 weeks, respectively). However, in the 
CByB6F1 hybrid mouse and the tg.rasH2 mouse, the liver and/or kidney have been identified 
as target organs as non-neoplastic lesions were noted following treatment for 28 days 
(CByB6F1 hybrid mouse) or 26 weeks (tg.rasH2 mouse). Nephrosis was the primary lesion 
noted in the kidneys, only in male mice and in a dose-dependent manner. In the liver, 
centrilobular hypertrophy and scattered single cell necrosis were present in male mice more 
than in the female mice in terms of the incidence of both lesions and the severity of the 
centrilobular hypertrophy. The incidence of both liver lesions was dose dependent.
However, the mouse (CByB6F1) did not demonstrate a unique monooxide metabolite that 
was not present in the rat or dog, nor has it been detected in the plasma of humans 
administered tafamidis.   However, a causal relationship between the monoxide metabolite 
and the liver and/or kidney lesions has not been established.
Generally, there were no significant toxicities observed in the repeated dose toxicology 
studies in the rat and dog. Therefore, tafamidis was considered to be well tolerated in the rat 
at dose levels up to 30 mg/kg/day for 26 weeks, providing an exposure ratio of 45- to 63-fold 
based on the human AUC at steady state, and in the dog at dose levels up to 45 mg/kg/day for 
39 weeks providing an exposure ratio of 29- to 36-fold based on the human AUC at steady 
state. Additionally, there was no evidence for an increased risk of neoplasia at exposures at 
least 31-fold the human AUC nor was there evidence of any tafamidis-related genotoxicity.
With the exception of the reproductive developmental toxicity findings, tafamidis has an 
excellent nonclinical safety profile.
Refer to the tafamidis Investigator Brochure for further details.


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1.2.4. Tafamidis (Fx-1006A) Clinical Experience
The clinical development program for tafamidis has included 13 controlled and uncontrolled 
clinical trials and two non-interventional, observational studies.  As of 13 May 2011, patients 
with TTR-FAP (n=127) received 20 mg of tafamidis administered daily for an average of 
538 days (range of 15 to 994 days) or approximately 187 patient-years. The mean duration 
of exposure was 17.7 months: 87 were treated for at least 1 year, 43 were treated for at least 
2 years, and 31 were treated for at least 30-<36 months.    
The tafamidis 20 mg soft gelatin capsule (as used in the clinical studies) demonstrated a half-life 
average of 59 hours and Cavg(SS) average of 2.07 μg/mL (SD=0.20). The tafamidis 20-mg soft 
gelatin capsule daily dose resulted in an average fluctuation (peak to trough) of 51.8%, with an 
average minimum concentration (Cmin) of 1.61 μg/mL and an average Cmax of 2.66 μg/mL. The 
average range was consistent with the 1 to 2 μg/mL required to stabilize the TTR tetramer; steady 
state was attained within 12 days, and exposure was consistent across subjects, with low 
variability across subjects for key PK parameters.  Note that steady-state exposure was similar 
between males and females.  Therefore, the 20 mg daily dose has been used in the development 
program.  
The primary purpose of a therapy such as tafamidis is to stabilize the TTR tetramer, thus 
inhibiting the amyloid cascade and ultimately halting or slowing TTR-FAP disease progression 
over a sustained period of time.  During the 18-month period of intervention in Study Fx-005, 
tafamidis slowed the course of neurological impairment and maintained quality of life in treated 
patients. Together, with the extension Study Fx-006 data, tafamidis demonstrated a sustained 
effect over 30 months, a period of time representing approximately 25% of the average 
TTR-FAP disease duration of 10 years. Further, Study Fx1A-201 was a small Phase II open 
label, single-treatment arm study designed primarily to determine the efficacy of tafamidis in 
stabilizing TTR variants other than the V30M (valine replaced by methionine at position 30) 
mutation. The results from this study of non-V30M TTR-FAP patients, which represented an 
older, more severely affected patient population, strongly supported the observed efficacy of 
tafamidis in V30M patients.  As in Study Fx-005, the consistency of response across endpoints 
measuring different aspects of this multi-faceted disease was again observed following 
12 months treatment with tafamidis.  The results indicated the disease-modifying utility of 
tafamidis in treating all patients with TTR-FAP, regardless of mutation. 
TTR-FAP is a rare disorder.  The safety data described reflect exposure of 127 TTR-FAP patients 
to 20 mg of tafamidis administered daily for an average of 538 days (ranging from 15 to 994 
days).  The population was composed of adult patients diagnosed with symptomatic TTR-FAP, 
with a mean age of approximately 44 years; approximately half of the patients were female, and 
approximately 90% of the patients were Caucasian. Note that primary evidence of safety and 
efficacy was obtained from a placebo-controlled 18-month study in patients with TTR-FAP.  
Table 1 provides a summary of the most common TEAEs (≥5% in tafamidis treatment group) 
and reported at a higher incidence in tafamidis than in placebo during the pivotal Phase 2/3 
study (Study Fx-005).


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Table 1.
Most Common (≥5% in Tafamidis Treatment Group) Treatment-Emergent 
Adverse Events Reported at a Higher Incidence for Tafamidis Than Placebo 
– TTR-FAP Patients in Study Fx-005
MedDRA Preferred Term
Fx-005
Tafamidis
(N=65)
n (%)
Placebo
(N=63)
n (%)
Patients With At Least One Event
60 (92.3)
61 (96.8)
Diarrhoea
17 (26.2)
11 (17.5)
Urinary tract infection
15 (23.1)
8 (12.7)
Pain in extremity
11 (16.9)
6 (9.5)
Influenza
10 (15.4)
9 (14.3)
Nasopharyngitis
9 (13.8)
8 (12.7)
Abdominal pain upper
8 (12.3)
2 (3.2)
Back pain
5 (7.7)
4 (6.3)
Punctate keratitis
5 (7.7)
3 (4.8)
Myalgia
5 (7.7)
2 (3.2)
Upper respiratory tract infection
4 (6.2)
3 (4.8)
Anxiety
4 (6.2)
3 (4.8)
Depression
4 (6.2)
3 (4.8)
Vaginal infection
4 (6.2)
1(1.6)
There were no meaningful changes in vital signs, clinical laboratory parameters, ECG 
parameters (including QTc interval), or other safety parameters measured.  No meaningful 
changes in echocardiogram and ECG were observed for patients with a medical history of 
cardiomyopathy.  Tafamidis has been well tolerated by both healthy subjects during the 
Phase I clinical studies as well as in patients during the Phase II and III clinical studies.   
The primary purpose of a therapy such as tafamidis is to stabilize the TTR tetramer, thus 
inhibiting the amyloid cascade and ultimately halting or slowing TTR-FAP disease 
progression over a sustained period of time.  During the 18-month period of intervention in 
Study Fx-005, tafamidis significantly and consistently altered the course of neurological 
impairment and maintained quality of life in treated patients across multiple measures of 
treatment efficacy.  Together, with the extension Study Fx-006 data, tafamidis has 
demonstrated a sustained disease-modifying effect over 30 months, a period of time 
representing approximately 25% of the average TTR-FAP disease duration of 10 years.  
Tafamidis has not specifically been evaluated in patients with renal impairment.  Tafamidis is 
primarily metabolized by glucuronidation and excreted via the hepatobiliary pathway.  The 
effects of creatinine clearance on tafamidis pharmacokinetics (PK) were evaluated in the 
population PK analysis in patients with creatinine clearance >30 mL/min.  Pharmacokinetic 
estimates indicated no difference in steady-state clearance of tafamidis in patients with 
creatinine clearance <80 mL/min compared to those with creatinine clearance >80 mL/min.  
Therefore, dosage adjustment in patients with mild to moderate renal impairment is not 
necessary.  No data are available in patients with severe renal impairment (≤30 mL/min). 


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Pharmacokinetic data indicated decreased systemic exposure (approximately 40%) and 
increased total clearance (0.52 L/h vs. 0.31L/h) of tafamidis in patients with moderate hepatic 
impairment (Child-Pugh Score of 7-9 inclusive) compared to healthy subjects.  As patients 
with moderate hepatic impairment have lower TTR levels than healthy subjects, dosage 
adjustment is not necessary as the stoichiometry of tafamidis with its target protein TTR 
would be sufficient for stabilization of the TTR tetramer in these patients.  The exposure in 
patients with severe hepatic impairment is unknown.
Complete information for this compound may be found in the Single Reference Safety 
Document, which for this study is the Investigators Brochure.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
•
To obtain additional, long-term, open-label safety and efficacy data for tafamidis 
(Fx-1006A) in subjects with TTR-FAP.
•
To continue to provide the investigational product tafamidis (Fx-1006A) to subjects 
with TTR-FAP who have completed Protocol Fx-006 or Protocol Fx1A-201.
2.2. Endpoints
The efficacy endpoints for this study are:
•
The Neuropathy Impairment Score (NIS);
•
The Total Quality of Life (TQOL) score as measured using the Norfolk Quality of 
Life for diabetic neuropathy (QOL-DN) questionnaire;
•
The Karnofsky Performance Scale Index;
•
Assessment of subject ambulation.
The safety endpoints for this study are:
•
The incidence of treatment-emergent adverse events (TEAEs), physical examinations, 
clinical laboratory testing, use of concomitant medications, ECGs and vital signs
3. STUDY DESIGN
This is a Phase 3, open-label study designed to obtain additional long-term safety and 
efficacy data for once-daily tafamidis (20 mg soft gel capsule).  In addition, this study will 
continue to provide subjects with tafamidis who have completed either Protocol Fx-006 
(a 1-year, open-label extension study to Protocol Fx-005 which is a randomized, 
double-blind, placebo-controlled, 18-month study to evaluate the safety and efficacy of 
tafamidis) or Protocol Fx1A-201 (a Phase 2, open-label study to evaluate TTR stabilization, 


Tafa mi dis me gl u mi ne
F x 1 A -3 0 3/ B 3 4 6 1 0 2 3
Fi nal Pr ot oc ol A me n d me nt 2 , 0 5 J u ne 2 0 1 2
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
safety a n d t olera bilit y of tafa mi dis) f or u p t o 1 0 ye ars or u ntil s u bject has access t o tafa mi dis
f or T T R-F A P via prescri pti o n.  U p o n re g ulat or y  a p pr o val f or t he treat me nt of T T R-F A P i n 
t heir res pecti ve c o u ntr y a n d access t o prescri pti o n tafa mi dis, s u bjects ma y be wit h dra w n 
fr o m t he st u d y.  S uc h s u bjects will be c o nsi dere d st u d y  c o m pleters. T he decisi o n t o wit h dra w 
s u bjects i n a c o u ntr y will be d o ne i n c o ns ultati o n bet wee n t he i n vesti gat or a n d t he s p o ns or 
(see S ecti o n 6. 3 ).  
 
 
 
 
 
3. 1. R ati o n ale f or St u d y Desi g n a n d C o ntr ol Gr o u p
T his is a n o pe n -la bel st u d y desi g ne d t o o btai n a d diti o nal safet y a n d efficac y data a n d t o 
c o nti n ue t o pr o vi de tafa mi dis t o s u bjects w h o ha ve n ot ha d a li ver or heart tra ns pla nt a n d 
w h o ha ve c o m plete d eit her Pr ot oc ol F x -0 0 6 or Pr ot oc ol F x 1 A -2 0 1.  A c o ntr ol gr o u p is n ot 
a p plica ble t o t his o pe n-la bel st u d y desi g n.
3. 2. St u d y D ur ati o n a n d D ates
T he st u d y  will c o nti n ue f or u p t o 1 0 years or u ntil s u bject has access t o tafa mi dis f or 
T T R -F A P via prescri pti o n.  U p o n re g ulat or y  a p pr o val f or t he treat me nt of T T R-F A P i n t heir 
res pecti ve c o u ntr y a n d access t o prescri pti o n tafa mi dis, s u bjects ma y be wit h dra w n fr o m t he 
st u d y.  T he decisi o n t o wit h dra w s u bjects i n a c o u ntr y will be d o ne i n c o ns ultati o n bet wee n 
t he i n vesti gat or a n d t he s p o ns or (see Secti o n  6. 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 pr ot oc ol treat me nt is c o nsi dere d 
a p pr o priate. All rele va nt me dical a n d n o n -me dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n deci di n g w het her t his pr ot oc ol is s uita ble f or a partic ular s u bject.
4. 1. I ncl usi o n Criteri a
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 priately q ual ifie d me m ber 
of t he i n vesti gat or’s st u d y  tea m bef ore s u bjects are i ncl u de d i n t he st u d y.
S u bjects 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:

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 ( or a le gal re prese ntati ve) has bee n i nf or me d of all perti ne nt as pects of t he 
st u d y.
 
C CI


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•
Subject has successfully completed either Protocol Fx-006 or Fx-1A-201.
•
If female, subject is post-menopausal, surgically sterilized, or willing to use an 
acceptable method of birth control (ie, hormonal contraceptive, intra-uterine device, 
diaphragm with spermicide, condom with spermicide) throughout the study and for 
3 months from the end of the study.  (A condom alone is not considered an acceptable 
method of birth control.)
•
Male or female subjects with TTR-FAP who have not undergone liver or heart 
transplantation at time of enrollment and who have successfully completed Protocol 
Fx-006 or Protocol Fx1A-201.
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Subject has not successfully completed either Protocol Fx-006 or Fx1A-201.
2. Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 3 to 4 times/month.  The following NSAIDs are 
allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethacin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac.
3. If female, subject is pregnant or breast feeding.
4. Clinically significant medical condition that, in the opinion of the investigator, would 
place the subject at an increased risk to participate in the study.
5. An ALT and AST value >3X ULN that in the medical judgment of the investigator is 
due to reduced liver function or active liver disease.
6. The subject has received a liver or heart transplant at time of enrollment.
7. Sexually active males with partners of childbearing potential not using highly 
effective contraception or not agreeing to continue highly effective contraception for 
at least 3 months after last dose of investigational product
4.3. Life Style Guidelines 
4.3.1. Contraception
Females must be postmenopausal, surgically sterilized or willing to use two acceptable 
methods of birth control.  All female subjects who, in the opinion of the investigator, are 
biologically capable of having children and are sexually active, must agree to use two  
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for 3 months after the last dose of investigational product.  The 
investigator, in consultation with the subject, will select the most appropriate method of 


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contraception for the individual subject (ie,: hormonal contraception, intra-uterine device, 
diaphragm with spermicide, condom with spermicide; a condom alone is not considered an 
acceptable method of birth control).  The investigator, at each study visit, will confirm and 
document consistent and correct use.  In addition, the investigator will instruct the subject to 
call immediately if the selected birth control method is discontinued or if pregnancy is known 
or suspected.
All sexually active male subjects with partners of childbearing potential must agree to use a 
highly effective method of contraception consistently and correctly for the duration of the 
active treatment period and for at least 3 months after the last dose of investigational product.  
The investigator, in consultation with the subject, will select the most appropriate method of 
contraception for the individual subject.  The investigator, at each study visit, will confirm 
and document consistent and correct use.  In addition, the investigator will instruct the 
subject to call immediately if the selected birth control method is discontinued or if 
pregnancy is known or suspected.  
5. STUDY TREATMENTS
5.1. Allocation to Treatment
This is an open-label, single-treatment study. All enrolled subjects will be assigned to receive 
a single oral daily dose of 20 mg Tafamidis.
5.2. Drug Supplies
5.2.1. Formulation and Packaging
Tafamidis meglumine (tafamidis), d-glucitol, 1-deoxy-1-(methylamino)-, 
2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate (1:1), is the salt form of 
2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, or tafamidis (Fx-1006), the free acid.  
The only active ingredient in tafamidis meglumine is tafamidis. 
The tafamidis meglumine drug product will be supplied by the Sponsor as opaque 12 oblong 
soft gelatin capsules filled with a suspension containing 20 mg of tafamidis meglumine.
Investigational product will be supplied in 10-count child resistant blisterpacks.  
Investigational product labels will contain the appropriate country-specific information in 
accordance with relevant regulatory requirements.
5.2.2. Preparation and Dispensing
Investigational product will be dispensed to subjects according to the following schedule:
•
On Day 0 (Baseline), an initial 3-month supply of investigational product will be 
dispensed to subjects at the clinical unit.  Subjects will take their first dose of 
investigational product at home beginning on Day 1 (ie, first dose).  


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•
At 3-month intervals between clinic visits, 3-month supplies of investigational 
product will be mailed from the clinical site directly to subjects at home.
•
Every 6 months, subjects will return to the clinical unit and will be instructed to bring 
all investigational product and packaging with them to determine investigational 
product compliance and accountability.  At these clinic visits, 3-month supplies of 
investigational product will be dispensed directly to subjects for self-administration at 
home.
5.2.3. Administration
All enrolled subjects will self-administer a once-daily oral dose of 20 mg tafamidis at home 
as instructed by the clinical staff.  All investigational product is to be taken by mouth, with 
water. Subjects will be instructed to take investigational product at the same time each day 
throughout the treatment period.
Medication errors may result, in this study, from the administration or consumption of the 
drug by the subject at the wrong time, or at the wrong dose strength. Such medication errors 
occurring to a study participant are to be captured on the adverse event (AE) page of the 
CRFs and on the SAE form when appropriate.  In the event of medication dosing error, the 
sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:
•
Medication errors involving subject exposure to the product.
•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is 
captured on an adverse event (AE) CRF page (refer to ADVERSE EVENT REPORTING
section for further details).
5.2.4. Compliance
All investigational product will be self-administered by subjects at home. Subjects should be 
instructed to bring all investigational product and packaging to each follow-up visit to the 
clinical unit every six months. Compliance to investigational product will be determined 
through capsule counting procedures at subject visits to clinic. Compliance will be 
monitored and recorded in each subject’s case report form (CRF). Additionally, 
investigational product accountability audits will be performed by the study monitor during 
routine monitoring visits.


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5.3. Drug Storage and Drug Accountability 
All investigational product (tafamidis) should be stored at controlled room temperature 
15-25°C (59-77°F). Investigational product should be stored in its original package and 
should be protected from light.
Storage conditions stated in the SRSD (Investigator Brochure (IB),) may be superseded by 
the label storage.
Temperature of storage conditions should be monitored using validated devices that record 
maximum and minimum temperatures, are regularly calibrated, and data are regularly 
recorded.  Should the product experience temperature excursion, relative to label instruction, 
during storage, then the impact to product quality and use should be addressed with relavant 
subject matter experts and documented accordingly.
Occasional short-term excursions from the intended storage conditions may occur. If the 
duration is short and the deviation in temperature is small, an investigation into the quality of 
the product is generally not required.
Subjects should be reminded of the storage conditions when drug is dispensed.
5.4. Concomitant Medication(s)
5.4.1. Allowed Medications
On Day 0, in conjunction with the review of their medical history, all subjects will be asked 
what medications they are taking.  Thereafter, subjects will be asked what medications they 
have been taking at 3-month intervals (ie, during clinic visits every 6 months and via 
telephone contact at 3-month intervals between clinic visits).  All concomitant medications 
will be recorded on the CRF.
5.4.2. Medication Restrictions 
The following medications and substances are prohibited during the study, as specified 
below:
•
Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 3-4 times/month.  The following NSAIDs are 
allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethacin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac.
Of note, in the presence of tafamidis, the plasma protein binding of prednisone was decreased 
by approximately 10%.  As prednisone is rapidly metabolized to the active metabolite, 
prednisolone, the clinical relevance of these findings are unknown.  


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6. STUDY PROCEDURES 
Every effort should be made to ensure that scheduled visits are made and protocol required 
tests and procedures are completed as described.  From time to time there may be 
circumstances, outside of the control of the investigator, which may not make a clinic visit 
possible.  In these cases, and with prior discussion and approval from the sponsor, alternative 
options may be considered. Approved alternative study visit options will not be considered 
protocol deviations.
Study procedures are outlined in the Schedule of Activities.
6.1. Screening/Baseline Assessment
The end of study physical examination (including weight) and vital sign assessments from 
Protocols Fx-006 and Fx1A-201 will serve as Day 0 (Baseline) for Protocol 
Fx1A-303/B3461023 if these examinations were performed within 30 days of Day 0. If more 
than 30 days has passed between the final study visit of Protocols Fx-006 or Fx1A-201 and 
Day 0 (Baseline) for Protocol Fx1A-303/B3461023, all Day 0 study procedures will be 
performed (ie, no data from the final study visits from the previous studies will be utilized).  
For subjects who successfully completed Protocol Fx1A-201, the NIS, Norfolk QOL-DN, 
and Karnofsky scores from the end of study visit of Protocol Fx1A-201 will serve as Day 0 
(Baseline) assessments for Protocol Fx1A-303/B3461023 if these procedures were performed 
within 30 days of Day 0.  For subjects who successfully completed Protocol Fx-006, the 
Norfolk QOL-DN from the end of study visit from Protocol Fx-006 will serve as Day 0 
(Baseline) if it was performed within 30 days of Day 0.  In addition, the cranial nerve and 
upper limb components of the NIS will be performed on Day 0 and combined with the 
NIS-LL data from the end of study visit from Protocol Fx-006 and the Karnofsky 
Performance Scale Index will be assessed on Day 0 of Protocol Fx1A-303/B3461023.
Subjects will be required to sign an informed consent form before beginning participation in 
Protocol Fx1A-303/B3461023. The following procedures will be performed on Day 0:
•
All inclusion and exclusion criteria will be reviewed to ensure eligibility for 
participation in this study;
•
Demographics (date of birth, age, gender, and race) for all subjects will be collected;
•
A complete medical history will be obtained;
•
Urine test for pregnancy (women of child bearing potential only);
•
Complete physical exam including weight and vital signs (if not conducted within 
30 days of Day 0);
•
NIS;


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•
For subjects who completed Fx1A-201, only if not performed within 30 days of 
Day 0;
•
For subjects who completed Fx-006, the cranial nerve and upper limb components 
will be performed on Day 0 and combined with the NIS-LL from end of study 
visit from Fx-006, if performed within 30 days of Day 0.  Otherwise all three 
components of NIS will be performed on Day 0.
•
Norfolk QOL-DN, only if not performed within 30 days of Day 0.
•
Karnofsky Performanceperformance Scale Index.
•
For subjects completing Fx1A-201, only if not performed within 30 days of 
Day 0.
•
Adverse events;
•
Concomitant medications;
•
Dispense 3 month supply of investigational product with instructions that subject is to 
administer the first dose at home on the following day as instructed (Section 5.2.3).
6.2. Study Period
6.2.1. Months 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, 99, 105, 111, 117
Subjects will be contacted by telephone, contact is to be made ± 1 week of scheduled time:
•
Assessment of ambulatory status (mPND);
•
Ask subjects non-leading questions such as “How do you feel?” and document 
adverse events;
•
Record concomitant medications;
•
Ask about possibility of pregnancy;
•
Mail 3 month supplies of investigational product following telephone contact;
•
These telephone visits can be conducted in person at the clinic at the discretion of the 
sites.


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6.2.2. Months 6, 18, 30, 42, 54, 66, 78, 90, 102, 114
Subjects will return to the clinic for the following assessments.  Visits are to occur ± 2 weeks 
of the scheduled time:
•
Collect blood/urine samples for laboratory assessments (section 7.3);
•
Urine pregnancy test (for women of childbearing potential);
•
Assessment of ambulatory status (mPND);
•
Ask subjects non-leading questions such as “How do you feel?” and record adverse 
events;
•
Record concomitant medications;
•
Determine drug compliance and accountability;
•
Dispense 3 month supply of investigational product.
6.2.3. Months 12, 24, 36, 48, 60, 72, 84, 96, 108
Subjects will return to the clinic for the following assessments.  Visits are to occur ± 2 weeks 
of the scheduled time:
•
Perform abbreviated physical exam and measure vital signs;
•
Collect blood/urine samples for laboratory assessments (section 7.3);
•
ECG;
•
Urine pregnancy test (for women of childbearing potential);
•
Assessment of ambulatory status (mPND);
•
Perform NIS;
•
Administer Norfolk QOL-DN;
•
Determine Karnofsky Performance Scale Index;
•
Ask subjects non-leading questions such as “How do you feel?” and record adverse 
events;
•
Record concomitant medications;
•
Determine drug compliance and accountability;


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•
Dispense 3 month supply of investigational product.
6.2.4. End of Study Visit
The end of study visit will occur upon subject withdrawal from the study or upon subject
completion, which will be up to 10 years or until subject has access to tafamidis for 
TTR-FAP via prescription.  Upon regulatory approval for the treatment of TTR-FAP in their 
respective country and access to prescription tafamidis, subjects may be withdrawn from the 
study.  The decision to withdraw subjects in a country will be done in consultation between 
the investigator and the sponsor (see Section 6.3), subject withdrawal (for any reason), or 
program discontinuation by the Sponsor.  The following activities will be completed:
•
Complete physical examination, weight and vital signs, including assessment of the 
following body systems: general appearance, head and neck, eyes, ears, nose, throat, 
respiratory, genitourinary, endocrine, cardiovascular, abdomen, skin, 
musculoskeletalmuscoluskelatal, neurological, immunologic/allergies, 
hematologic/lymphatic;
•
ECG;
•
Urine pregnancy test (for women of childbearing potential) and determination of 
pregnancy;
•
Assessment of ambulatory status (mPND);
•
Perform NIS;
•
Administer Norfolk QOL-DN;
•
Determine Karnofsky Performance Scale Index;
•
Ask subjects non-leading questions such as “How do you feel?” and record adverse 
events;
•
Electrocardiogram (unless performed within 6 months prior);
•
Collect blood/urine samples for laboratory assessments (Section 7.3);
•
Record concomitant medications;
•
Determine drug compliance and accountability.


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In the event a subject is unable to return to the study site for the end of study visit, telephone 
contact with the subject approximately 30 days after the last dose of medication to assess 
adverse events and concomitant medications and treatments is expected. If laboratory 
assessments are needed to follow-up unresolved adverse events, retrieval of assessments 
performed at an institution local to the subject is acceptable.
The outcome of adverse events with a date of onset during the study period should be 
reevaluated, and any new adverse events should be recorded. All serious adverse events, and 
those non-serious adverse events assessed by the investigator as possibly related to study 
drug should continue to be followed even after subject withdrawal from study. These 
adverse events should be followed until they resolve or until the investigator assesses them to 
be “chronic” or “stable”. Additional information on ADVERSE EVENT REPORTING can 
be found in Section 8.
6.3. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site. In addition, the Sponsor may choose to discontinue 
this study, at which time all subjects will be withdrawn.
A subject may be withdrawn from the study for any of the following reasons:
•
Withdrawal of consent;
•
Adverse event;
•
Protocol noncompliance;
•
Subject lost to follow-up;
•
Subject death.
Subjects who are prematurely withdrawn from the study will not be replaced.  Subjects who 
discontinue from the study at any time following enrollment will have a final end of study 
visit performed, including all safety and efficacy assessments, at the time of discontinuation.  
Subjects undergoing liver and or heart transplantation while participating in this study will no 
longer receive investigational product.  However, subjects who do undergo a liver transplant 
will not be withdrawn from this study and will be asked to return to the clinical unit 
post-transplantation on an annual basis for NIS, Norfolk QOL-DN, and Karnofsky 
Performance Scale Index evaluations, safety assessments, and to assess subject ambulation.  
Further relevant information for the Investigator to consider for any subject undergoing liver 
transplantation is provided in Appendix 4.


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Upon regulatory approval of tafamidis for the treatment of TTR-FAP in their respective 
country, and access to prescription tafamidis, subjects may be withdrawn from the study.
The decision to withdraw subjects in a country will be done in consultation between the 
investigator and the sponsor. Subjects will have all end of study procedures completed prior 
to study withdrawal. These subjects are considered completers.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the subject 
to return all unused investigational product(s), request the subject to return for a final visit, if 
applicable, and follow-up with the subject regarding any unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the subject. When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.
The study team will be informed of these incidents in a timely fashion.
7.1. Efficacy Assessments
The NIS, Norfolk QOL-DN, and Karnofsky Performance Scale Index evaluations will be 
performed on an annual basis when subjects return to the clinical unit for study visits (ie, 
every other 6-month visit).  
For subjects who successfully completed Protocol Fx1A-201, the NIS, Norfolk QOL-DN, 
and Karnofsky scores from the end of study visit of Protocol Fx1A-201 will serve as Day 0 
(Baseline) assessments for Protocol Fx1A-303/B3461023 if these procedures were performed 
within 30 days of Day 0.  For subjects who successfully completed Protocol Fx-006, the 
Norfolk QOL-DN from the end of study visit from Protocol Fx-006 will serve as Day 0 
(Baseline) if it was performed within 30 days of Day 0.  In addition, the cranial nerve and 
upper limb components of the NIS will be performed on Day 0 and combined with the 
NIS-LL data from the end of study visit from Protocol Fx-006 and the Karnofsky 
Performance Scale Index will be assessed on Day 0 of Protocol Fx1A-303/B3461023.
Refer to Appendix 1, Appendix 2, and Appendix 3, respectively, for the NIS, Norfolk 
QOL-PN, and Karnofsky Performance Scale Index efficacy evaluation forms.


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The ambulatory status for each subject will be determined by the Investigator at each 
6-month visit to the clinic as well as during telephone follow-up at 3-month intervals 
between clinic visits.  The following scale, the modified polyneuropathy disability (mPND) 
score, will be used by clinical site staff to evaluate subject ambulation:
Score
Definition
0
Normal
I
Sensory disturbances in feet but able to walk without 
difficulty
II
Some difficulties walking but can walk without aid
IIIa
Able to walk with 1 cane or crutch
IIIb
Able to walk with 2 canes or crutches
IV
Not ambulatory; confined to wheelchair or bedridden
Source: (Suhr, 1995; Sharma, 2003) 9, 10
7.2. Pregnancy
The end of study visit urine pregnancy test from Protocols Fx-006 and Fx1A-201 will be 
used as Day 0 (Baseline) for Protocol Fx1A-303/B3461023.  If the pregnancy test is positive, 
the subject will be disallowed.  Female subjects of child-bearing potential will be re-tested 
for pregnancy at every 6-month visit to the clinical unit and will be asked via telephone 
contact of possible pregnancy at 3-month intervals between clinic visits.  A positive 
pregnancy test will lead to immediate discontinuation of investigational product and from the 
study.  Subjects will also be instructed to notify the site should they become pregnant. In the 
event of a pregnancy, all investigational product must be discontinued immediately.


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7.3. Clinical Laboratory Tests
The following laboratory parameters will be assessed upon the subjects return to the clinical 
unit every 6 months:
Serum chemistry
Sodium
Globulin
Potassium
Alkaline phosphatase
Chloride
AST
Bicarbonate
ALT
Blood urea nitrogen
Gamma glutamyl transferase
Creatinine
Cholesterol 
Calcium
Uric acid 
Inorganic Phosphorous
Thyroid-stimulating hormone
Glucose 
Total thyroxine (T4)
Total bilirubin
Free T4
Total proteins
Prealbumin (transthyretin)
Albumin
Retinol-binding protein
NT-pro-BNP
Troponin I
Coagulation
Prothrombin time
INR
Hematology
Hemoglobin
Platelets
Hematocrit
White blood cell count
Red blood cell count
Neutrophils 
Packed cell volume
Lymphocytes 
Mean corpuscular volume
Monocytes 
Mean corpuscular hemoglobin
Eosinophils 
Mean corpuscular hemoglobin concentration
Basophils
Urinalysis
pH
Blood (free Hb)
Protein
Nitrite
Glucose
Urobilinogen
Ketones
Specific gravity 
Bilirubin
A central laboratory will be used to assess the parameters above.  A manual will be provided 
to the sites describing the sample collection, storage, and shipping process. Approximately 
8 mLs of blood will be collected at every visit when the laboratory parameters listed above 
are assessed.
The staff at the clinical unit will be instructed to review the source documentation (ie, central 
laboratory reports).  For any abnormal laboratory result, the Investigator will be instructed to 
determine whether the result is “clinically significant” or “not clinically significant” by 
entering “CS” or “NCS”, respectively, directly on to source documentation.  If an abnormal 
laboratory result is assessed as CS, then a corresponding AE should be recorded in the CRF.


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7.4. Electrocardiograms
During the trial, a 12-lead ECGs will be performed every 12 months.  The following ECG 
parameters will be assessed: PR, RR, PRS, QT, QTc interval, heart rate and overall 
interpretation.  Each ECG will be recorded and reviewed locally by the Investigator.  
7.5. Physical Examinations and Vital Signs
The end of study physical examination (including weight) and vital sign assessments from 
Protocols Fx-006 and Fx1A-201 will serve as Day 0 (Baseline) for Protocol 
Fx1A-303/B3461023 if these examinations were performed within 30 days of Day 0.  An 
abbreviated physical examination (including weight and vital signs) will be conducted at 
every other 6-month visit to the clinical unit. 
For blood pressure and pulse, measurements will be taken lying and standing.
7.6. Adverse Events
Starting from the date the informed consent form is signed, adverse events (AEs) will be 
recorded in the CRF and monitored throughout the study. All adverse events should be 
monitored until they are resolved or are clearly determined to be due to a subject’s stable or 
chronic condition or intercurrent illness(es). All AEs will be recorded on the CRF. 
Definitions, documentation, and reporting of AEs are described in Section 8.
7.7. Concomitant Medications
On Day 0, in conjunction with the review of their medical history, all subjects will be asked 
about the medications they are taking. Thereafter, subjects will be asked about the 
medications they have been taking at 3-month intervals (ie, during clinic visits every six 
months and via telephone contact at 3-month intervals between clinic visits). All 
concomitant medications will be recorded on the CRF.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Pfizer or its 
designated representative.  For all adverse events, sufficient information should be obtained 
by the investigator to determine the causality of the adverse event.  The investigator is 
required to assess causality.  Follow-up by the investigator may be required until the event or 
its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs 
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As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
trial.  
8.2. Reporting Period
For serious adverse events, the active reporting period to Pfizer or its designated 
representative begins from the time that the subject provides informed consent, which is 
obtained prior to the subject’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving investigational product, through and including 
28 calendar days after the last administration of the investigational product.  Should an 
investigator be made aware of any SAE occurring any time after the active reporting period, 
it must be promptly reported.
•
Adverse events (serious and non-serious) should be recorded on the CRF from the 
time the subject has taken at least one dose of study treatment through last subject 
visit.
8.3. Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:  
•
Abnormal test findings;
•
Clinically significant symptoms and signs;
•
Changes in physical examination findings;
•
Hypersensitivity;
•
Progression/worsening of underlying disease;
•
Drug abuse;
•
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:
•
Drug overdose;
•
Drug withdrawal;


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•
Drug misuse; 
•
Drug interactions;
•
Extravasation;
•
Exposure during pregnancy;
•
Exposure via breast feeding;
•
Medication error.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 
•
Test result is associated with accompanying symptoms; and/or
•
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or
•
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or
•
Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.5. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:
•
Results in death;
•
Is life-threatening (immediate risk of death);
•
Requires inpatient hospitalization or prolongation of existing hospitalization;
•
Results in persistent or significant disability/incapacity (substantial disruption of 
the ability to conduct normal life functions);
•
Results in congenital anomaly/birth defect;


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other adverse event outcomes, 
the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.5.1. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:
•
Subjects with AST or ALT and total bilirubin baseline values within the normal 
range who subsequently present with AST or ALT ≥3X the upper limit of normal 
(X ULN) concurrent with a total bilirubin ≥2X ULN with no evidence of hemolysis 
and an alkaline phosphatase ≤2X ULN or not available. For subjects with preexisting 
ALT OR AST OR total bilirubin values above the upper limit of normal, the 
following threshold values should be used in the definition mentioned above:
•
For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT ≥2 times the baseline values and ≥3X ULN, or ≥8X ULN 
(whichever is smaller).
•
Concurrent with
•
For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by one time the upper limit of normal or ≥3X ULN 
(whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment. In addition to repeating 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/(INR) and 
alkaline phosphatase.  A detailed history, including relevant information, such as review of 


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ethanol, acetominophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
subject, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected. Further testing for acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted. All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above, with no other cause for LFT abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs. Such 
potential Hy’s Law cases should be reported as serious adverse events.
8.6. Hospitalization
Adverse events reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria.  Admission also includes transfer within the hospital 
to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit).
Hospitalization does not include the following:
•
Rehabilitation facilities;
•
Hospice facilities;
•
Respite care (eg, caregiver relief);
•
Skilled nursing facilities;
•
Nursing homes;
•
Routine emergency room admissions;
•
Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 
•
Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting 
condition (eg, for work-up of persistent pre-treatment lab abnormality);
•
Social admission (eg, subject has no place to sleep);
•
Administrative admission (eg, for yearly physical exam);


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•
Protocol-specified admission during a study (eg, for a procedure required by the 
study protocol);
•
Optional admission not associated with a precipitating clinical adverse event 
(eg, for elective cosmetic surgery);
•
Hospitalization for observation without a medical AE;
•
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
8.7. Severity Assessment
If required on the adverse event case report forms, the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  
For purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above.
8.8. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an adverse event; generally the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 


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investigational product” for reporting purposes, as defined by the Sponsor (see Section on 
Reporting Requirements).  If the investigator's causality assessment is "unknown but not 
related to investigational product", this should be clearly documented on study records.  
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
8.9. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as exposure in-utero [EIU] occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or being 
exposed (eg, due to treatment or environmental exposure) or after discontinuing or 
having been directly exposed to the investigational product; 
2. A male has been exposed (eg, due to treatment or environmental exposure)  to the 
investigational product prior to or around the time of conception or is exposed during 
his partner’s pregnancy 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to Pfizer on an EIU Form (this is a specific version of the Serious Adverse Event 
Form).  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EIU Form.  
This must be done irrespective of whether an adverse event has occurred and within 24 hours 
of awareness of the exposure.  The information submitted should include the anticipated date 
of delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain pregnancy outcome information for all EIU reports with an 
unknown outcome.  The investigator will follow the pregnancy until completion or until 
pregnancy termination and notify Pfizer of the outcome as a follow up to the initial EIU 
Form.  
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly 
and the findings are reported).


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If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as serious adverse events 
follows: 
•
Spontaneous abortion includes miscarriage and missed abortion;
•
Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as serious adverse events.  In addition, infant deaths after 
1 month should be reported as serious adverse events when the investigator 
assesses the neonatal death as related or possibly related to exposure to 
investigational product
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg,. follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study subject with the EIU Pregnant Partner 
Release of Information Form to deliver to his partner.  The Investigator must document on 
the EIU Form that the subject was given this letter to provide to his partner.
8.10. Withdrawal Due to Adverse Events (See Also Section 6.3)
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page.  
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below.
8.11. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject.  In addition, each study subject will be 
questioned about adverse events.
8.12. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.


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8.12.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator 
awareness of the event.  In particular, if the serious adverse event is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available 
adverse event information.  This timeframe also applies to additional new information 
(follow-up) on previously forwarded serious adverse event reports as well as to the initial and 
follow-up reporting of exposure during pregnancy and exposure via breast feeding cases.  
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information collected for serious adverse events is more detailed 
than that captured on the adverse event case report form.  In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant medications and illnesses must be 
provided.  In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative. 
8.12.2. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
adverse event CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same adverse event term should be used on both forms.  
Adverse events should be reported using concise medical terminology on the CRFs as well as 
on the form for collection of serious adverse event information.
8.12.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the sponsor.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.


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9.1. Sample Size Determination
There is no formal sample size calculation for this protocol.  Subjects who completed 
Protocols Fx-006 and Fx1A-201 are eligible for this study; up to 110 subjects are expected to 
enroll in Protocol Fx1A-303/B3461023.
9.2. Efficacy Analysis
Both safety and efficacy data will be summarized using descriptive statistics.  For continuous 
variables, mean, standard deviation, median, and ranges will be presented; for categorical 
variables, counts, and percentages will be presented. Safety and efficacy data collected will 
also be presented in data listings.  
Subjects who enroll into the study and receive any amount of investigational product will be 
included in the safety population.  Subjects who receive any amount of investigational 
product and have at least one post-baseline efficacy assessment will be included in the 
efficacy population.
9.2.1. Analysis of Primary Endpoint 
9.2.2. NIS-LL
NIS-LL data will be calculated using the NIS scoring manual (Appendix 1).  Change from 
Baseline for NIS-LL data (including data from this protocol and parent Protocols Fx-005, 
Fx-006, and Fx1A-201) will be analyzed using a mixed model analysis with baseline value as 
covariate, subjects as random effect, and time as fixed effect.  NIS-LL data will be 
summarized by each scheduled assessment and a graphical presentation of these data will be 
presented.
9.2.3. NIS
NIS data will be calculated using the NIS scoring manual (Appendix 1).  Change from 
Baseline for NIS data (including data from this protocol and Protocol Fx1A-201) will be 
analyzed using a mixed model analysis with baseline value as covariate, subjects as random 
effect, and time as fixed effect.  NIS data will be summarized by each scheduled assessment 
and a graphical presentation of these data will be presented.
9.2.4. Norfolk QOL-DN
Quality of life (QOL) data will be calculated using the Norfolk QOL-DN scoring manual 
(Appendix 2).  Change from Baseline for Norfolk QOL-DN data (including data from this 
protocol and parent Protocols Fx-005, Fx-006, and Fx1A-201) will be analyzed a using 
mixed model analysis (with baseline value as covariate, subjects as random effect, and time 
as fixed effect) to demonstrate the long term effects of tafamidis on QOL.  Also, QOL data 
will be summarized by each schedule assessment and a graphical presentation of these data 
will be presented.


Tafa mi dis me gl u mi ne
F x 1 A -3 0 3/ B 3 4 6 1 0 2 3
Fi nal Pr ot oc ol A me n d me nt 2 , 0 5 J u ne 2 0 1 2
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9
9. 2. 5. K ar n ofs k y Perf or m a nce Sc ale I n de x
T he Kar n ofs k y Perf or ma nce Scale I n de x will be assesse d f or eac h s u bject at e ver y ot her 
6- m o nt h visit t o t he cli nical u nit.  T he Kar n ofs k y Perf or ma nce Scale I n de x all o ws s u bjects t o 
be classifie d as t o t heir f u ncti o nal i m pair me nt.  T his t o ol ca n be use d t o c o m pare 
effecti ve ness of differe nt t hera pies a n d t o assess t he pr o g n osis i n i n di vi d ual s u bjects; t he 
l o wer t he Kar n ofs ky sc ore, t he w orse t he s ur vi val f or m ost seri o us ill nesses.  T he Kar n ofs k y 
Perf or ma nce Scale I n de x is pr o vi de d i n A p pe n di x 3.
9. 2. 6. A m b ul at or y St at us
A m b ulat or y  stat us f or eac h s u bject will be deter mi ne d b y  t he I n vesti gat or usi n g t he m P N D 
sc ore ( Secti o n 7. 1 ).  T he deter mi nati o n of a m b ulat or y stat us will occ ur at eac h 6-m o nt h visit 
t o t he cli nic as well as d uri n g tele p h o ne f oll o w-u p at 3 -m o nt h i nter vals bet wee n cli nic visits. 
Res ults f or s u bject a m b ulati o n will be s u m marize d b y  visit a n d will be pr o vi de d i n data 
listi n gs.  Refer t o t he statistical a nal ysis pla n f or f urt her details.
9. 4. De m o gr a p hics a n d B aseli ne C h ar acteristics
De m o gra p hics a n d Baseli ne data ( me dical hist or y , a ge, ge n der, race, wei g ht, a n d hei g ht) will 
be s u m marize d usi n g descri pti ve statistics or fre q ue nc y  distri b uti o ns, as a p pr o priate. 
9. 5. P h ysic al E x a mi n at i o n 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; a n d 
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 or fre q ue nc y  
distri b uti o ns, as a p pr o priate . 
9. 6. Cli nic al L a b or at or y T esti n g
See Secti o n  7. 3 f or la b orat or y para meters f or t his st u d y.  All la b orat or y data will be 
prese nte d i n b y- s u bject data listi n gs.  A b n or mal la b orat or y val ues meeti n g p ote ntiall y  
cli nicall y si g nifica nt ( P C S) criteria will be a nal yz e d.  La b orat or y P C S res ults a n d val ues 
o utsi de t he n or mal ra n ge will be fla g ge d i n t he listi n gs.  Refer t o t he statistical a nal ys is pla n 
f or f urt her a nalys is details.
9. 7. 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.
9. 8. C o nc o mit a nt Me dic ati o n
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.
 
C CI


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9.9. Pregnancy
Results from pregnancy testing will be presented in data listings.
9.10. ECGs
ECGs will be reviewed and summarized.  ECG data will be presented in data listings.
9.11. Interim Analysis 
Given the lack of long-term data in TTR-FAP, interim analyses will be performed during the 
course of the study to allow for the reporting of safety and efficacy data to the scientific 
community through presentation at scientific and professional meetings.
9.12. Data Monitoring Committee
This study will not use a Data Monitoring Committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.


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The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where
required by laws.
Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
subject. In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of subject personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document used in this study, and any changes made during the course 
of the study, must be prospectively approved by both the IRB/IEC and Pfizer before use.
The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legal representative before any study-specific 
activity is performed. The investigator will retain the original of each subject's signed 
consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of Tafamidis at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 28 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
Publication of study results is discussed in the CSA.


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Page 54
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of this study on www.clinicaltrials.gov (ClinicalTrials.gov).  Pfizer posts the results of 
all studies that it has registered on ClinicalTrials.gov regardless of the reason for registration.
The results are posted in a tabular format called Basic Results. 
For studies involving a Pfizer product, the timing of the posting depends on whether the 
Pfizer product is approved for marketing in any country at the time the study is completed:
•
For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, FDA-approved products, 
Pfizer posts results within one year of the primary outcome completion date (PCD). 
For studies involving products approved in any country, but not FDA approved, 
Pfizer posts results one year from last subject, last visit (LSLV). 
•
For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of  US regulatory approval, 
or one year after the first ex-US regulatory approval of the product (if only submitted 
for approval ex-US);
•
For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year of discontinuation of the program (if 
there are no plans for outlicensing or within two years if outlicensing plans have not 
completed).
Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.


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Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
Blake CC, Geisow MJ, Oatley SJ, Rerat B, C. Rerat.  Structure of Prealbumin: 
Secondary, Tertiary, and Quaternary Interactions Determined by Fourier Refinement at 
1.8 A.  J Mol Biol.  1978; 121: 339-356.
2.
Monaco HL, Rizzi M, Coda A.  Structure of a Complex of Two Plasma Proteins: 
Transthyretin and Retinol-Binding Protein.  Sci.  1995; 268: 1039-1041.
3.
Nilsson SF, Rask L, Peterson PA.  Studies on Thyroid Hormone-Binding Proteins. II. 
Binding of Thyroid Hormones, Retinol-Binding Protein, and Fluorescent Probes to 
Prealbumin and Effects of Thyroxine on Prealbumin Subunit Self Association.  J Biol 
Chem.  1975; 250: 8554-8563.
4.
Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW.  Sequence-Dependent 
Denaturation Energetics: A Major Determinant in Amyloid Disease Diversity.  Proc 
Natl Acad Sci USA.  2002; 99 Suppl 4: 16427-16432.
5.
Quintas A, Vaz DC, Cardoso I, Saraiva MJ, Brito RM. Tetramer Dissociation and 
Monomer Partial Unfolding Precedes Protofibril Formation in Amyloidogenic 
Transthyretin Variants.  J Biol Chem.  2001; 276: 27207-27213.
6.
Colon W, Kelly JW.  Partial Denaturation of Transthyretin is Sufficient for Amyloid 
Fibril Formation In Vitro.  Biochemistry.  1992; 31: 8654-8660.
7.
Adams D, Samuel D, Goulon-Goeau C, et al. The course and prognostic factors of 
familial amyloid polyneuropathy after liver transplantation. Brain. 
2000;123(7):1495-1504.
8.
Sousa A, Coelho T, Barros J, et al. Genetic epidemiology of familial amyloidotic 
polyneuropathy (FAP)-type I in Póvoa do Varzim and Vila do Conde (North of 
Portugal). Am J Med Genet. 1995;60:512-521. 
9.
Suhr O, Holmgren G, Steen L, Wikstrom L, Norden G, Friman S, et al.  Liver 
Transplantation in Familial Amyloidotic Polyneuropathy. Transplantation. 
1995;60(9):933-8.
10.
Sharma P, Perri R, Sirven J, Zeldenrust S, Brandhagen D, Rosen C, et al.  Outcome of 
Liver Transplantation for Familial Amyloidotic Polyneuropathy. Liver Transplantation. 
2003;9(12): 1273-80.


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Tafa mi dis me gl u mi ne
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SAP_001.pdf: 
Protocol B3461023 Statistical Analysis Plan 
 
 
 
 
Protocol B3461023 
 
 
 
 
 
OPEN-LABEL SAFETY AND EFFICACY EVALUATION OF FX-1006A IN 
SUBJECTS WITH TRANSTHYRETIN (TTR) AMYLOIDOSIS  
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
Version: 
 2 
 
Author:  
 GIPB Multi-TA Group 
 
 
 GIPB Multi-TA Group 
Date:  
Sep 11, 2014 
 
 
PFIZER CONFIDENTIAL 
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Protocol B3461023 Statistical Analysis Plan 
 
 
TABLE OF CONTENTS  
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................4 
2. INTRODUCTION .......................................................................................................................6 
2.1. Study Design ...................................................................................................................6 
2.2. Study Objectives .............................................................................................................6 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................7 
4. HYPOTHESES AND DECISION RULES .................................................................................7 
4.1. Statistical Hypotheses .....................................................................................................7 
4.2. Statistical Decision Rules ................................................................................................7 
5. ANALYSIS SETS .......................................................................................................................7 
5.1. Intention to Treat (ITT) Population .................................................................................7 
5.2. Safety Analysis Population .............................................................................................7 
5.3. Liver and/or Heart Transplant Subjects...........................................................................8 
5.4. Protocol Deviations .........................................................................................................8 
6. ENDPOINTS AND COVARIATES ...........................................................................................8 
6.1. Efficacy Endpoint(s) .......................................................................................................8 
6.2. Safety Endpoints .............................................................................................................8 
6.2.1. Clinical Laboratory Endpoints ............................................................................8 
6.2.1.1. Serum chemistry ................................................................................8 
6.2.1.2. Coagulation .......................................................................................9 
6.2.1.3. Hematology .......................................................................................9 
6.2.2. Urinalysis ............................................................................................................9 
6.2.3. Physical exam and Medical history ..................................................................10 
6.2.4. ECG ..................................................................................................................10 
6.3. Adverse Events ..............................................................................................................10 
6.4. Discontinuations ............................................................................................................10 
6.5. Covariates ......................................................................................................................11 
6.6. Baseline .........................................................................................................................11 
7. HANDLING OF MISSING VALUES ......................................................................................11 
7.1. Norfolk Quality of Life – Diabetic Neuropathy (QOL-DN) .........................................11 
7.2. Neuropathic Impairment Score (NIS) ...........................................................................11 
 
PFIZER CONFIDENTIAL 
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Protocol B3461023 Statistical Analysis Plan 
 
7.3. The Karnofsky Performance Scale Index ......................................................................12 
7.4. Assessment of Subject Ambulation ...............................................................................12 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................12 
8.1. Statistical Methods ........................................................................................................12 
8.1.1. Analyses for Continuous Data ..........................................................................12 
8.1.2. Analyses for Categorical Data ..........................................................................13 
8.1.3. Analyses for Time to Event Endpoints .............................................................13 
8.2. Efficacy Analyses ..........................................................................................................13 
8.3. Safety Analyses .............................................................................................................14 
9. LIST OF TABLES .....................................................................................................................16 
10. LIST OF LISTINGS ................................................................................................................16 
11. LIST OF FIGURES .................................................................................................................16 
12. APPENDICES .........................................................................................................................17 
 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFIZER CONFIDENTIAL 
Page 3 
CCI


Protocol B3461023 Statistical Analysis Plan 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
Version 2 is amended from version 1 to include the following: 
 
 
 
Change 
 
 
 
Date 
 
 
Section(s) 
Affected 
Corresponds 
to a 
Protocol 
Amendment 
 
 
 
Statistician 
1. Additional clarification of 
visit windowing 
 
 
May 29, 2014 
 
Appendix 
1.5 
 
 
No 
 
 
2. An appendix describing 
how to combine the two 
forms of data collected 
describing the subject’s 
ambulatory status and 
analyses has been added.  
The treatment of missing 
data has also been 
expanded for the 
ambulatory status data. 
 
 
 
 
 
 
 
 
 
May 29, 2014 
 
 
 
 
 
 
 
 
Appendix 
1.8 
 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
 
3. Additional details around 
the analyses of ambulatory 
status, including removing  
the Cox Regression. 
 
 
 
 
 
 
Sep 11, 2014 
 
 
 
 
8.1.3 
Appendix 
1.8 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
4. Additional details about 
the analysis of the NIS 
Total and NIS-UL scores 
were added for the non-
V30M population.  Details 
were added for the 
MMRM model in the case 
it doesn’t converge. 
 
 
 
 
 
 
 
May 29, 2014 
 
 
 
 
 
 
6.1 
8.1.1 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
5. Additional details around 
the scoring of the NIS and 
the Norfolk TQoL-DN, 
including the treatment of 
missing data for the 
Norfolk TQoL-DN. 
 
 
 
 
 
May 29, 2014 
 
 
Appendix 
1.1 
Appendix 
1.2 
 
 
 
 
 
No 
 
 
 
 
 
6. The LOCF analysis has 
been removed, due to the 
nature of the 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol B3461023 Statistical Analysis Plan 
 
discontinuation criteria 
from this study LOCF is 
not an appropriate analysis. 
 
 
May 29, 2014 
 
 
8.1.1 
 
 
No 
 
 
7. The list of the laboratory 
measures to be 
summarized was shortened 
to those laboratory 
measures which are 
potentially related to 
disease.  All values will be 
listed in the subject 
listings. 
 
 
 
 
 
 
 
 
May 29, 2014 
 
 
 
 
 
 
 
 
6.2.1 
 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
 
8. An Appendix was added 
describing the summary 
and handling of the post 
transplant data.  
Additionally, the transplant 
category has been 
expanded to include heart 
transplant. 
 
 
 
 
 
 
 
May 29, 2014 
 
 
 
 
 
 
 
Appendix 2 
 
 
 
 
 
 
 
No 
 
 
 
 
 
 
 
9. Additional details on the 
definition of orthostatic 
hypotension were added. 
An additional summary 
table was added for 
treatment emergent 
orthostatic hypotension. 
 
 
 
 
 
 
May 29, 2014 
 
 
 
 
 
 
8.3 
 
 
 
 
 
 
No 
 
 
 
 
 
 
10. Added formulae for 
calculating QTc correction 
factors (QTcB  and QTcF) 
 
 
May 29, 2014 
 
Appendix 
1.4 
 
 
No 
 
 
11. Removed TTR mutation as 
a covariate and stated that 
the analyses will be 
separate for V30M and 
non-V30M 
 
 
 
 
May 29, 2014 
 
 
 
 
6.5 
 
 
 
 
No 
 
 
 
 
12. Added analysis of time to 
death 
July 29, 2014 
6.2.5 
No 
 
13. Modified ambulatory 
status mapping algorithm 
by assigning subjects who 
required brace assistance to 
normal category  
July 29, 2014 
Appendix 
1.8 
No 
  
14. Updated algorithm for 
imputing missing last dose 
date of study drug. 
July 29, 2014 
Appendix 
1.6 
No 
 
 
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2. INTRODUCTION 
This current study is being conducted to obtain additional safety and efficacy data and to 
provide continued dosing of tafamidis for up to 10 years, or until subject has access to 
tafamidis for TTR-FAP via prescription, to patients with TTR-FAP who have not undergone 
liver or heart transplantation and who have completed either Protocol Fx-006 (EudraCT 
2008-001262-87) or Protocol Fx1A-201 (EudraCT 2007-006791-12).  Upon regulatory 
approval for the treatment of TTR-FAP in their respective country and access to prescription 
tafamidis, subjects may be withdrawn from the study.  The decision to withdraw subjects in a 
country will be done in consultation between the investigator and the sponsor.  Subjects will 
continue to receive once-daily 20 mg tafamidis.  Safety will be assessed via the incidence of 
treatment-emergent AEs, the use of concomitant medications, and by results from clinical 
laboratory testing, physical examinations, ECGs, and vital signs. 
Prior to enrollment in this current study, subjects who complete Protocol Fx-006 will have 
received study medication for a total of 30 months (18 months of double-blinded treatment in 
Protocol Fx-005 plus 12 months of open-label treatment in Protocol Fx-006); subjects who 
complete Protocol Fx1A-201 will have received open-label tafamidis for 12 months. 
2.1. Study Design 
This is a Phase 3, open-label study designed to obtain additional long-term safety and 
efficacy data for once-daily tafamidis (20 mg soft gel capsule).  In addition, this study will 
continue to provide subjects with tafamidis who have completed either Protocol Fx-006 
(a 1-year, open-label extension study to Protocol Fx-005 which is a randomized, 
double-blind, placebo-controlled, 18-month study to evaluate the safety and efficacy of 
tafamidis) or Protocol Fx1A-201 (a Phase 2, open-label study to evaluate TTR stabilization, 
safety and tolerability of tafamidis) for up to 10 years or until subject has access to tafamidis 
for TTR-FAP via prescription.  Upon regulatory approval for the treatment of TTR-FAP in 
their respective country and access to prescription tafamidis, subjects may be withdrawn 
from the study.  Such subjects will be considered study completers. The decision to withdraw 
subjects in a country will be done in consultation between the investigator and the sponsor.  
Any subject who is determined during this study to have developed severe chronic renal 
impairment (creatinine clearance <30 mL/minute as determined by the Investigator) will be 
asked to participate in a renal sub-study. 
 
 
  
2.2. Study Objectives 
x To obtain additional, long-term, open-label safety and efficacy data for tafamidis 
(Fx-1006A) in subjects with TTR-FAP. 
x To continue to provide the investigational product tafamidis (Fx-1006A) to subjects 
with TTR-FAP who have completed Protocol Fx-006 or Protocol Fx1A-201. 
 
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3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
Given the lack of long-term data in TTR-FAP, interim analyses will be performed during the 
course of the study to allow for the reporting of safety and efficacy data to the scientific 
community through presentation at scientific and professional meetings or for regulatory 
purposes. Analyses can also be performed for publication of safety and efficacy data 
provided there is Pfizer cross functional line review and agreement. 
This is an open-label study as such the data will not need to be unblinded. 
Final analyses will be performed after database release. 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
This study is descriptive in nature, and as such, there are no formal hypotheses to be tested. 
4.2. Statistical Decision Rules 
The data will be summarized using descriptive measures with 95% confidence intervals.  
Additionally, the data will be presented by treatment group (from the Fx-005 randomization) 
and TTR mutation.  The two treatment groups will be referred to as Tafamidis-Tafamidis and 
Placebo-Tafamidis based on the original randomization to Tafamidis and Placebo in Fx-005. 
5. ANALYSIS SETS 
5.1. Intention to Treat (ITT) Population 
The intent to treat (ITT) population consists of all subjects who are enrolled in this study, 
who have taken at least one dose of study medication, and who have baseline and at least one 
post-baseline NIS-LL measure. This population will be used for efficacy analysis.   
5.2. Safety Analysis Population 
The safety analysis population consists of all subjects who are enrolled in this study and who 
have taken at least one dose of study medication. 
Per the protocol, subjects undergoing liver and/or heart transplantation while participating 
in this study will no longer receive investigational product. However, subjects who do 
undergo a liver transplant will not be withdrawn from this study and will be asked to return 
to the clinical unit post-transplantation on an annual basis for NIS, Norfolk QOL-DN, and 
Karnofsky Performance Scale Index evaluations, safety assessments, and to assess subject 
ambulation. If a subject has had a liver transplant and remains in the study, that subject’s data 
will be omitted for all post-transplant visits from the summary analyses in the ITT and safety 
populations. 
 
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5.3. Liver and/or Heart Transplant Subjects 
Data for subjects who have received a liver transplant during the course of this study and 
who remain in the study will have their post-transplant data summarized separately.  
Appendix 2 will describe the summary table and listings to be produced. 
5.4. Protocol Deviations 
In order to closely mimic actual drug behavior in medical practice, no protocol deviation will 
exclude a subject from the summaries for either the ITT or safety populations.  
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoint(s) 
• The Neuropathy Impairment Score (NIS): the following subscales from the NIS will 
be summarized: (NIS-LL, NIS-LL-MW, NIS-LL-Reflexes, NIS-LL Sensory, NIS-LL 
scores for: toe, ankle, knee and hip); 
Due to the fact that the full NIS was not collected in the parent studies, the NIS Total 
Score and NIS-UL will not be summarized for the V30M population, since there is no 
pre-study baseline.  However, the NIS Total Score and NIS-UL will be summarized 
for the non-V30M population. 
• The Total Quality of Life (TQOL) score as measured using the Norfolk Quality of 
Life for diabetic neuropathy (QOL-DN) questionnaire (including the following 
subscales:  Total QOL, Physical Functioning/Large Fiber, Activities of Daily Living 
(ADLs), Symptoms, Small Fiber, Autonomic); 
• The Karnofsky Performance Scale Index; 
• BMI and mBMI; 
• Assessment of subject ambulation. 
6.2. Safety Endpoints 
6.2.1. Clinical Laboratory Endpoints 
The following list of clinical laboratory endpoints was collected during the course of the 
study.  However, the summary tables will be restricted to the measures indicated with an 
asterisk (*).  All measures will be included in the subject listings. 
6.2.1.1. Serum chemistry 
a. Sodium 
b. Globulin 
c. Potassium 
d. Alkaline phosphatase (ALP)* 
e. Alanine aminotransferase (ALT)* 
f. Chloride 
g. Aspartate aminotransferase (AST)* 
 
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h. Bicarbonate 
i. Blood urea nitrogen* 
j. Gamma glutamyl transferase* 
k. Creatinine* 
l. Cholesterol  
m. Calcium 
n. Uric acid  
o. Inorganic Phosphorous 
p. Thyroid-stimulating hormone* 
q. Glucose * 
r. Total thyroxine (T4)* 
s. Total bilirubin* 
t. Free T4* 
u. Total proteins 
v. Prealbumin (transthyretin)* 
w. Albumin* 
x. Retinol-binding protein 
y. NT-pro-BNP* 
z. Troponin I* 
aa. Troponin T* 
 
6.2.1.2. Coagulation 
a. Prothrombin time* 
b. INR* 
 
 
6.2.1.3. Hematology 
a. Hemoglobin 
b. Platelets 
c. Hematocrit 
d. White blood cell count* 
e. Red blood cell count 
f. Neutrophils*  
g. Lymphocytes*  
h. Mean corpuscular volume 
i. Monocytes*  
j. 
Mean corpuscular hemoglobin 
k. Eosinophils*  
l. Mean corpuscular hemoglobin concentration 
m. Basophils* 
 
 
6.2.2. Urinalysis 
a. pH 
b. Blood (free Hb) 
 
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c. Protein 
d. Nitrite 
e. Glucose 
f. Urobilinogen 
g. Ketones 
h. Specific gravity  
i. Bilirubin 
 
6.2.3. Physical exam and Medical history 
Physical exam will be listed by subject and visit in the listings.  Medical history will be listed 
by subject. 
 
6.2.4. ECG 
ECG data will be summarized at each visit.  A summary of ECG abnormalities will be 
presented, including changes from normal to abnormal or abnormal to normal. In addition, a 
summary of the number of subjects who meet the following criteria for QTc, using both the 
Bazett’s and Frederica correction factors, will be presented:  
• a change from baseline > 60 msec,  
• a change from baseline > 90 msec;  
• a change from baseline between 30 msec (inclusive) and < 60 msec; 
• a reading of greater than 450 msec at any visit;  
• a reading of greater than 480 msec at any visit; 
• a reading of greater than 500 msec at any visit.  
 
6.2.5. Death 
Time to death will be calcuated from the first dose of the treatment (either Fx-005 or Fx1A-
201), from active treatment start, and from onset of symptom, respectively.  Subjects alive at 
the end of the study will be censored at the last visit date.  For subjects who have received a 
liver and/or heart transplant, time will be censored at the time of transplant.  Death after 
discontinuation will be censored at time of discontinuation.  The date of onset of symptom is 
the start date of the earliest symptom related to ATTR in the Medical History CRF. 
 
6.3. Adverse Events 
Treatment emergent adverse events will be summarized by all causes and treatment 
relatedness groupings.  For the purposes of this study, treatment emergent is defined as an 
event which begins after enrollment in the current study (B3461023) or which worsens 
during the course of the current study.  In addition, severity of the adverse events will be 
summarized by all causes and treatment relatedness. 
6.4. Discontinuations  
All reasons for discontinuation will be summarized including: discontinuations due to 
adverse events, discontinuations due to laboratory abnormalities, discontinuations due to 
 
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death, discontinuations due to liver and/or heart transplant, discontinuations due to other 
causes (not laboratory abnormalities, death or liver transplant), and all cause discontinuation.   
 
6.5. Covariates  
Due to the small number of subjects and the descriptive nature of this study, baseline will be 
used as a covariate in the change from baseline models and where appropriate, gender.  TTR 
mutations will be categorized as V30M or nonV30M and all analyses will be done separately 
by these TTR mutation groupings. 
6.6. Baseline 
The baseline for all measures will be the last measurement prior to the first dose of study 
drug in study Fx-005 or Fx1A-201.  For the V30M subjects, an additional set of analyses will 
be performed using a second baseline, the last measurement prior to active treatment from 
study Fx-005 or Fx-006. 
7. HANDLING OF MISSING VALUES 
Data based on entire scales which are missing will be analyzed as follows: 
If the data are time until event data and there is no observed event (at any point during the 
trial) the observation will be censored at the last observation.  If there was an observed event, 
the data associated with the first observation of that event will be used, all other observations 
will not be needed. 
For all change from baseline analyses, the data will be analyzed as follows:  for analyses at 
each visit, the missing observations will not be used as the models will be estimated using an 
Mixed Model Repeated Measure (MMRM) model for the analysis.   
7.1. Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) 
If missing responses to questions occur, missing scores will be imputed as the mean of the 
non-missing questions within the domain for that visit as long as at least 60% of the items 
within the domain have a non-missing response.  The domain score will then be the sum of 
the non-missing and imputed questions.  If all 35 questions are non-missing or imputed as 
defined above, then the TQOL will be calculated as the sum of the non-missing items and the 
imputed values.  If questions could not be imputed as defined above due to less than 60% of 
responses in a domain; however, at least 60% of the total questions are either non-missing or 
imputed, then the TQOL will be calculated as the mean of the non-missing and imputed 
questions times 35.  If greater than 40% of the items in a domain or TQOL are missing, then 
the domain is deemed missing. 
7.2. Neuropathic Impairment Score (NIS) 
If any question is answered as ‘N/A’ then the score for that question will be 0.  Additional 
missing imputation rules are provided in Appendix 1.1. 
 
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7.3. The Karnofsky Performance Scale Index 
The Karnofsky Performance Scale Index is a single item scale, and, as such; missing values 
will be excluded from analyses. 
7.4. Assessment of Subject Ambulation 
If the first available assessment indicates no impairment of ambulation, then all previous 
missing assessments will be set to no impairment of ambulation.  However, if the first 
available assessment indicates any level of impairment then all previous missing assessments 
will remain as missing.   
If an assessment is missing but there are assessments surrounding the missing assessment and 
the assessments surrounding the missing assessment are the same, the missing assessment 
will be set to that value.  If the assessment before the missing assessment is different from the 
assessment after the missing assessment, then the missing assessment will be excluded from 
the analyses.  Missing assessment after the date of change or start of ambulatory status will 
be set to the value last seen with the change or start of the status. 
Changes in ambulatory assessment that are noted as due to circumstances unrelated to 
disease progression (determined either through investigator determination or clinical 
definition) will be set to the status last seen for that subject for that visit; an example would 
be: leg fracture requiring crutches.  
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
8.1.1. Analyses for Continuous Data 
All continuous data will be summarized with descriptive statistics, including mean, standard 
deviation, median, range and 95% confidence intervals.   In addition, change from baseline 
statistics will be presented as appropriate, to include the appropriate descriptive statistics.  
For the change from baseline statistics, the estimate will be adjusted for baseline (where 
appropriate) and the LSMean and standard error will be presented with the 95% confidence 
interval. 
These summaries will be provided by treatment group and by TTR mutation.   
For the V30M subjects, a repeated measures analysis of covariance model with change from 
baseline as the dependent variable, an unstructured covariance matrix, treatment, month and 
treatment-by-month as fixed effects, baseline as covariate and subject as a random effect in 
the model will be used to estimate the LSMeans and confidence intervals as indicated above. 
A sensitivity analysis will also be conducted using the model shown above however, without 
baseline as a covariate.  See Appendix 1.7 for an example of the SAS code for this analysis. 
In the event that the model will not converge due to the limited amount of data at the later 
visits, the model will be evaluated up to the point that it will converge.  The data after that 
 
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point will be summarized using descriptive statistics only and for the T-T and P-T groups 
will not be compared and no p value will be produced. 
Separate analyses will be conducted using both measurements of baseline, at study start and 
at active treatment start as specified above.  Due to the 18 month length of Fx-005 and the 
fact that many of the outcomes are measured annually, the measurements aren’t at the same 
time points (for example, 3 years of active treatment); this disparity of treatment schedules 
will not allow a direct comparison of the subjects’ change from baseline on active treatment, 
at any time point after the parent trials; therefore, just descriptive statistics will be reported 
for the outcomes measured annually. 
For the non V30M subjects, a repeated measures analysis of covariance model with change 
from baseline as the dependent variable, an unstructured covariance matrix, month as fixed 
effect, baseline as covariate and subject as a random effect in the model will be used to 
estimate the LSMeans and confidence intervals.  A sensitivity analysis will also be conducted 
using the model shown above however, without baseline as a covariate. 
 
8.1.2. Analyses for Categorical Data  
All categorical data will be summarized as n, percentage and 95% confidence intervals.  
These summaries will be provided by treatment group and by TTR mutation.  Separate 
analyses will be conducted using both measurements of baseline, at study start and at active 
treatment start as specified above. 
Confidence intervals will be based on estimates of the binomial probabilities with no 
adjustments to the probabilities. 
8.1.3. Analyses for Time to Event Endpoints 
Kaplan-Meier estimates will be computed for all time to event endpoints, including median , 
interquartile ranges, and 95% confidence intervals. Kaplan-Meier curves will be presented at 
yearly intervals.  These analyses will be provided by treatment group and by TTR mutation.  
Separate analyses will be conducted using both measurements of baseline, at study start and 
at active treatment start as specified above.  Additionally, a set of analyses will be done for 
the time from onset of symptom.  
8.2. Efficacy Analyses 
The efficacy endpoints for this study are the cumulative efficacy data as measured by the 
Neuropathy Impairment Score (NIS); the Total Quality of Life (TQOL) score as measured 
using the Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) questionnaire; the 
Karnofsky Performance Scale Index; and the Modified Polyneuropathy Disability (mPND) 
score of ambulatory status. 
 
 
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The following measures will be analyzed using the methods described above for continuous 
outcomes in Section 8.1.1:  NIS-LL, TQOL, Karnofsky Performance Scale Index.   These 
analyses will be provided by treatment group and by TTR mutation. 
The assessment of subject ambulation will be analyzed using the methods described above 
for categorical measures in Section 8.1.2.  Due to the fact that there are two substantially 
different versions of the CRF page, the data will be summarized three ways: for the original 
CRF, for the revised CRF and for the combined recoded data.  In addition, shift tables will be 
presented showing the distribution of subjects with a change in ambulation based on the 
combined recoded data.  Finally, if there are sufficient numbers of subjects who demonstrate 
a change in ambulation stage, , then Kaplan-Meier estimates will be computed for the time to 
the next ambulatory stage  (see details in Appendix 1.8).  These analyses will be provided by 
treatment group and by TTR mutation.   
8.3. Safety Analyses 
Safety data will be summarized for the safety analysis population. 
Treatment and Disposition of Subjects: Subject evaluation groups will show end of study 
subject disposition and will show which subjects were analyzed for efficacy, as well as for 
safety (adverse events and laboratory data).  Frequency counts will be supplied for subject 
discontinuation(s) by treatment. 
A listing of treatment duration for each subject will be reported in accordance with the 
sponsor reporting standards. 
Demographic and Baseline Characteristics.  A break-down of demographic data will be 
provided for age, gender, race, weight, body mass index, and height.  Each will be 
summarized by treatment group, sex at birth and ‘All Subjects’ in accordance with the 
sponsor reporting standards.  All baseline and disease characteristics will also be 
summarized.   
Discontinuations. Subject discontinuations due to adverse events will be detailed and 
summarized.  
Adverse events (AEs): Treatment emergent adverse events will be summarized by causality 
and severity. 
Hematology, Biochemistry and Urinalysis:  Descriptive statistics will be provided for each 
test result and for change from baseline by visit. Additional summaries for abnormalities in 
laboratory measures will be provided for the following populations:  without regard to 
baseline, abnormal at baseline and normal at baseline. 
Baseline is defined in two ways as described above. 
ECG: Changes from baseline (defined as the last evaluation prior to the first dose of study 
drug) will be summarized for each of the ECG measures listed above.  In addition, ECG 
changes from baseline will be categorized as follows:   
 
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x a change from baseline > 60 msec,  
x a change from baseline > 90 msec;  
x a change from baseline between 30 msec (inclusive) and < 60 msec; 
x a reading of greater than 450 msec at any visit;  
x a reading of greater than 480 msec at any visit; 
x a reading of greater than 500 msec at any visit.  
 
Baseline is defined in two ways as described above. 
Note:  In Italy only Echocardiograms and Holter Monitoring were performed, and therefore, 
the Italian subjects will not be included in these summaries. 
Vital signs: Will be summarized using descriptive statistics, to include:  values at each visit, 
change from baseline to each visit and a categorization of clinically significant changes.  A 
summary table of subjects experiencing orthostatic hypotension at each visit will be included.  
A table summarizing the subjects who experienced treatment emergent hypotension will be 
created.   
Baseline is defined in two ways as described above. 
Significant changes from baseline are defined as follows: 
x Systolic Blood Pressure (mmHg) Decrease (Change < -20, or Value < 90) 
x Systolic Blood Pressure (mmHg) Increase (Change > 20, or Value > 180)  
x Diastolic Blood Pressure (mmHg) Decrease (Change < -15, or Value < 50)  
x Diastolic Blood Pressure (mmHg) Increase (Change > 15, or Value > 105)  
x Heart Rate (bpm) Decrease (Change < -15, or Value < 50)  
x Heart Rate (bpm) Increase (Change > 15, or Value > 120)  
x Weight (kg) Decrease (Change < -7%)  
x Weight (kg) Increase (Change > 7%) 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
Concomitant medications: will be summarized. 
Physical Examination: Results will be listed. 
 
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9. LIST OF TABLES  
The List of Tables will be provided in a separate addendum. 
 
10. LIST OF LISTINGS  
The List of Listings will be provided in a separate addendum. 
 
11. LIST OF FIGURES  
The List of Figures will be provided in a separate addendum. 
 
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12. APPENDICES  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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