Tafamidis 61mg, Outcomes in ATTR Amyloidosis With Neurologic and Multisystemic Involvement - TRAMA
Conditions: Hereditary Transthyretin Amyloidosis (ATTRv), Polyneuropathy
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
 
 Study information 
Title 
Tafamidis 61mg, Outcomes in ATTR Amyloidosis with 
Neurologic and Multisystemic Involvement - TRAMA 
Protocol number 
B3461104 
Protocol version 
identifier 
1.0 
Date  
17 February  2022 
Active substance 
Tafamidis free acid 61 mg 
 
Hypotheses and 
Objectives 
Hypotheses and Objectives: Tafamidis free acid 61 mg has 
been shown (compared to placebo) to reduce the combination of 
all-cause mortality and the frequency of cardiovascular (CV) 
related hospitalizations, as well as to slow the decline in 
functional capacity and quality of life (QoL) of patients with 
ATTR-CM of hereditary (v) or wild-type (wt) origin. In this 
study the hypothesis is that tafamidis free acid 61 mg reduces the 
progression of neurological variables in ATTRv and ATTRwt 
patients with neurologic involvement. 
 
The objective of the study is to conduct a retrospective study to 
evaluate the efficacy of tafamidis 61 mg on non-cardiac variables 
in patients with ATTRv and ATTRwt, included in the ATTR-
ACT (B3461028) and/or LTE (extension study) studies 
(B3461045) in Spain, with a minimum neurological follow-up of 
12 months. In addition, these populations will be described. 
 
Author 
. Sr. Medical Advisor Pfizer S.L.U. 
 
 
 
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. Sr. Medical Advisor Pfizer S.L.U. 
 
 
 
 
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. 
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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS .............................................................................................................3 
2. LIST OF ABBREVIATIONS ......................................................................................................5 
3. RESPONSIBLE PARTIES ..........................................................................................................6 
4. ABSTRACT .................................................................................................................................8 
5. AMENDMENTS AND UPDATES .............................................................................................8 
6. MILESTONES .............................................................................................................................8 
7. RATIONALE AND BACKGROUND ........................................................................................9 
8. RESEARCH QUESTION AND OBJECTIVES .......................................................................11 
9. RESEARCH METHODS ..........................................................................................................12 
9.1. Study design ..................................................................................................................12 
9.2. Setting ............................................................................................................................13 
9.2.1. 
Inclusion criteria ...........................................................................................14 
9.2.2. 
Exclusion criteria ..........................................................................................14 
9.3. Variables ........................................................................................................................15 
9.4. Data source ....................................................................................................................19 
9.5. Study size ......................................................................................................................19 
9.6. Data management ..........................................................................................................20 
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data 
record ............................................................................................................20 
9.6.2. Record retention ................................................................................................20 
9.7. Data analysis .................................................................................................................21 
9.8. Quality control ...............................................................................................................21 
9.9. Limitations of the research methods .............................................................................22 
9.10. Other aspects ...............................................................................................................22 
10. PROTECTION OF HUMAN SUBJECTS ..............................................................................22 
10.1. Patient information ......................................................................................................22 
10.2. Patient consent .............................................................................................................23 
10.3. Institutional Review Board (IRB) or Independent Ethics Committee (IEC) ..............23 
10.4. Ethical conduct of the study ........................................................................................23 
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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS .......................................................................................................................24 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .............26 
13. REFERENCES ........................................................................................................................26 
14. LIST .........................................................................................................................................27 
15. LIST OF FIGURES .................................................................................................................27 
ANNEX 1: LIST OF STAND ALONE DOCUMENTS ...............................................................27 
 
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2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ATTR 
Transthyretin Amyloidosis 
ATTR-ACT 
Tafamidis Treatment Study 
for Patients with 
Transthyretin Amyloid Cardiomyopathy 
ATTR-CM 
Transthyretin cardiac amyloidosis  
ATTR-PN 
Transthyretin amyloidosis with polyneuropathy  
ATTRv 
Hereditary transthyretin amyloidosis 
ATTRwt 
Natural or wild-type transthyretin amyloidosis 
CCE 
Conductance Cutaneous Electrochemistry 
CNS 
Central nervous system 
COMPASS-31 
Composite Autonomic Symptom Score 31 
CV 
Cardiovascular 
CVR-R 
Coefficient of Variation of the R-R interval 
eGFR 
Estimated Glomerular Filtration Rate 
EMG 
Electromyogram 
HF 
Heart failure  
LTE 
ATTR-ACT Long-term Extension Study 
mBMI 
Modified body mass index  
NCS 
Nerve conduction studies  
NIS 
Neuropathy Impairment Score  
NIS-LL 
Neuropathy Impairment Score Lower Limbs  
Norfolk QoL-DN 
Norfolk Quality of Life-Diabetic Neuropathy  
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PN 
Polyneuropathy  
PND 
Polyneuropathy Disability Score  
QoL 
Quality of Life 
SCR 
Sympathocutaneous response  
TTR 
Transthyretin 
 
3. RESPONSIBLE PARTIES 
 
Name 
Job title 
Affiliation 
Address 
 
 
Section Head 
 
 
 
 
 
 
 
 
Attending Physician 
 
 
 
 
 
 
 
 
 
Sr. Medical Advisor 
 
 
 
 
 
 
 
 
 
 
Sr. Medical Advisor 
 
Principal Investigators 
They will be included as a stand-alone document in Annex 1. 
 
Country Coordinating Investigators  
The scientific coordinators will be responsible for maintaining the methodological rigor of the 
study, both in the design phase, as well as in the evaluation of the outcomes and in the preparation 
of the final report. They will ensure the ethical development of the study by maintaining scientific 
support to all participating physicians until the publication of the study outcomes: 
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Name 
Job title 
Affiliation 
Address 
 
 
Section Head 
 
 
 
 
 
 
 
 
 
Attending Physician 
 
 
 
  
 
 
 
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4. ABSTRACT 
Title: “Tafamidis 61mg, Outcomes in ATTR Amyloidosis with Neurological and Multisystemic 
Involvement - TRAMA.” B3461104 
Hypotheses and Objectives: Tafamidis free acid 61 mg has been shown (compared to placebo) 
to reduce the combination of all-cause mortality and the frequency of cardiovascular-related (CV) 
hospitalizations, as well as to slow the decline in functional capacity and quality of life (QoL) of 
patients with ATTR-CM of hereditary or wt origin. In this study the hypothesis is that tafamidis 
free acid 61 mg reduces the progression of neurological variables in ATTRv and ATTRwt patients 
with neurologic involvement. 
 
The objective of the study is to conduct a retrospective study to evaluate the efficacy of tafamidis 
61 mg on non-cardiac variables in patients with ATTRv and ATTRwt, included in the ATTR-ACT 
(B3461028) and/or LTE (extension study) studies (B3461045) in Spain, with a minimum 
neurological follow-up of 12 months. In addition, these populations will be described. 
EVALUATING IEC: 
 
Sponsor: 
 
  
• Protocol Version 1.0. Date: February 17, 2022  
Contact person: 
. Sr. Medical Advisor Pfizer S.L.U. 
 
5.  AMENDMENTS AND UPDATES 
Not applicable 
 
 
 
 
 
 
  
 
  
 
 
 
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7. RATIONALE AND BACKGROUND 
Transthyretin amyloidosis (ATTR) is a rare, progressive, clinically heterogeneous, and 
life-threatening disease caused by pathogenic mutations in the transthyretin (TTR) gene, resulting 
in the hereditary form (ATTRv), or due to factors related to aging, resulting in the natural or wild-
type form (ATTRwt) of the disease. (Adams D, et al; Nativi Nicolau JN, et al)1,2 
 
ATTR is a systemic disease in which deposition of TTR amyloid insoluble fibers can occur 
in multiple tissues, including the peripheral nervous system, heart, kidneys, gastrointestinal tract, 
and eyes, resulting in, as most common phenotypes, peripheral and/or autonomic polyneuropathy 
(ATTR-PN), restrictive cardiomyopathy (ATTR-CM), or a mixed phenotype (Adams D, et al)1. 
More than 140 mutations in the TTR gene have been described, with different phenotypes based 
on the mutation that the patient has (Adams D, et al)1. However, with disease progression, unique 
phenotypes generally become mixed phenotypes where cardiomyopathy can be accompanied by 
polyneuropathy and vice versa. In the case of ATTRwt, although the disease usually manifests 
with cardiac symptomatology, patients may present with sensory-motor and autonomic 
neurological disturbances, which in any case are less prominent in the clinical condition (Nativi 
Nicolau JN, et al)2.  
 
Cardiac transthyretin amyloidosis (ATTR-CM) is caused by extracellular deposition of 
TTR amyloid fibers in the heart, both in the ATTRwt form and in the ATTRv form, resulting in 
restrictive cardiomyopathy that clinically manifests as heart failure (HF) (Ruberg FL, et al)3. At 
least 22 mutations associated with ATTR-CM have been described, with Val122Ile, Thr60Ala, 
Leu111Met and Ile68Leu being the most common mutations (Rowczenio DM, et al; Caponetti 
AG, et al; González-Moreno J, et al)4-6.  
  
Globally, the inherited form of the disease can occur in both endemic and non-endemic 
areas. In Spain at the national level, there are two endemic foci where the prevalence of the disease 
is higher: Palma de Majorca and Huelva. There is currently little information on the clinical 
profiles of patients in Spain. The majority of the information is from endemic areas, while data 
from non-endemic areas remains scarce (González-Moreno J, et al; Silva Hernández, et al; 
Álvarez-Rubio J, et al.)6-8. Regarding neurologic involvement in ATTRwt patients, few descriptive 
and prevalence data are published internationally and all point to the need for a multidisciplinary 
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approach at follow-up (González-Moreno J, et al; Kharoubi M, et al; Wajnsztajn Yungher F, et al; 
Russell A, et al; Papagianni A, et al; Kleefeld F, et al)5, 9-13. 
  
Recently published data on the demographics and clinical characteristics of clinically overt 
Spanish patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS), a global, 
multicenter, longitudinal, observational survey of ATTR patients and asymptomatic carriers, 
shows phenotypic heterogeneity associated with this disease in Spain (González-Moreno J, et al)6. 
Specifically, for patients carrying the Val122Ile variant, only 20% had a purely cardiac phenotype, 
while many had a neurological phenotype (40%) or mixed phenotype (40%). On the other hand, 
most patients with ATTRwt had a mixed phenotype (64.9%), whereas only one third had purely 
cardiac (22.8%) or neurological (12.3%) phenotype. The results of this analysis highlight the 
importance of a multidisciplinary approach and the need for a comprehensive neurological and 
cardiological assessment in both ATTRv and wt patients (González-Moreno J, et al)6.  
Tafamidis is a benzoxazole derivative without nonsteroidal anti-inflammatory activity that 
binds to TTR thyroxine binding sites with high affinity and slectivity. This leads to inhibition of 
dissociation of TTR tetramer into monomers, preventing the formation of amyloid fibers (Bulawa 
CE, et al)14. Tafamidis 20 mg has been shown to slow the progression of peripheral neurological 
deterioration in patients with ATTR polyneuropathies (ATTR-PN) at stage 1 (Coelho T, et al)15 
and has been approved in Spain since 2011 for the treatment of transthyretin amyloidosis in adult 
patients with stage 1 polyneuropathy to delay peripheral neurological impairment (Information 
available on AEMPS)16.  
 
In the clinical trial to evaluate the safety and efficacy of tafamidis in transthyretin cardiac 
amyloidosis (ATTR-ACT), tafamidis at a dose of 20 mg and 80 mg (4 x 20 mg) was shown 
(compared to placebo) to reduce the combination of all-cause mortality and the frequency of 
cardiovascular-related (CV) hospitalizations, as well as to slow down the decline in functional 
capacity and quality of life (QoL) of patients with ATTR-CM of hereditary origin or wt (Maurer 
MS, et al)17. Based on these outcomes, tafamidis obtained FDA and EMA approval for the 
treatment of patients with ATTR-CM (Information available at: AEMPS; FDA)18,19. 
 
Upon completion of the ATTR-ACT study, patients had the option to participate in the 
extension study, LTE (NCT02791230)20 (B3461045), in which patients could be treated with 
tafamidis for an additional 60 months (Damy T, et al)21. In the LTE, patients who in the 
ATTR-ACT study received tafamidis continued to receive the same dose, while patients who 
received placebo were randomly reassigned to receive tafamidis 80 mg or 20 mg at a 2:1 ratio. 
Following the July 20, 2018 protocol addendum, all patients were switched to 61 mg of tafamidis 
free acid, a new single capsule formulation that is bioequivalent to 80 mg of tafamidis meglumine 
used in the ATTR-ACT (Lockwook PA, et al)22. Published outcomes show that tafamidis 
80 mg/61 mg has greater efficacy by reducing all-cause mortality by 30% versus tafamidis 20 mg 
(Damy T, et al)20. 
 
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In a retrospective study conducted in 210 patients with ATTRv in treatment with tafamidis 
20 mg and with a follow-up of 18-66 months, it was observed that patients classified as non-
responders had lower drug concentrations. The outcomes of this study support the hypothesis that 
ATTRv patients with polyneuropathy may benefit from a higher dose of tafamidis (Monteiro C, et 
al)23.  
  
Due to the phenotypic heterogeneity of ATTR patients and the growing demand for real-
world data on the effect of tafamidis 61 mg in patients with systemic involvement, our objective 
is to conduct a retrospective study to evaluate the efficacy of tafamidis 61 mg in non-cardiac 
variables in patients with ATTRv and ATTRwt, included in the ATTR-ACT (B3461028) and LTE 
(B3461045) in Spain. To do this, extra-cardiac clinical data will be collected throughout the 
follow-up and treatment period with tafamidis 61 mg, in order to evaluate the efficacy of treatment 
in ATTR patients with neurologic involvement.  
 
To date, little information has been published on the demographic and clinical 
characteristics of clinically overt Spanish ATTR patients (González-Moreno J, et al; Silva 
Hérnandez, et al; Álvarez-Rubio J, et al.)6-8, and even less international data have been published 
on neurologic involvement in ATTRwt patients (González-Moreno J, et al; Kharoubi M, et al; 
Wajnsztajn Yungher F, et al; Russell A, et al; Papagianni A, et al; Kleefeld F, et al)6, 9-13. In 
addition, this study will provide an overview of Spanish patients with mixed phenotype and 
provide real-world data on the deterioration of polyneuropathy and management of ATTRwt 
patients. 
  
There is currently no published data on the use of tafamidis free acid 61 mg in patients with 
ATTR-PN, therefore this study addresses an unmet medical need and may yield on the efficacy of 
tafamidis free acid 61 mg in patients with mixed phenotype ATTRv and in ATTRwt patients with 
neurologic involvement. 
8. RESEARCH QUESTION AND OBJECTIVES 
Based on the outcomes from previous studies (Coelho T, et al; Maurer MS, et al)15,17, the 
hypothesis of the present study is that tafamidis free acid 61 mg decreases the progression of 
polyneuropathy caused by transthyretin amyloidosis in ATTRv and ATTRwt patients with 
neurological or mixed phenotype. 
 
The study’s primary objective is: 
• To determine the efficacy of tafamidis free acid 61 mg in ATTRv patients with neurologic 
involvement included in studies B3461028 and/or LTE (B3461045) in Spain through 
changes in the NIS scale at 12 months. 
 
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The secondary objectives of this study are: 
• To determine the efficacy of tafamidis 61 mg in ATTRv patients with neurologic 
involvement included in studies B3461028 and/or LTE (B3461045) in Spain using 
additional non-cardiac variables at 6, 12, 18, 24 and 36 months after the start of treatment. 
• To determine the efficacy of tafamidis free acid 61 mg in ATTRwt patients with 
neurological symptoms included in studies B3461028 and/or LTE (B3461045) in Spain, 
through non-cardiac variables at 6, 12, 18, 24 and 36 months after treatment initiation. 
• To describe the extra-cardiac characteristics of ATTRv and ATTRwt patients included in 
studies B3461028 and/or LTE (B3461045) in Spain with mixed phenotype treated with 
tafamidis free acid 61 mg.  
 
9. RESEARCH METHODS 
9.1. Study design 
Retrospective, multicenter, non-interventional, observational and descriptive study. 
It will by no means interfere with the investigator’s decision on the most appropriate medical 
care or treatment for the patient or carrier. 
The variables collected are consistent with the objectives of the study and will be described in 
more detail in Section 9.3: 
 
Primary objective 
Primary variables 
To determine the efficacy of tafamidis free acid 
61 mg in ATTRv patients with neurologic 
involvement included in studies B3461028 
and/or LTE (B3461045) in Spain through 
changes in the NIS scale at 12 months. 
Neuropathy Impairment Score (NIS)  
Secondary objectives 
Secondary variables 
To determine the efficacy of tafamidis 61 mg in 
ATTRv patients with neurologic involvement 
included in studies B3461028 and/or LTE 
(B3461045) in Spain using additional non-
cardiac variables at 6, 12, 18, 24 and 36 months 
after the start of treatment. 
- 
NIS at 6, 18, 24 and 36 months 
- 
NIS-LL, Norfolk QoL-DN, COMPASS-31 
and FAP-RODs, FAP  
- 
% of patients who do not have stage 
progression in the PND score 
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- 
% of patients responding to treatment 
(defined as <4p in NIS and <2p in NIS-LL)  
- 
R-R Range Variability 
- 
mBMI 
- 
Amplitude of the potentials measured in 
sural sensory and ulnar, tibial and peroneal 
motor NCS 
To determine the efficacy of tafamidis free acid 
61 mg in ATTRwt patients with neurological 
symptoms included in studies B3461028 and/or 
LTE (B3461045) in Spain, through non-cardiac 
variables at 6, 12, 18, 24 and 36 months after 
treatment initiation. 
- 
NIS, NIS-LL, Norfolk QoL-DN, 
COMPASS-31 and FAP-RODs, FAP  
- 
% of patients who do not have stage 
progression in the PND score 
- 
% of patients responding to treatment 
(defined as <4p in NIS and <2p in NIS-LL)  
- 
R-R Range Variability 
- 
mBMI.  
- 
Amplitude of the potentials measured in 
sural sensory and ulnar, tibial and peroneal 
motor NCS 
To describe the extra-cardiac characteristics of 
ATTRv and ATTRwt patients included in 
studies B3461028 and/or LTE (B3461045) in 
Spain with mixed phenotype treated with 
tafamidis free acid 61 mg. 
- 
Demographic variables 
- 
Age of onset symptoms and at diagnosis 
- 
Neurological and extra-cardiac clinical 
variables 
 
 
This study, despite the limited sample size, will provide data on the efficacy of tafamidis 
free acid 61 mg in hereditary ATTR and wt patients with neurologic involvement. 
9.2. Setting 
The current study population consists of ATTRv and ATTRwt patients who have participated 
in studies B3461028 and B3461045 in Spain, with cardiac and neurologic involvement receiving 
or have received tafamidis free acid 61 mg for at least 12 months, and who are in neurological 
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follow-up for no less than 12 months. To our knowledge, 17 ATTRv patients have been included 
in these studies. 
Individuals participating in the TRAMA study must meet all of the inclusion and none of the 
exclusion criteria described in Section 9.2.1. 
 
9.2.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the study: 
1. Be of legal age (>18 years).  
2. Have participated in studies B3461028 and/or B3461045 in Spain. 
3. Have been treated for at least 12 months with tafamidis free acid 61 mg. 
4. Have a minimum of 12 months of neurological follow-up after starting treatment with 
tafamidis free acid 61 mg and have data from previous neurological evaluation or at the time 
of starting treatment with tafamidis free acid 61 mg. 
5. Have been diagnosed with ATTR amyloidosis polyneuropathy (ATTR-PN), based on any of 
the following criteria: 
a. Decreased amplitude in EMG studies, at least two nerves below normal, excluding 
median, or other nerve entrapment sites. 
b. A reduction in amplitude by more than 50% by at least two nerves above the 
patient’s baseline value, excluding the median. 
c. Two different altered fine fiber tests (Sudoscan, CRS, RR interval variability, skin 
biopsy...).  
d. A clinic compatible with small fiber neuropathy (painful or dysautonomic) and an 
altered fine fiber test. 
9.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. Treatment with tafamidis free acid 61 mg for less than 12 months. 
2. Not having a minimum of 12 months of neurological follow-up after starting treatment with 
tafamidis free acid 61 mg. 
3. Etiological diagnosis of polyneuropathy other than ATTR. 
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9.3. Variables 
The variables to be collected from each patient at participating sites will be: 
 
• Clinical parameters available in their medical history in the 12 months prior to their 
inclusion in studies B3461028 and/or LTE (B3461045). 
• Clinical parameters available in their medical history at the time of inclusion in studies 
B3461028 and/or LTE (B3461045) (last visit to the site before inclusion in the study). 
• Routine follow-up visits (up to the last available visit prior to enrollment in the TRAMA 
study). 
 
The variables to be collected from each individual’s medical history during the course of this study 
will be: 
 
• Treatment-related variables:  
 
▪ Date of consent signature for entry into study B3461028 and B3461045 
▪ ATTR Treatment Start Date: 
▪ Initiation of treatment with commercial medication (tafamidis 20 mg) 
▪ Treatment regimen in the trial of ATTR-ACT or LTE tafamidis 20 mg 
▪ Treatment regimen in the ATTR-ACT or LTE tafamidis 80 mg or 61 mg 
trial 
▪ Patient is currently on treatment with tafamidis free acid 61 mg (if not, specify stop 
date) 
 
• Demographic variables: 
 
▪ Age, gender  
▪ Genotype: mutations (homozygosis/heterozygosis) or wt 
▪ Age of disease onset (in order to characterize whether the disease onset was 
neurological or cardiological and to understand why it was not treated with 
available therapeutic options) 
▪ First disease-related sign or symptom 
▪ Age at disease diagnosis 
 
 
• Variables collected at each follow-up visit: 
 
▪ Extra-cardiac ‘red flags’ medical history:  
 
- 
Carpal tunnel syndrome (if yes, if there was a surgery/date) 
- 
Lumbar stenosis 
- 
Gastrointestinal disturbances: diarrhea/constipation, early satiety 
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- 
Urological disturbances: urinary tract infections, urinary incontinence, urinary 
infections, incomplete emptying sensation 
- 
Ophthalmological disturbances 
- 
Central nervous system (CNS) disturbances (seizures, stroke or transient ischemic 
attack, cognitive impairment) 
- 
Symptoms of autonomic neuropathy: impaired sweating, sexual dysfunction, 
orthostatic hypotension 
- 
Symptoms of peripheral neuropathy (allodynia, paresthesia, hyperalgesia...) 
- 
Unintentional weight loss 
 
▪ Modified Body Mass Index (mBMI) 
 
▪ Neurological variables: 
 
- 
NIS (Neuropathy Impairment Score) 
- 
NIS-LL (Neuropathy Impairment Score Lower Limbs) 
- 
PND (Polyneuropathy disability score) 
- 
FAP (Family Amyloidotic polyneuropathy stage) 
 
▪ Neurophysiological variables: 
 
- 
NCS (EMG): sural sensory nerves, ulnar, tibial and peroneal motor  
- 
CCE - Sudoscan (feet and hands, if available) 
- 
R-R Range Variability 
 
▪ Scales: 
- 
Norfolk QoL-DN (Norfolk Quality of Life-Diabetic Neuropathy) 
- 
FAP-RODS (Familial Amyloid Polyneuropathy Specific Rasch-Built Overall 
Disability Scale) 
- 
COMPASS-31 (Composite Autonomic Symptom Score 31) 
 
▪ Renal Assessment Variables: 
- 
Proteinuria, albuminuria/microalbuminuria; eGFR 
- 
Creatinine Clearance  
 
▪ Ophthalmologic Assessment Variables: 
- 
Intraocular pressure  
- 
Glass opacity classification 
 
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Variable 
Role 
Source 
Document(s) 
Operational Definition  
Date of birth 
Baseline 
Characteristic 
Medical 
Record  
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record  
Sex 
Genotype: mutation 
(homozygous/heterozygous) or wt 
Age at onset of the disease 
Subgroup 
Identifier 
Medical 
Record  
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record  
First sign or symptom of disease 
Age at disease diagnosis 
Date of consent signature for entry into 
study B3461028 and B3461045 
Subgroup 
Identifier 
Medical 
Record 
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record 
ATTR Treatment Start Date 
Treatment regimen in the trial of ATTR-
ACT origin (tafamidis 80 mg or 61 mg) 
Carpal tunnel syndrome (if yes, if there 
was a surgery/date) 
Result 
Medical 
Record 
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record 
Lumbar stenosis 
Gastrointestinal 
disturbances: 
diarrhea/constipation, early satiety 
Urological disturbances 
Ophthalmological disturbances 
Central Nervous System (CNS) Disorders 
Symptoms of autonomic neuropathy: 
impaired sweating, sexual dysfunction, 
orthostatic hypotension 
Symptoms of peripheral neuropathy 
(allodynia, paresthesia, hyperalgesia...) 
Unintentional weight loss 
mBMI 
mBMI 
(modified 
BMI) 
corrects 
hypoalbuminemia effects, thus better 
reflecting nutritional health (mBMI=BMI 
x albumin level) 
Result 
Medical 
Record 
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record or 
calculated from the medical record data 
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NIS 
NIS (Neuropathy Impairment Score) is a 
clinically important, sensitive measure of 
individual 
neurological 
function, 
assessing sensory function, reflexes, and 
muscle weakness 
Result 
Medical 
Record 
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record or 
calculated from the medical record data 
NIS-LL 
NIS-LL (Neuropathy Impairment Score 
Lower Limbs) is a clinically important, 
sensitive 
measure 
of 
neurological 
function in individuals, assessing sensory 
function, reflexes, and muscle weakness 
of the lower limbs 
PND 
PND (Polyneuropathy disability score) is 
a simple staging system according to the 
degree of neuropathic dysfunction and its 
impact on ambulation 
FAP  
FAP 
(Family 
Amyloidotic 
polyneuropathy stage) is a staging system 
based on symptom severity and disease 
progression 
NCS (EMG): sural sensory, ulnar, tibial 
and peroneal nerves 
Result 
Medical 
Record  
 
 
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record  
 
 
 
CCE - Sudoscan (feet and hands) 
Electrochemical Cutaneous Conductance 
allows 
us 
to 
measure 
autonomic 
sudomotor function in a non-invasive, 
rapid and accurate manner 
CVR-R 
The coefficient of variation of the R-R 
interval is a measure of cardiovascular 
autonomic dysfunction. It is calculated as 
the standard deviation percentage of the 
R-R intervals divided by their mean 
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Norfolk QoL-DN 
Norfolk Quality of Life Questionnaire for 
Diabetic Neuropathy is a standardized 
and validated instrument that assesses the 
effect 
of 
polyneuropathy 
on 
the 
functionality and quality of life of the 
individual 
Result 
Medical 
Record  
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record  
FAP-RODS 
FAP-RODS 
(Familial 
Amyloid 
Polyneuropathy 
Specific 
Rasch-Built 
Overall 
Disability 
Scale) 
is 
a 
questionnaire that assesses the effect of 
neuropathy on daily activities 
COMPASS-31 
COMPASS-31 (Composite Autonomic 
Symptom Score 31) is a questionnaire 
designed to assess the severity and 
functional 
ability 
in 
patients 
with 
autonomic dysfunction 
Proteinuria 
Result 
Medical 
Record  
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record  
Albuminuria/microalbuminuria levels 
eGFR (estimated Glomerular Filtration 
Rate) 
Creatinine Clearance 
Intraocular pressure 
Result 
Medical 
Record  
The investigator will collect the data in 
the CRF reflecting the information 
included in the medical record  
Glass opacity classification 
 
9.4. Data source 
The source document used will be electronic or physical medical record of the patient. 
 
9.5. Study size 
The population of this study consists of the ATTRv and ATTRwt patients included in studies 
B3461028 and B3461045 in Spain, who present with multisystem involvement (cardiac and 
neurological), who are currently receiving or have received treatment with tafamidis free acid 
61 mg for at least 12 months; and who have a neurological follow-up of at least 12 months. To our 
knowledge, 
 ATTRv patients have been included in studies B3461028 and B3461045 studies in 
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Spain. Patients who respond to the inclusion criteria are estimated to be 
 with ATTRv and 
 
with ATTRwt. 
9.6. Data management 
The investigator will collect data from patients included in an electronic Case Report Form 
specially designed for this study.  
The number of patients will be a correlative number without any identifying value.  
The information will be stored in a database which will in turn be associated with a file, detailing 
the permissions within the database.  
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/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 patient.  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.  The investigator shall ensure that the CRFs are securely 
stored at the study site in encrypted electronic form and will be password protected  to prevent 
access by unauthorized third parties. 
 
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 
are true.  Any corrections to entries made in the CRFs or source documents must be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. 
 
The source documents are the hospital or the physician's chart.  In these cases, data collected on 
the CRFs must match those charts. 
 
9.6.2. Record retention 
 
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To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, e.g., CRFs and hospital records), copies of all CRFs, safety reporting 
forms, source documents, detailed records of treatment disposition, and adequate documentation 
of relevant correspondence (e.g., letters, meeting minutes, and telephone call reports).  The 
records should be retained by the investigator according to local regulations or as specified in the 
clinical study agreement (CSA), whichever is longer.  The investigator must ensure that the 
records continue to be stored securely for so long as they are retained. 
 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., 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.  
 
 
 
 
  
 
The investigator must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met. 
9.7. Data analysis 
 Detailed methodology for summary and statistical analyses of data collected in this study will be 
documented in a Statistical Analysis Plan (SAP), which will be dated, filed and maintained by the 
sponsor. The SAP may modify the plans  outlined in the protocol;  any major modifications of 
primary endpoint definitions or their analyses would be reflected in a protocol amendment. 
9.8. Quality control 
The study will be governed by the basic ethical principles contained in the Declaration of Helsinki.  
The highest levels of professional conduct and confidentiality will always be maintained and 
applicable national data protection laws will be followed at all times. The right to patient 
confidentiality is critical. The patient’s identity in the study documents will be encrypted and only 
authorized persons will have access to personal details that could identify the patient if data 
verification procedures require it. The personal details that could identify the patient will always 
be confidential.  
The investigator will collect data from patients included in a Case Report Form (CRF) specially 
designed for this study. The patient number to be provided will be a correlative number without 
any identifying value. The recruited patients will be entered via dedicated data entry software and 
stored in the study database. A Data Management Plan (DMP) will be developed in which we will 
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detail the different steps to be followed to ensure consistency of the data and to ensure data quality 
standards.  
Random monitoring will be performed in at least 20% of sites included in the study. The study 
monitor will review the information recorded in the CRFs against the investigator in order to verify 
the data collected for all study variables.  
Each participating investigator will be contacted by the study monitor whenever necessary in order 
to assist in the data collection process and to resolve any potential occurrences. Upon completion 
of the CRFs, the study monitor will review the CRFs and may ask the physicians questions (called 
queries) regarding the most important missing variables (according to a predefined list of key 
variables). In this phase, the queries will be generated electronically by 100% of the patients and 
the researchers must resolve them before the closure of the database. The investigator may contact 
the study monitor when necessary.  
A personal statistical team of the CRO hired by the sponsor of the study, will be responsible for 
the treatment and analysis of the data collected in the CRF for subsequent statistical analysis. 
9.9. Limitations of the research methods 
The main limitation of the study is the small sample size. Another limitation may be related to the 
scarcity of the data collected during the follow-up visits, which may provide a partial view of the 
progression of the disease at the systemic level.  
Other causes of neuropathy are also common, particularly for ATTRwt, which can reduce sample 
size.  
 
9.10. Other aspects 
N/A 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information  
 
All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures to ensure protection of patient personal data.  Such measures 
will include omitting patient names or other directly identifiable data in any reports, publications, 
or other disclosures, except where required by applicable laws.  
The personal data will be stored at the study site in encrypted electronic and form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data can 
be recovered in the event of disaster.  In the event of a potential personal data breach, the study 
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site shall be responsible for determining whether a personal data breach has in fact occurred and, 
if so, providing breach notifications as required by law. 
 
To protect the rights and freedoms of natural persons with regard to the processing of personal 
data, when study data are compiled for transfer to Pfizer and other authorized parties, patient names 
will be removed and will be replaced by a single, specific, numerical code, based on a numbering 
system defined by Pfizer.  All other identifiable data transferred to Pfizer or other authorized 
parties will be identified by this single, patient-specific code.  The investigator site will maintain a 
confidential list of patients who participated in the study, linking each patient’s numerical code to 
his or her actual identity.  In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patients’ personal data consistent with the clinical study 
agreement and applicable privacy laws. 
10.2. Patient consent 
 As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required 
 
10.3. Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
There must be prospective approval of the study protocol, protocol amendments, and other relevant 
documents (e.g., informed consent forms, if applicable) from the relevant IRBs/IECs. All 
correspondence with the IRB/IEC must be retained by the investigator. Copies of IRB/IEC 
approvals must be forwarded to Pfizer 
10.4. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well  with 
scientific purpose, value and rigor, and  follow generally accepted research practices generally and 
described in: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
 
This study protocol requires human review of patient-level unstructured data; unstructured data 
refer to verbatim medical data, including text-based descriptions and visual depictions of medical 
information, such as medical records, images of physician notes, neurological scans, X-rays, or 
narrative fields in a database.  The reviewer is obligated to report adverse events (AEs) with 
explicit attribution to any Pfizer drug that appear in the reviewed information (defined per the 
patient population and study period specified in the protocol).  Explicit attribution is not inferred 
by a temporal relationship between drug administration and an AE, but must be based on a definite 
statement of causality by a healthcare provider linking drug administration to the AE. 
 
The requirements for reporting safety events on the non-interventional study (NIS) adverse event 
monitoring (AEM) Report Form to Pfizer Safety are as follows: 
 
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• All serious and non-serious AEs with explicit attribution to any Pfizer drug that appear 
in the reviewed information must be recorded on the case report Form and reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
 
• Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy, 
and occupational exposure associated with the use of a Pfizer product must be reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
 
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, the 
safety information identified in the unstructured data reviewed is captured in the Event Narrative 
section of the report form, and constitutes all clinical information known regarding these AEs.  
No follow-up on related AEs will be conducted. 
 
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, as 
the form designates, since not all elements will be available due to privacy concerns with the use 
of secondary data sources.  While not all demographic fields will be completed, at the very least, 
at least one patient identifier (e.g., gender, age as captured in the narrative field of the form) will 
be reported on the NIS AEM Report Form, thus allowing the report to be considered a valid one 
in accordance with pharmacovigilance legislation.  All identifiers will be limited to generalities, 
such as the statement “A 35-year-old female...” or “An elderly male...”  Other identifiers will 
have been removed.  
 
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug Name” 
may be documented  in month/year (mmm/yyyy) format rather than identifying the actual date of 
occurrence within the month /year of occurrence in the day/month/year (DD/MMM/YYYY ) 
format. 
All research staff members must complete the following Pfizer training requirements:    
•  “Your Reporting Responsibilities (YRR) Training for Vendors”.  
 
These trainings must be completed by research staff members prior to the start of data collection.  
All trainings include a “Confirmation of Training Certificate” (for signature by the trainee) as a 
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record of completion of the training, which must be kept in a retrievable format.  Copies of all 
signed training certificates must be provided to Pfizer.  
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials. 
  
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
  
In the event of any prohibition or restriction imposed (e.g., 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 a Pfizer product, 
Pfizer should be informed immediately.   
. 
13. REFERENCES 
1. Adams D, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a 
fatal disease. Nat Rev Neurol. 2019 Jul;15(7):387-404 
2. Nativi-Nicolau JN, et al. Screening for ATTR amyloidosis in the clinic: overlapping 
disorders, misdiagnosis, and multiorgan awareness. Heart Fail Rev. 2021 Feb 20. 
3. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012 Sep 
4;126(10):1286-300. 
4. Rowczenio DM, et al. Online registry for mutations in hereditary amyloidosis including 
nomenclature recommendations. Hum Mutat. 2014 Sep;35(9):E2403-12. 
5. Caponetti AG, et al. Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin 
Amyloidosis: Insights From THAOS. JACC Heart Fail. 2021 Oct;9(10):736-746. 
6. González-Moreno J, et al. A Descriptive Analysis of ATTR Amyloidosis in Spain from 
the Transthyretin Amyloidosis Outcomes Survey. Neurol Ther. 2021 Jul 30. 
7. Silva-Hernández L., et al. Red flags in patients with hereditary transthyretin amyloidosis 
at diagnosis in a non-endemic area of Spain. Neurologia (Engl Ed). 2020 Sep 4;S0213-
4853(20)30212-7 
8. Álvarez-Rubio J., et al. Characterization of hereditary transthyretin cardiac amyloidosis in 
Spain. Rev Esp Cardiol (Engl Ed). 2021 Oct 25:S1885-5857(21)00292-9. 
9. Kharoubi M., et al. Prevalence and prognostic value of autonomic neuropathy assessed by 
Sudoscan® in transthyretin wild-type cardiac amyloidosis. ESC Heart Fail. 2021 
Apr;8(2):1656-1665; 
10. Wajnsztajn Yungher F., et al. Peripheral neuropathy symptoms in wild type transthyretin 
amyloidosis. J Peripher Nerv Syst. 2020 Sep;25(3):265-272. 
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11. Russell A., et al. Utility of Neuropathy Screening for Wild-Type Transthyretin 
Amyloidosis Patients. Can J Neurol Sci. 2021 Sep;48(5):607-615. 
12. Papagianni A, et al. Clinical and apparative investigation of large and small nerve fiber 
impairment in mixed cohort of ATTR-amyloidosis: impact on patient management and 
new insights in wild-type. Amyloid. 2021 Oct 11:1-9. 
13.  Kleefeld F, et al. Same same, but different? The neurological presentation of wildtype 
transthyretin (ATTRwt) amyloidosis. Amyloid. 2022 Jan 7:1-10. 
14. Bulawa CE, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that 
inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9629-34. 
15. Coelho T, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a 
randomized, controlled trial. Neurology. 2012 Aug 21;79(8):785-92. 
16. AEMPS. Tafamidis 20 mg information: .:: CIMA ::. Medication search results (aemps.es) 
17. Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid 
Cardiomyopathy. N Engl J Med. 2018;379(11):1007‐1016. 
18. AEMPS. Vyndaqel 20 mg and Vyndaqel 61 mg Sheet. 
19. Tafamidis 61 approval by the Food and Drug Administration FDA: Drug Approval 
Package: Vyndaqel & Vyndamax (fda.gov) 
20. Clinical Trials NCT02791230. Long-term Safety of Tafamidis in Subjects With 
Transthyretin Cardiomyopathy. 
21. Damy T, et al. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin 
Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Eur J Heart 
Fail. 2021 Feb;23(2):277-285. 
22. Lockwood PA, et al. The Bioequivalence of Tafamidis 61-mg Free Acid Capsules and 
Tafamidis Meglumine 4 × 20-mg Capsules in Healthy Volunteers. Clin Pharmacol Drug 
Dev. 2020;9(7):849-854. 3. 
23. Monteiro C, et al. Predictive model of response to tafamidis in hereditary ATTR 
polyneuropathy. JCI Insight. 2019 Jun 20;4(12):e126526. 
14. LIST 
Not applicable 
15. LIST OF FIGURES 
Not applicable 
ANNEX 1: LIST OF STAND ALONE DOCUMENTS 
List of Principal Investigators.  
 
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