Clinical trial NCT03860935
Conditions: Amyloidosis Amyloid Cardiomyopathy Transthyretin Amyloidosis Cardiomyopathies Heart Diseases
Keywords: Amyloidosis ATTR-CM Transthyretin Amyloid TTR
Sponsor: Eidos Therapeutics, a BridgeBio company
Start date: 2019-03-19; Completion date: 2023-05-11
Enrollment: 632 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 3 efficacy and safety study to evaluate acoramidis (AG10) HCl 800 mg administered orally twice a day compared to placebo in subjects with symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM).

Detailed description:
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed condition believed to affect more than 400,000 people worldwide. In ATTR-CM, the accumulation of transthyretin (TTR) amyloid results in thickening and stiffening of the heart, which often leads to heart failure or even death.

There are two forms of ATTR-CM:

* Wild Type\* This form of the condition primarily develops in older individuals who do not carry gene mutations.
* Hereditary\* This form of the condition comes from gene mutations passed down in families.

In this study we are researching the investigational drug acoramidis HCl 800 mg administered orally twice a day. Through the study, we want to evaluate the efficacy and safety of acoramidis in patients with ATTR-CM versus placebo.

This is a 30 month, randomized, double-blind, placebo-controlled study. This means that, during the 30 month study, investigators conducting the research and study participants will not know whether the study participant is receiving acoramidis or placebo.

The primary outcomes of the study are:

1. The impact of acoramidis versus placebo on the change in distance walked on the 6 minute walk test (6MWT) after 12 months of treatment compared to baseline.
2. The impact of acoramidis versus placebo on the hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP, and change in from baseline in 6MWT over a 30-month fixed treatment duration.

At the end of 30 months, participants may be eligible to receive investigational acoramidis, and there is no placebo. This is called an "open label extension." This separate study may help us better understand the safety related to taking acoramidis over a longer period of time.

Arms: arm 1: Subjects will receive acoramidis HCl 800 mg twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment. arm 2: Subjects will receive placebo to match twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment.
Interventions: intervention 1: acoramidis intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: TTR stabilizer administered orally twice daily (BID) intervention 2: Non-active control administered orally twice daily (BID)

Protocol documents:
Prot_000.pdf: 
 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
1 
 
Protocol Number: 
Eidos AG10-301 
EudraCT Number: 
2018-004280-32 
IND number: 
133574 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
of the Efficacy and Safety of AG10 in Subjects with Symptomatic 
Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM Trial) 
Indication: 
Transthyretin Amyloid Cardiomyopathy 
Phase: 
3 
Investigational Medicinal 
Product: 
Acoramidis (AG10)  
Sponsor: 
Eidos Therapeutics, Inc. 
1800 Owens Street, Suite C-1200 
San Francisco, CA 94158 
Key Sponsor Contacts: 
 
Alternate Sponsor Contact: 
Previous Version: 
Amendment 5.0; Dated 31 March 2021 
Version: 
Amendment 6.0 
Date: 
16 June 2022  
Confidentiality Statement 
This document contains information proprietary to Eidos Therapeutics, Inc. The information is being provided to you for the 
purpose of conducting a clinical trial for Eidos Therapeutics, Inc. You may disclose the contents of this document to study 
personnel under your supervision who need to know for the purpose, provided such study personnel are bound by confidentiality 
obligations to keep this document and its contents confidential. You are allowed to disclose the contents of this document to your 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) or Research Ethics Board (REB) as required for the 
purpose. Persons to whom the information is disclosed must be informed that the information is confidential and proprietary to 
Eidos Therapeutics, Inc. and that it may not be further disclosed to third parties. You may not disclose the contents of this 
document to any other party, unless government regulations or laws require such disclosure, without prior written permission 
from Eidos Therapeutics, Inc. Any supplemental information that may be added to this document is proprietary to Eidos 
Therapeutics, Inc. and should be handled in accordance with the conditions described above. 
 
 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
2 
INVESTIGATOR’S STATEMENT 
I agree to conduct the study (Study AG10-301) in accordance with the protocol and with all 
applicable government regulations and Good Clinical Practice (GCP) guidance. 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date (DD/MMM/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name 
 
 
 
 
 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
3 
CLINICAL STUDY SYNOPSIS 
Study Number: AG10-301 
Title of Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety 
of AG10 in Subjects with Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM Trial) 
Study Centers: Approximately 130 centers worldwide 
Development Phase: 3 
Objectives and Endpoints: 
Objectives 
Endpoints 
Key Primary 
Part A 
 
To determine the efficacy of acoramidis (AG10) 
in the treatment of subjects with symptomatic 
transthyretin amyloid cardiomyopathy 
(ATTR-CM) by evaluating the difference 
between the acoramidis and placebo groups in the 
change from baseline in the Six-Minute Walk test 
(6MWT) 
Part A 
 
Change from baseline to Month 12 of 
treatment in distance walked during the 
6MWT 
Part B 
 
To determine the efficacy of acoramidis in the 
treatment of subjects with symptomatic 
ATTR-CM by evaluating the difference between 
the acoramidis and placebo groups in the 
combined endpoint of All-Cause Mortality, the 
cumulative frequency of cardiovascular 
(CV)-related hospitalization, change from 
baseline in NT-proBNP, and change from 
baseline in 6MWT 
Part B 
 
A hierarchical combination of 
All-Cause mortality, cumulative frequency 
of CV-related hospitalization, change from 
baseline in NT-proBNP, and change from 
baseline in 6MWT over a 30-month fixed 
treatment duration 
 
Key Secondary 
Part A 
 
To evaluate the effects of acoramidis on quality 
of life (QoL) in subjects with symptomatic 
ATTR-CM 
Part A 
 
Change from baseline to Month 12 of 
treatment in Kansas City Cardiomyopathy 
Questionnaire Overall Score (KCCQ-OS) 
Part B 
 
To evaluate the effects of acoramidis on 6MWT 
Part B 
 
Change from baseline to Month 30 of 
treatment in distance walked during the 
6MWT 
 
 
To evaluate the effects of acoramidis on 
health-related QoL as measured by a heart failure 
(HF)-specific instrument (KCCQ) in subjects with 
symptomatic ATTR-CM 
 
 
To assess the pharmacodynamic (PD) effects of 
acoramidis by assessing circulating prealbumin 
(transthyretin [TTR]) concentration as an in vivo 
biomarker of stabilization 
 
 
To assess the effect of acoramidis on all-cause 
mortality 
 
Change from baseline to Month 30 of 
treatment in KCCQ-OS 
 
 
 
 
Change from baseline to Month 30 in serum 
TTR (prealbumin) level (an in vivo measure 
of TTR stabilization) 
 
 
 
All-Cause Mortality by Month 30 including 
death due to any cause, heart transplant, or 
CMAD 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
4 
Secondary 
Part A 
 
To assess safety and tolerability of acoramidis in 
subjects with symptomatic ATTR-CM 
 
Part A 
 
Safety parameters to be assessed: treatment- 
emergent serious adverse events (SAEs) and 
adverse events (AEs), AEs leading to 
treatment discontinuation, abnormal 
physical exam findings of clinical relevance, 
abnormal vital signs of clinical relevance, 
abnormal ECG parameters of clinical 
relevance, and changes in clinical safety 
laboratory parameters of potential clinical 
concern 
 
 
To assess the pharmacodynamic (PD) effects of 
acoramidis as assessed by 
 
o 
circulating prealbumin (transthyretin, TTR) 
concentration as an in vivo biomarker of 
stabilization and  
o established ex vivo assays of TTR stabilization 
 
Change from baseline in TTR (prealbumin) 
level (an in vivo measure of TTR 
stabilization) at Month 12  
 
TTR stabilization as measured in 
established ex-vivo assays (fluorescent 
probe exclusion [FPE] and Western blot) at 
Month 12 in the PK-PD substudy 
Secondary 
 
Part B: 
 
To determine the efficacy of acoramidis treatment 
as measured by the individual components of the 
primary endpoint and hierarchical combinations 
thereof  
Part B: 
 
A hierarchical combination of 
All-Cause mortality and cumulative 
frequency of CV-related hospitalization 
over a 30-month fixed treatment duration 
 
A hierarchical combination of 
All-Cause mortality, cumulative frequency 
of CV-related hospitalization, and change 
from baseline in 6MWT over a 30-month 
fixed treatment duration 
 
Change in NT-proBNP from baseline to 
Month 30 of treatment  
 
Cumulative frequency of CV-related 
hospitalization by Month 30 
 
 
To determine the efficacy of acoramidis in 
reducing CV mortality in subjects with 
symptomatic ATTR-CM 
 
CV mortality by Month 30 
 
To evaluate the safety and tolerability of 
acoramidis administered for 30 months in subjects 
with symptomatic ATTR-CM 
 
Safety parameters: treatment-emergent 
SAEs and AEs, AEs leading to treatment 
discontinuation, abnormal physical exam 
findings of clinical relevance, abnormal 
vital signs of clinical relevance, abnormal 
ECG parameters of clinical relevance, and 
changes in clinical safety laboratory 
parameters of potential clinical concern 
 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
5 
 
To assess the pharmacodynamic (PD) effects of 
acoramidis as assessed by 
o 
circulating prealbumin (transthyretin, TTR) 
concentration as an in vivo biomarker of 
stabilization and  
o established ex vivo assays of TTR stabilization 
 
 
Change from baseline in TTR (prealbumin) 
level (an in vivo measure of TTR 
stabilization) at Month 30 
 
TTR stabilization measured in established 
ex-vivo assays (FPE and Western blot) in 
the PK-PD substudy 
Exploratory  
Part A 
 To evaluate the effects of acoramidis on circulating 
biomarker of myocardial wall stress in subjects 
with symptomatic ATTR-CM 
Part A 
 Change from baseline in NT-proBNP 
Part A and B: 
 
To evaluate the effects of acoramidis on 
circulating biomarker of microvascular ischemia in 
subjects with symptomatic ATTR-CM 
 
Part A and B: 
 
Change from baseline in Troponin I (TnI)  
 
To characterize PK of acoramidis (and its 
predominant metabolite) when acoramidis-HCl 
800 mg is administered orally twice daily (BID) in 
subjects with symptomatic ATTR-CM 
 
PK measures of acoramidis and its 
predominant metabolite after oral 
administration of acoramidis-HCl 800 mg 
BID in subjects with symptomatic 
ATTR-CM for steady state (every 
3 months), in a subgroup of subjects 
followed at centers participating in the 
PK-PD substudy 
 
 
To describe the population PK (PopPK) of 
acoramidis in subjects with ATTR-CM 
 
 
PopPK analysis of acoramidis in the PK-PD 
substudy 
 
To describe the PD properties and the 
pharmacokinetic (PK)-PD relationship of 
acoramidis as assessed by circulating prealbumin 
(transthyretin, TTR) concentration as an in vivo 
biomarker of stabilization and by established 
ex vivo assays of TTR stabilization, and correlated 
with acoramidis PK 
 
 
Describe the PK-PD relationship of 
acoramidis in adult subjects with 
symptomatic ATTR-CM in the PK-PD 
substudy 
 
 
To evaluate the effects of acoramidis on health-
related QoL as measured by EuroQol Health 
Outcomes Assessment tool (EQ-5D-5L) in subjects 
with symptomatic ATTR-CM 
 
 
Change from baseline in the EQ-5D-5L 
 
 
To assess the ability of acoramidis to bind and 
stabilize a diverse array of pathogenic and likely 
pathogenic variant TTR tetrameric species, 
representing amino acid substitutions located 
throughout the sequence of TTR that are 
responsible for a spectrum of clinical 
presentations, from sera and/or plasma of subjects 
with ATTR-CM 
 
 
 
 
Additional assays comparing acoramidis 
activity across a panel of TTR variants. 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
6 
Study Design and Investigational Plan 
This prospective, Phase 3, randomized, multicenter, parallel-group study will evaluate the efficacy and safety 
of acoramidis in symptomatic subjects compared to placebo, administered on a background of stable heart 
failure therapy. Screening and randomization will be followed by a total of 30 months of blinded, placebo-
controlled treatment. At the end of 12 months of treatment (Part A) efficacy of acoramidis will be assessed 
through analyses of the functional (6MWT) and health-related QoL (as measured by HF-specific instrument 
KCCQ) endpoints. At the end of 30 months of treatment (Part B), efficacy of acoramidis will be further 
assessed through analysis of All-cause mortality, cumulative frequency of CV-related hospitalization, change 
from baseline in NT-proBNP, and change from baseline in 6MWT. 
Subjects are not allowed to be treated with any ATTR-CM specific therapy during the first 12 months of the 
study. If a subject chooses treatment with ATTR-CM specific therapy, they will be asked to complete an early 
termination visit prior to discontinuation/withdrawal.  
If, during participation in the study, tafamidis becomes available for the indication of ATTR-CM and subjects 
have access to it, subjects will be permitted to initiate therapy with tafamidis as a concomitant medication if 
they have completed at least 12 months of blinded study therapy. Currently, tafamidis is approved for the 
treatment of ATTR-CM in some regions. Subjects initiating therapy with tafamidis indicated for ATTR-CM 
must have completed the Month 12 visit. If a subject plans to initiate therapy with tafamidis more than 7 days 
after the Month 12 visit or a later scheduled visit, that subject should have an unscheduled visit with study 
assessments prior to initiation of the concomitant therapy. No other approved or investigational treatments, or 
therapies used off-label or as nonprescription supplements for the treatment of ATTR-CM will be permitted at 
any time during the study. 
If a subject chooses to discontinue investigational medicinal product (IMP), discontinue or withdraw from the 
trial at any time, they will be asked to complete an early termination visit and associated procedures. If a 
subject chooses to initiate treatment with another therapy, including tafamidis in the first 12 months of the 
study, they will be asked to complete an ET visit and associated procedures prior to 
discontinuation/withdrawal. Subjects will continue monthly telephone contact up to Month 30. All 
participating subjects will be asked to consent to determination of vital status (alive, death, heart transplant, 
receiving cardiac mechanical assist device [CMAD]) at Month 30, either via direct contact or through public 
records, regardless of discontinuation or withdrawal status. Unless precluded by governing law or regulation, 
consent for determination of vital status through public records may not be withdrawn. 
All subjects who complete 30 months of blinded study therapy and the final assessments of the double-blind 
treatment period (Month 30 visit) may be eligible to participate in an Open Label Extension (OLE) study 
(Study AG10-304, a separate protocol) of long-term acoramidis treatment. 
 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
7 
  
Eligible subjects will be randomized in a 2:1 ratio to acoramidis HCl 800 mg or matching placebo 
administered orally BID. Subjects will be stratified at randomization based on whether they have wild-type 
ATTR-CM (ATTRwt-CM) or mutant ATTR-CM (ATTRm-CM) with a target of 20% of subjects with 
ATTRm-CM. Subjects will also be stratified according to NT-proBNP level (≤ 3000 vs > 3000 pg/mL) and 
renal function defined by eGFR (≥ 45 vs < 45 mL/min/1.73 m2) at Screening. Samples for plasma PK and 
serum/plasma PD will be collected in the PK-PD substudy.  
Information on AEs and concomitant medications will be collected throughout the study. The safety and 
conduct of the study will be monitored by an independent Data Monitoring Committee (DMC). 
Number of Subjects: Approximately 510 subjects (340 subjects randomized to acoramidis and 170 subjects 
randomized to matching placebo) 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
8 
Inclusion Criteria 
To be eligible to participate in the study, subjects must meet all the following criteria: 
1. Have the ability to understand and sign a written informed consent form, which must be obtained prior to 
initiation of study procedures. 
2. Male or female ≥ 18 to ≤ 90 years of age at time of randomization. 
3. Have an established diagnosis of ATTR-CM with either wild-type TTR or a variant TTR genotype 
(confirmed by genotyping) based on either:  
1. endomyocardial biopsy with confirmatory TTR amyloid typing by either mass spectrometry, 
immunoelectron microscopy, or immunohistochemistry; or 
2. positive technetium-99m (99mTc)-pyrophosphate (PYP) or -bisphosphonate (DPD or HMDP/HDP) 
scan, combined with accepted laboratory criteria excluding a diagnosis of AL amyloidosis (based on both 
immunofixation electrophoresis (IFE) of serum and urine, and serum free light chain (sFLC) analysis).  
Subjects with concurrent monoclonal gammopathy of undetermined significance (MGUS) may require 
confirmation of the diagnosis of ATTR-CM by tissue biopsy with confirmatory TTR amyloid typing by 
either mass spectrometry, immunoelectron microscopy, or immunohistochemistry.  
4. Have 
a. 
a history of heart failure evidenced by at least one prior hospitalization for heart failure or 
b. clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or 
symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous 
pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, or 
peripheral edema) or 
c. 
heart failure symptoms that required or require ongoing treatment with a diuretic. 
5. Have NYHA Class I-III symptoms due to ATTR-CM. 
6. Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use a 
highly effective method of contraception beginning with randomization and continuing for 30 days after 
the last dose of IMP. A male subject who is sexually active with a female of childbearing potential and 
has not had a vasectomy must agree to use a double-barrier method of birth control. 
7. Subjects taking cardiovascular medical therapy, with the exception of diuretic dosing, must be on stable 
doses (defined as no greater than 50% dose adjustment and no categorical changes of medications) for at 
least 2 weeks prior to Screening. 
8. Have completed ≥ 150 m on the 6MWT on at least 2 tests > 24 hours to ≤ 3 weeks apart and prior to 
randomization. The distance walked must be within 15% on two tests. 
If one of the first two tests is not ≥ 150 m or the first two tests are not within 15% of distance walked, a 
third test must be conducted ≤ 3 weeks of the first test. If the third test is still not ≥ 150 m or within 15% 
of one of the first two tests, the subject will not be eligible for participation. 
9. Must have NT-proBNP levels ≥ 300 pg/mL at Screening. 
10. Must have LV wall (interventricular septum or LV posterior wall) thickness ≥ 12 mm as measured by 
transthoracic echocardiogram (ECHO) or cardiac magnetic resonance (CMR) documented in medical 
history within 10 years of Screening or at Screening ECHO or CMR. 
Exclusion Criteria 
Subjects who meet any of the following criteria at the Screening visit will not be eligible to participate in the 
study: 
1. Acute myocardial infarction, acute coronary syndrome or coronary revascularization within 90 days prior 
to Screening. 
2. Stroke or transient ischemic attack (TIA) within 90 days prior to Screening. 
3. Has hemodynamic instability at Screening or Randomization that, in the judgment of the Investigator, 
would pose too great a risk for participation in the study. 
4. Is likely to undergo heart transplantation within a year of Screening. 
5. Has confirmed diagnosis of light-chain (AL) amyloidosis. 




 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
10 
30 meters with an estimated within group standard deviation of 70 meters. Under these assumptions, with a t-
test, a total sample size of approximately 365 subjects will provide 90% power to reject the null hypothesis of 
no mean difference between groups. To allow for the possibility that approximately 20% of subjects may not 
complete the Month 12 6MWT, and that approximately 10% of subjects will have baseline eGFR 
< 30 mL/min/1.73 m2 the adjusted sample size is approximately 510 subjects (340 allocated to acoramidis and 
170 allocated to placebo). 
Part B: The power for Part B was originally estimated based on the primary endpoint of a hierarchical 
combination of All-cause mortality and CV-related hospitalizations over a 30-month treatment period. The test 
statistic for the combined endpoint is Finkelstein and Schoenfeld’s (Finkelstein 1999) adaptation of the 
generalized Gehan Wilcoxon test (and will be referred to as the Finkelstein-Schoenfeld test). Simulations based 
on estimates of mortality and CV-related hospitalizations from ATTR-ACT result in greater than 90% power 
with two-sided alpha = 0.04 with total N = 460 (= 0.9*510, i.e., after excluding 10% of subjects with baseline 
eGFR < 30 mL/min/1.73 m2) for the Finkelstein-Schoenfeld test to reject the null hypothesis that neither All-
cause mortality nor CV-related hospitalizations is different between acoramidis and placebo. Simulations 
assumed an All-cause mortality rate of 40% for placebo with a hazard ratio of 0.7, mean number of CV-related 
hospitalizations by Month 30 of 1.15 and 0.75 in the placebo and acoramidis groups, respectively.  
The primary endpoint is a hierarchical combination of All-cause mortality, cumulative frequency of CV-related 
hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT over a 30-month 
fixed treatment duration.  
The number of subjects who will initiate, and when they will initiate, tafamidis after Month 12 is unknown 
and is not possible to estimate with any precision. Simulations to assess power for the four-component 
hierarchical endpoint (All-cause mortality, cumulative frequency of CV-related hospitalization, change from 
baseline in NT-proBNP, and change from baseline in 6MWT) were conducted under various scenarios taking 
into consideration potential tafamidis use and potentially missing data. The estimated power across the various 
scenarios remains above 80%. 
Efficacy Analyses 
The alpha for Part A is 0.01 and 0.04 for Part B. 
Part A: The primary analysis will be the change from baseline to Month 12 in the distance walked during the 
6MWT. The key secondary endpoint will be the change from baseline to Month 12 on the KCCQ-OS.  
The primary efficacy endpoint will be analyzed using a mixed model repeated measures (MMRM). The model 
will include terms for randomization stratification factors, treatment, time, treatment by time interaction. An 
unstructured variance-covariance model will be used. The key secondary endpoint will be analyzed similarly. 
The secondary endpoint of change from baseline in TTR level will also be analyzed similarly at Month 12. To 
control alpha, KCCQ-OS and change from baseline in TTR level will be formally tested sequentially in this 
order at significance level of 0.01 if the primary endpoint is statistically significant at the 0.01 level.  
An additional secondary endpoint will be measurements of TTR stabilization at Month 12. 
Part B: The primary analysis will use a hierarchical combination of the Finkelstein-Schoenfeld method 
applied to All-cause mortality, cumulative frequency of CV-related hospitalization, change from baseline in 
NT-proBNP, and change from baseline in 6MWT at the last available visit over the 30-month fixed treatment 
duration. 
The key secondary endpoints adjusted for alpha are: 
 
Change from baseline to Month 30 in the distance walked during the 6MWT 
 
Change from baseline to Month 30 on the KCCQ-OS 
 
Change from baseline to Month 30 in serum TTR level 
 
All-Cause Mortality by Month 30, including death due to any cause, heart transplant, or CMAD 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
11 
To control alpha at the 0.04 level, the key secondary endpoints will be formally tested sequentially in the order 
shown above if the primary endpoint is statistically significant at the 0.04 level.  
Additional secondary endpoints (not adjusted for alpha) include: 
 
A hierarchical combination of All-cause mortality and cumulative frequency of CV-related 
hospitalization over a 30-month fixed treatment duration 
 
A hierarchical combination of All-Cause mortality, cumulative frequency of CV-related 
hospitalization, and change from baseline in 6MWT over a 30-month fixed treatment duration  
 
Change in NT-proBNP from baseline to Month 30 of treatment  
 
Cumulative frequency of CV-related hospitalization by Month 30   
 
CV mortality by Month 30 
 
TTR stabilization measured in established ex-vivo assays (FPE and Western blot) in the PK-PD 
substudy  
Safety Analyses: 
In Part A, safety and tolerability data, excluding adjudicated CV-related hospitalizations, will be summarized 
for the entire study cohort after data freeze that will occur after the last subject for analysis has completed 
12 months of double-blind study treatment. 
Following the conclusion of Part B, all safety data will be analyzed and summarized. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The 
incidence of each treatment-emergent AE will be summarized by system organ class, preferred term and 
treatment assignment. Multiple AEs mapped to the same preferred term will be counted once per subject. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug Dictionary with 
generic term and Anatomical Therapeutic Chemical (ATC) code and summarized by ATC code, WHO 
generic name, and treatment. Safety laboratory findings, vital signs, and 12-lead ECGs will be summarized 
descriptively and listed by treatment assignment and visit. Values and changes from baseline at scheduled 
time points will be summarized. Laboratory data will be listed and values and changes from baseline at each 
visit will be summarized. An additional listing of treatment-emergent laboratory abnormalities will be 
provided. 
Blinding for Part A and Part B 
Analysis for Part A will be performed by a team within an independent data reporting center who will be 
unblinded after the last enrolled subject in Part A has completed 12 months of treatment. Subject level 
CV-related hospitalizations data will not be available to the Sponsor Part A team; however, the aggregated 
overall summary without treatment group information may be available to the Sponsor Part A team. 
A separate Part B team within the independent data reporting center will remain blinded to Part A subject level 
data prior to and following unblinding of Part A. 
Blinding to individual subject treatment allocation will be maintained for the subjects, Investigators, Clinical 
Events Committee (CEC), and Sponsor designated site monitoring personnel throughout the study to 
completion. The operational details of maintaining the blind and data access will be described and the process 
will be governed by a Data Access Management Plan. 
 
 


 
Eidos Therapeutics Inc. 
Treatment of Symptomatic ATTR Cardiomyopathy 
Acoramidis (AG10)  
Protocol AG10-301 Amendment 6.0 
 
Confidential 
 
12 
TABLE OF CONTENTS 
INVESTIGATOR’S STATEMENT ................................................................................................2 
CLINICAL STUDY SYNOPSIS .....................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS ....................................................................16 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Background .................................................................................................................19 
1.2. 
Clinical Benefit-Risk Assessment of Acoramidis ......................................................19 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................20 
3. 
INVESTIGATIONAL PLAN .....................................................................................24 
3.1. 
Overall Study Design and Plan: Description ..............................................................24 
3.2. 
Discussion of Study Design and Rationale .................................................................25 
3.2.1. 
Subject Population and Stratification .........................................................................25 
3.2.2. 
Duration of Treatment ................................................................................................26 
3.2.3. 
Selection of Study Population ....................................................................................26 
3.3. 
Eligibility Criteria .......................................................................................................26 
3.3.1. 
Inclusion Criteria ........................................................................................................26 
3.3.2. 
Exclusion Criteria .......................................................................................................27 
3.4. 
Discontinuation of Subjects from Therapy or Withdrawal from the Study ................28 
3.4.1. 
Lost to Follow-Up.......................................................................................................30 
3.5. 
Contraception and Pregnancy Avoidance ...................................................................30 
3.6. 
End of Study Definition ..............................................................................................31 
3.7. 
Treatments ..................................................................................................................32 
3.7.1. 
Treatments Administered ............................................................................................32 
3.7.2. 
Identity of Investigational Products ............................................................................32 
3.7.3. 
Packaging ....................................................................................................................32 
3.7.4. 
Storage, Dispensing, and Return of Investigational Product ......................................32 
3.7.5. 
Method of Assigning Subjects to Treatment Groups .................................................33 
3.7.6. 
Selection of Dosages in the Study ..............................................................................33 
3.7.7. 
Selection and Timing of Dose for Each Subject .........................................................33 
3.7.8. 
Blinding ......................................................................................................................33 
3.7.9. 
Emergency Unblinding ...............................................................................................34 
3.7.10. 
Prior and Concomitant Therapy ..................................................................................34 


 
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3.7.11. 
Prohibited Medications ...............................................................................................34 
3.7.12. 
Treatment Compliance ................................................................................................35 
3.8. 
Study Procedures ........................................................................................................35 
3.8.1. 
Schedule of Assessments ............................................................................................35 
3.8.2. 
Screening (Day -35 to Day -1) ....................................................................................35 
3.8.3. 
Treatment Days ...........................................................................................................36 
3.8.4. 
Day 1 and Repeated Assessments ...............................................................................36 
3.8.5. 
Day 28 (±3 Days) ........................................................................................................37 
3.8.6. 
Month 12 (±7 Days) ....................................................................................................37 
3.8.7. 
Monthly Telephone Contact (±7 Days) ......................................................................38 
3.8.8. 
Month 30 (±7 Days) ....................................................................................................38 
3.8.9. 
Unscheduled Visit .......................................................................................................39 
3.8.10. 
Follow-up 30 days After Last Dose of IMP (± 7 Days) .............................................40 
3.8.11. 
Early Termination (ET) ..............................................................................................41 
3.9. 
Drug Concentration Measurements ............................................................................42 
3.9.1. 
PK Blood Draw Schedule ...........................................................................................42 
3.9.2. 
PD Blood Draw Schedule ...........................................................................................42 
3.9.3. 
Prealbumin Blood Sampling Procedures ....................................................................42 
3.10. 
Efficacy Assessments at Scheduled Visits .................................................................43 
3.10.1. 
Six-Minute Walk Test (6MWT) .................................................................................43 
3.10.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ...............................................43 
3.10.3. 
EuroQoL 5-Dimensions 5-Level Health Outcomes Assessment (EQ-5D-5L) ...........43 
3.11. 
Safety Assessments .....................................................................................................44 
3.11.1. 
Adverse Events ...........................................................................................................44 
3.11.2. 
Causality Assessment .................................................................................................45 
3.11.3. 
Severity Assessment ...................................................................................................45 
3.11.4. 
Serious Adverse Events ..............................................................................................46 
3.11.5. 
Reporting Adverse Events and Serious Adverse Events ............................................46 
3.11.6. 
Reporting of Pregnancies Occurring During the Study ..............................................47 
3.11.7. 
Immediate Reporting of Serious Adverse Events and Events of Clinical 
Interest ........................................................................................................................48 
3.11.8. 
Clinical Laboratory Determinations ...........................................................................49 


 
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3.11.9. 
Vital Signs ..................................................................................................................50 
3.11.10. 
Electrocardiograms .....................................................................................................51 
3.11.11. 
Physical Examinations ................................................................................................51 
3.11.12. 
Definition of Cardiac Mechanical Assist Device, Cardiovascular-related 
Hospitalization and Events of Clinical Interest ..........................................................51 
3.12. 
Study Committees .......................................................................................................52 
3.12.1. 
Data Monitoring Committee .......................................................................................52 
3.12.2. 
Clinical Events Committee .........................................................................................52 
3.12.3. 
Diagnostic Confirmation Committee ..........................................................................52 
3.13. 
Statistical Methods and Determination of Sample Size .............................................52 
3.13.1. 
General Considerations ...............................................................................................52 
3.13.2. 
Determination of Sample Size ....................................................................................53 
3.13.3. 
Timing of Analyses .....................................................................................................54 
3.13.4. 
Analysis Sets and Analysis Conventions ....................................................................54 
3.13.5. 
Demographics and Other Baseline Characteristics .....................................................54 
3.13.6. 
Extent of Exposure and Treatment Compliance .........................................................54 
3.13.7. 
Efficacy Analyses .......................................................................................................54 
3.13.8. 
Pharmacokinetic Analyses ..........................................................................................57 
3.13.9. 
Pharmacodynamic Analyses .......................................................................................57 
3.13.10. 
Exploratory Analyses ..................................................................................................57 
3.13.11. 
Safety Analyses ..........................................................................................................57 
3.13.12. 
Adverse Events ...........................................................................................................57 
3.13.13. 
Interim Analysis ..........................................................................................................57 
4. 
REFERENCES ...........................................................................................................58 
APPENDIX A. SCHEDULE OF ASSESSMENTS ...................................................................59 
APPENDIX B. ETHICS .............................................................................................................62 
APPENDIX C. DATA QUALITY ASSURANCE .....................................................................63 
APPENDIX D. STUDY SPONSORSHIP ..................................................................................64 
APPENDIX E. INVESTIGATOR OBLIGATIONS ..................................................................65 
APPENDIX F. NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION ....................................................................................................67 
APPENDIX G. SUMMARY OF CHANGES.............................................................................68 
 


 
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LIST OF FIGURES 
Figure 1: 
Study Schematic 
25 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AL 
Light-chain 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATTR  
TTR amyloidosis  
ATTR-CM  
ATTR cardiomyopathy  
ATTRm  
Mutant ATTR  
ATTRm-CM 
Familial ATTR-CM 
ATTR-PN 
ATTR polyneuropathy 
ATTRwt 
ATTRwt-CM 
Wild-type ATTR 
Wild-type ATTR-CM 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass surgery 
CBC 
Complete blood count 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CK-MB 
Creatine kinase-MB fraction 
CMAD 
Cardiac mechanical assist device 
CMR 
Cardiac magnetic resonance 
CRF 
Case report form 
CRT 
Cardiac resynchronization therapy 
CTFG 
Clinical Trials Facilitation and Coordination Group 
CV 
Cardiovascular 
DCC 
Diagnostic Confirmation Committee 
DMC 
Data Monitoring Committee 
DPD 
3,3-diphosphono-1,2-propanodicarboxylic acid 
ECG 
Electrocardiogram, electrocardiographic 
ECHO 
Echocardiogram 
ECMO 
Extra-corporeal membrane oxygenation 
EDC 
Electronic Data Capture 


 
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eGFR 
Estimated glomerular filtration rate 
EOCI 
Events of clinical interest  
EQ-5D-5L 
EuroQol 5-dimensions 5-levels Health Outcomes Assessment 
EQ VAS 
EuroQol-Visual Analogue Scale 
ET 
Early termination 
FAC 
Familial ATTR-CM 
FAP 
Familial amyloid polyneuropathy 
FDA 
Food and Drug Administration 
FPE 
Fluorescent Probe Exclusion 
FSH 
Follicle-stimulating hormone 
FT4 
Free Thyroxine 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
HDP 
Hydroxylmethylene diphosphonate 
HMDP 
Hydroxylmethylene diphosphonate 
HF 
Heart Failure 
HIPAA 
Health Insurance Portability and Accountability Act 
IABP 
Intra-Aortic Balloon Pump 
ICD 
Implantable cardioverter defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IFE 
Immunofixation electrophoresis 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
KCCQ-OS 
Kansas City Cardiomyopathy Questionnaire Overall Score 
LV 
Left ventricular 
MAD 
Multiple Ascending Dose 
MDRD 
Modification of diet for renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGUS 
Monoclonal gammopathy of undetermined significance 
mITT 
MMRM 
Modified ITT 
Mixed model repeated measures 


 
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NT-proBNP 
N-terminal prohormone of Brain Natriuretic Peptide 
NYHA 
New York Heart Association 
OLE 
Open Label Extension 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamic 
PE 
Physical examination 
PK 
Pharmacokinetic 
PopPK 
Population Pharmacokinetic 
PP 
Per-protocol 
PYP 
Pyrophosphate 
QoL 
Quality of Life 
RBP 
Retinol-binding protein 
REB 
Research Ethics Board 
sFLC 
Serum free light chain 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Assessments 
SSA 
Senile Systemic Amyloidosis 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TIA 
Transient ischemic attack 
TnI 
Troponin I 
TTR 
Transthyretin 
TSH 
Thyroid-stimulating hormone 
TUDCA 
Tauroursodeoxycholic acid 
ULN 
Upper Limit of Normal 
WBC 
White blood cell 
WHO 
World Health Organization 
99mTc 
Technetium-99m 
6MWT 
Six-Minute Walk Test 


 
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1. 
INTRODUCTION 
1.1. 
Background 
Acoramidis is a potent and selective stabilizer of transthyretin (TTR) that is being developed by 
Eidos Therapeutics, Inc. for the treatment of TTR amyloidosis (ATTR), a progressive, fatal 
disease in which deposition of amyloid derived from either mutant or wild-type TTR causes 
severe organ damage and dysfunction. 
Clinically, ATTR presents as either a cardiomyopathy (ATTR-CM), an infiltrative, restrictive 
cardiomyopathy characterized by progressive left and right heart failure, or as a peripheral 
polyneuropathy (ATTR-PN), a length-dependent neurodegenerative disease affecting 
sensorimotor and autonomic functions. 
Familial ATTR-CM (ATTRm-CM), or FAC, and familial ATTR-PN or familial amyloid 
polyneuropathy (FAP), are driven by pathogenic point mutations in the TTR gene; over 140 such 
mutations have been described. In addition, older individuals may develop ATTR derived from 
wild-type TTR (ATTRwt, formerly called Senile Systemic Amyloidosis [SSA]). In ATTRwt, the 
major organ involved is the heart (ATTRwt-CM), although carpal tunnel syndrome and tendon 
involvement are also common. 
Destabilization, misfolding, and aggregation of TTR lead to deposition of TTR amyloid and 
tissue damage. Several small molecules have been shown to bind to and stabilize TTR, 
potentially preventing the initiating event in amyloidogenesis. Eidos’ therapeutic hypothesis is 
that a highly effective TTR stabilizer will halt or slow ATTR disease progression in ATTR-CM 
(both mutant ATTR [ATTRm] and ATTRwt) and ATTR-PN. 
Acoramidis is a potent, highly selective, small molecule TTR stabilizer. It has demonstrated 
ability to stabilize TTR in vivo following oral dosing to nonhuman mammals, in healthy 
volunteers and in patients with ATTR-CM. 
1.2. 
Clinical Benefit-Risk Assessment of Acoramidis 
ATTR-CM is a serious, progressive, and life-threatening disease associated with either wild-type 
TTR or, in the familial form of the disease, with pathogenic mutations in the TTR gene. While 
such loss-of-function mutations may accelerate the development and progression of ATTR-CM, 
age-related dissociation of the destabilized, native tetrameric form of the protein is the initiating 
pathophysiological event. The degree to which individual mutations promote destabilization of 
the tetramer is associated with a higher degree of penetrance, an earlier onset of symptoms, 
and/or a more aggressive and rapidly progressive clinical course. 
Dissociation of tetrameric TTR into intrinsically unstable monomeric TTR favors misfolding and 
aggregation into amyloidogenic precursors, which can form amyloid fibrils that are deposited in 
affected tissues and organs, leading to local cytotoxicity and both architectural and functional 
disruption. Small molecule stabilizers like acoramidis reduce the likelihood of tetramer 
dissociation and this mechanism provides the therapeutic rationale supporting their use in halting 
or slowing progression of the disease. The preclinical data and clinical safety data collected to 


 
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date have shown an acceptable safety profile and support the continued clinical assessment of 
acoramidis in patients with ATTR-CM. 
Acoramidis has been well-tolerated in toxicology studies at what are predicted to be supra-
therapeutic exposures. Results from Phase 1 and Phase 2 studies to date, have shown that 
administration of acoramidis has demonstrated good tolerability with no safety signals of 
potential clinical concern at proposed therapeutic exposures (Fox 2019, Judge 2019). 
For current nonclinical and clinical data for acoramidis, please refer to the acoramidis 
Investigator’s Brochure. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Key Primary 
Part A:  
 
To determine the efficacy of acoramidis (AG10) 
in the treatment of subjects with symptomatic 
transthyretin amyloid cardiomyopathy (ATTR-
CM) by evaluating the difference between the 
acoramidis and placebo groups in the change 
from baseline in the Six-Minute Walk test 
(6MWT) 
Part A:  
 
Change from baseline to Month 12 of 
treatment in distance walked during the 
6MWT 
Part B:  
 
To determine the efficacy of acoramidis in the 
treatment of subjects with symptomatic ATTR-
CM by evaluating the difference between the 
acoramidis and placebo groups in the combined 
endpoint of All-Cause Mortality, the cumulative 
frequency of cardiovascular (CV)-related 
hospitalization, change from baseline in NT-
proBNP, and change from baseline in 6MWT 
Part B:  
 
A hierarchical combination of All-Cause 
mortality, cumulative frequency of CV-
related hospitalization, change from baseline 
in NT-proBNP, and change from baseline in 
6MWT over a 30-month fixed treatment 
duration 
Key Secondary 
Part A 
 
To evaluate the effects of acoramidis on quality 
of life (QoL) in subjects with symptomatic 
ATTR-CM 
Part A 
 
Change from baseline to Month 12 of 
treatment in Kansas City Cardiomyopathy 
Questionnaire Overall Score (KCCQ-OS) 
Part B 
 
To evaluate the effects of acoramidis on 6MWT 
Part B 
 
Change from baseline to Month 30 of 
treatment in distance walked during the 
6MWT 
 
To evaluate the effects of acoramidis on health-
related QoL as measured by a heart failure (HF)-
specific instrument (KCCQ) in subjects with 
symptomatic ATTR-CM 
 
Change from baseline to Month 30 of 
treatment in KCCQ-OS 
 


 
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 
To assess the pharmacodynamic (PD) effects of 
acoramidis by assessing circulating prealbumin 
(transthyretin [TTR]) concentration as an in vivo 
biomarker of stabilization 
 
Change from baseline to Month 30 in serum 
TTR (prealbumin) level (an in vivo measure 
of TTR stabilization) 
 
To assess the effect of acoramidis on all-cause 
mortality 
 
All-Cause Mortality by Month 30 including 
death due to any cause, heart transplant, or 
CMAD 
Secondary 
Part A 
 
To assess safety and tolerability of acoramidis in 
subjects with symptomatic ATTR-CM 
Part A 
 
Safety parameters to be assessed: treatment-
emergent serious adverse events (SAEs) and 
adverse events (AEs), AEs leading to 
treatment discontinuation, abnormal physical 
exam findings of clinical relevance abnormal 
vital signs of clinical relevance, abnormal 
ECG parameters of clinical relevance, and 
changes in clinical safety laboratory 
parameters of potential clinical concern 
 
 
To assess the pharmacodynamic (PD) effects of 
acoramidis as assessed by 
 
o 
circulating prealbumin (transthyretin, TTR) 
concentration as an in vivo biomarker of 
stabilization and 
o 
established ex vivo assays of TTR stabilization 
 
Change from baseline in TTR (prealbumin) 
level (an in vivo measure of TTR 
stabilization) at Month 12 
 
TTR stabilization as measured in established 
ex-vivo assays (fluorescent probe exclusion 
[FPE] and Western blot) at Month 12 in the 
PK-PD substudy 
Secondary 
Part B 
 
To determine the efficacy of acoramidis 
treatment as measured by the individual 
components of the primary endpoint and 
hierarchical combinations thereof 
Part B 
 
A hierarchical combination of All-Cause 
mortality and cumulative frequency of CV-
related hospitalization over a 30-month fixed 
treatment duration 
 
A hierarchical combination of All-Cause 
mortality, cumulative frequency of CV-
related hospitalization, and change from 
baseline in 6MWT over a 30-month fixed 
treatment duration 
 
Change in NT-proBNP from baseline to 
Month 30 of treatment 
 
Cumulative frequency of 
CV-related hospitalization by Month 30 
 
 
To determine the efficacy of acoramidis in 
reducing CV mortality in subjects with 
symptomatic ATTR-CM 
 CV mortality by Month 30 


 
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 
To evaluate the safety and tolerability of 
acoramidis administered for 30 months in 
subjects with symptomatic ATTR-CM 
 
Safety parameters: treatment-emergent SAEs 
and AEs, AEs leading to treatment 
discontinuation, abnormal physical exam 
findings of clinical relevance, abnormal vital 
signs of clinical relevance, abnormal ECG 
parameters of clinical relevance, and changes 
in clinical safety laboratory parameters of 
potential clinical concern 
 
To assess the pharmacodynamic (PD) effects of 
acoramidis as assessed by  
 
o 
circulating prealbumin (transthyretin, TTR) 
concentration as an in vivo biomarker of 
stabilization and  
o 
established ex vivo assays of TTR 
stabilization 
 
Change from baseline in TTR (prealbumin) level 
(an in vivo measure of TTR stabilization) at 
Month 30 
 
TTR stabilization measured in established ex-vivo 
assays (FPE and Western blot) in the PK-PD 
substudy 
Exploratory 
Part A 
 To evaluate the effects of acoramidis on 
circulating biomarker of myocardial wall stress in 
subjects with symptomatic ATTR-CM 
Part A 
 Change from baseline in NT-proBNP 
Part A and B: 
 
To evaluate the effects of acoramidis on 
circulating biomarker of microvascular ischemia 
in subjects with symptomatic ATTR-CM 
 
Part A and B: 
 
Change from baseline in Troponin I (TnI)  
 
To characterize the PK of acoramidis (and its 
predominant metabolite) when acoramidis-HCl 
800 mg is administered orally twice daily (BID) 
in subjects with symptomatic ATTR-CM 
 
 
PK measures of acoramidis and its 
predominant metabolite after oral 
administration of acoramidis-HCl 800 mg 
BID in subjects with symptomatic ATTR-CM 
for steady state (every 3 months), in a 
subgroup of subjects followed at centers 
participating in the PK-PD substudy 
 
 
To describe the population PK (PopPK) of 
acoramidis in subjects with ATTR-CM 
 
PopPK analysis of acoramidis in the PK-PD 
substudy 


 
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 
To describe the PD properties and the 
pharmacokinetic (PK)-PD relationship of acoramidis 
as assessed by circulating prealbumin (transthyretin, 
TTR) concentration as an in vivo biomarker of 
stabilization and by established ex vivo assays of 
TTR stabilization, and correlated with acoramidis 
PK 
 
Describe the PK-PD relationship of 
acoramidis in adult subjects with 
symptomatic ATTR-CM in the PK-PD 
substudy 
 
To evaluate the effects of acoramidis on health-
related QoL as measured by EuroQol Health 
Outcomes Assessment tool (EQ-5D-5L) in subjects 
with symptomatic ATTR-CM 
 
Change from baseline in the EQ-5D-5L 
 
 
To assess the ability of acoramidis to bind and 
stabilize a diverse array of pathogenic and likely 
pathogenic variant TTR tetrameric species, 
representing amino acid substitutions located 
throughout the sequence of TTR that are 
responsible for a spectrum of clinical 
presentations, from sera and/or plasma of 
subjects with ATTR-CM 
 
Additional assays comparing acoramidis 
activity across a panel of TTR variants. 


 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan: Description 
This prospective, Phase 3, randomized, multicenter, parallel-group study will evaluate the 
efficacy and safety of acoramidis in symptomatic subjects compared to placebo, administered on 
a background of stable heart failure therapy. Screening and randomization will be followed by a 
total of 30 months of blinded, placebo-controlled treatment. At the end of 12 months of treatment 
(Part A), efficacy of acoramidis will be assessed through analyses of the functional (6MWT) and 
health-related QoL (as measured by HF-specific instrument KCCQ) endpoints (Terms KCCQ 
overall score and KCCQ overall summary score are interchangeably used in this document). At 
the end of 30 months of treatment (Part B), efficacy of acoramidis will be further assessed 
through analysis of All-cause mortality, cumulative frequency of CV-related hospitalization, 
change from baseline in NT-proBNP, and change from baseline in 6MWT. 
Subjects are not allowed to be treated with any ATTR-CM specific therapy during the first 
12 months of the study. If a subject chooses treatment with ATTR-CM specific therapy during 
the first 12 months of the study, they will be asked to complete an early termination visit prior to 
discontinuation/withdrawal. 
If during participation in the study, tafamidis becomes available for the indication of ATTR-CM 
and subjects have access to it, subjects will be permitted to initiate therapy with tafamidis as a 
concomitant medication if they have completed at least 12 months of blinded study therapy. 
Currently, tafamidis is approved for the treatment of ATTR-CM in some regions. Subjects 
initiating therapy with tafamidis indicated for ATTR-CM must have completed the Month 12 
visit. If a subject plans to initiate therapy with tafamidis more than 7 days after the Month 12 
visit or a later scheduled visit, they should have an unscheduled visit with study assessments 
prior to initiation of the concomitant therapy. No other approved or investigational treatments or 
therapies used off-label or as nonprescription supplements for the treatment of ATTR-CM will 
be permitted at any time during the study. 
If a subject chooses to discontinue investigational medicinal product (IMP), discontinue or 
withdraw from the trial at any time, they will be asked to complete an early termination visit and 
associated procedures. If a subject chooses to initiate treatment with another therapy, including 
tafamidis in the first 12 months of the study, they will be asked to complete an ET visit and 
associated procedures prior to discontinuation/withdrawal. Subjects will continue monthly phone 
contact up to Month 30. All participating subjects will be asked to consent to determination of 
vital status (alive, death, heart transplant, receiving cardiac mechanical assist device [CMAD]) at 
Month 30, either via direct contact or through public records, regardless of discontinuation or 
withdrawal status. Unless precluded by governing law or regulation, consent for determination of 
vital status through public records may not be withdrawn. 
All subjects who complete 30 months of blinded study therapy and the final assessments of the 
double-blind treatment period (Month 30 visit) may be eligible to participate in an Open-Label 
extension (OLE) study (Study AG10-304, a separate protocol) of long-term acoramidis 
treatment. 


 
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Information on AEs and concomitant medications will be collected throughout the study. The 
safety and conduct of the study will be monitored by an independent Data Monitoring 
Committee (DMC). 
The Schedule of Assessments is provided in Appendix A. Detailed descriptions of study visits 
can be found in Section 3.8. 
The study schematic is provided in Figure 1. 
Figure 1: 
Study Schematic 
 
3.2. 
Discussion of Study Design and Rationale 
This prospective study is designed to evaluate the efficacy and safety of acoramidis in subjects 
with ATTR-CM, administered on a background of stable heart failure therapy. A randomized, 
double-blind, placebo-controlled design is considered to be the most appropriate study design to 
meet this objective. On the basis of information gained from previous clinical experience with 
acoramidis, the dose of acoramidis HCl 800 mg BID has been selected for this study to represent 
the optimal combination of potential efficacy, safety, and tolerability. 
3.2.1. 
Subject Population and Stratification 
Approximately 510 males and females ≥ 18 and ≤ 90 years of age (at time of randomization) 
with chronic, stable, symptomatic (NYHA Class I-III) ATTR-CM will be randomized in a 2:1 
ratio (340 subjects to active treatment, 170 to matching placebo) in the study. Subjects will be 
stratified at randomization based on whether they have ATTRwt-CM or ATTRm-CM with a 
target of 20% of subjects with ATTRm-CM. Subjects will also be stratified according to 


 
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NT-proBNP level (≤ 3000 vs > 3000 pg/mL) and renal function defined by eGFR (≥ 45 vs 
< 45 mL/min/1.73 m2) at Screening.  
3.2.2. 
Duration of Treatment 
Subjects will be treated with the IMP (acoramidis or placebo) for 30 months. IMP may be 
discontinued without discontinuing/withdrawing from the study (refer to Section 3.4 for details). 
Part A and Part B will be reported separately. All subjects who complete 30 months of blinded 
study therapy and the final assessments of the double-blind treatment period may be eligible to 
participate in an Open Label Extension (OLE) study (Study AG10-304, a separate protocol) of 
long-term acoramidis treatment. 
3.2.3. 
Selection of Study Population 
Approximately 510 males and females ≥ 18 and ≤ 90 years of age with symptomatic ATTR-CM 
(NYHA Class I-III) will be randomized in a 2:1 ratio (340 subjects to acoramidis and 
170 subjects to matching placebo) in the study. 
3.3. 
Eligibility Criteria 
3.3.1. 
Inclusion Criteria 
To be eligible to participate in the study, subjects must meet all the following criteria: 
1. Have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures. 
2. Male or female ≥ 18 to ≤ 90 years of age at time of randomization. 
3. Have an established diagnosis of ATTR-CM with either wild-type TTR or a variant TTR 
genotype (confirmed by genotyping) based on either: 
a. endomyocardial biopsy with confirmatory TTR amyloid typing by either mass 
spectrometry, immunoelectron microscopy, or immunohistochemistry; or 
b. positive technetium-99m (99mTc)-pyrophosphate (PYP) or -bisphosphonate (DPD or 
HMDP/HDP) scan, combined with accepted laboratory criteria excluding a diagnosis 
of AL amyloidosis (based on both immunofixation electrophoresis (IFE) of serum 
and urine, and serum free light chain (sFLC) analysis). 
Subjects with concurrent monoclonal gammopathy of undetermined significance (MGUS) may 
require confirmation of the diagnosis of ATTR-CM by tissue biopsy with confirmatory TTR 
amyloid typing by either mass spectrometry, immunoelectron microscopy, or 
immunohistochemistry. 
4. Have 
a. a history of heart failure evidenced by at least one prior hospitalization for heart 
failure or 
b. clinical evidence of heart failure without prior heart failure hospitalization manifested 
by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., 


 
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elevated jugular venous pressure, shortness of breath or signs of pulmonary 
congestion on x-ray or auscultation, or peripheral edema) or 
c. heart failure symptoms that required or require ongoing treatment with a diuretic. 
5. Have NYHA Class I-III symptoms due to ATTR-CM. 
6. Female subjects of childbearing potential who engage in heterosexual intercourse must 
agree to use a highly effective method of contraception beginning with randomization and 
continuing for 30 days after the last dose of IMP. A male subject who is sexually active 
with a female of childbearing potential and has not had a vasectomy must agree to use a 
double-barrier method of birth control (as described in Section 3.5). 
7. Subjects taking cardiovascular medical therapy, with the exception of diuretic dosing, 
must be on stable doses (defined as no greater than 50% dose adjustment and no 
categorical changes of medications) for at least 2 weeks prior to Screening. 
8. Have completed ≥ 150 m on the 6MWT on at least 2 tests > 24 hours to ≤ 3 weeks apart 
and prior to randomization. The distance walked must be within 15% on two tests. 
9. If one of the first two tests is not ≥ 150 m or the first two tests are not within 15% of 
distance walked, a third test must be conducted ≤ 3 weeks of the first test. If the third test 
is still not ≥ 150 m or within 15% of one of the first two tests, the subject will not be 
eligible for participation. 
10. Must have NT-proBNP levels ≥ 300 pg/mL at Screening. 
11. Must have LV wall (interventricular septum or LV posterior wall) thickness ≥ 12 mm as 
measured by transthoracic echocardiogram (ECHO) or cardiac magnetic resonance 
(CMR) documented in medical history within 10 years of Screening or at Screening 
ECHO or CMR. 
3.3.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria at the Screening visit will not be eligible to 
participate in the study: 
12. Acute myocardial infarction, acute coronary syndrome or coronary revascularization 
within 90 days prior to Screening. 
13. Stroke or transient ischemic attack (TIA) within 90 days prior to Screening. 
14. Has hemodynamic instability at Screening or Randomization that, in the judgment of the 
Investigator, would pose too great a risk for participation in the study. 
15. Is likely to undergo heart transplantation within a year of Screening. 
16. Has confirmed diagnosis of light-chain (AL) amyloidosis. 
17. Has abnormal liver function tests at Screening, defined as alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) > 3× upper limit of normal (ULN) or total 
bilirubin > 3× ULN. 
18. Has NT-proBNP levels ≥ 8500 pg/mL at Screening. 


 
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19. Has estimated glomerular filtration rate (eGFR) by modification of diet for renal disease 
(MDRD) formula < 15 mL/min/1.73 m2 at Screening. 
20. Known hypersensitivity to IMP (acoramidis or placebo), its metabolites, or formulation 
excipients. 
21. Treatment for ATTR-CM with tafamidis, with marketed drug products lacking a labeled 
indication for ATTR-CM (e.g., diflunisal, doxycycline), or with natural products or 
derivatives used as unproven therapies for ATTR-CM (e.g., green tea extract, 
tauroursodeoxycholic acid [TUDCA]/ursodiol) within 14 days prior to dosing; treatment 
with patisiran, inotersen, or other gene silencing agent: within 90 days for patisiran, 180 
days for inotersen, and 5 half-lives for any other gene silencing agent, prior to dosing. 
22. If, during participation in the study, subjects gain access to tafamidis, they will be 
permitted to initiate therapy with tafamidis as a concomitant medication if they have 
completed at least 12 months of blinded study therapy. 
23. Requires treatment with calcium channel blockers with conduction system effects (e.g., 
verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. 
The use of digitalis will only be allowed if required for management of atrial fibrillation 
with rapid ventricular response. 
24. Females who are pregnant or breastfeeding. Lactating females must agree to discontinue 
nursing before IMP is administered. A negative urine pregnancy test at Screening and at 
Randomization are required for female subjects of childbearing potential. 
25. In the judgment of the Investigator or Medical Monitor, has any clinically important 
ongoing medical condition or laboratory abnormality or condition that might jeopardize 
the subject’s safety, increase their risk from participation, or interfere with the study. 
26. Participation in another investigational clinical trial within 30 days prior to dosing with 
potential residual effects that might confound the results of this study. Participation in 
observational and/or registry studies should be discussed with the Medical Monitor. 
27. Has any condition that, in the opinion of the Investigator or Medical Monitor, would 
preclude compliance with the study protocol such as a history of substance abuse, 
alcoholism or a psychiatric condition. 
3.4. 
Discontinuation of Subjects from Therapy or Withdrawal from the 
Study 
Subjects have the right to discontinue IMP or discontinue/withdraw from the study at any time 
and for any reason without prejudice to their future medical care by the physician or at the 
institution. 
The Investigator can discontinue a subject from IMP or withdraw a subject from the study at any 
time prior to study completion. 
Reasons for discontinuation of IMP or/and withdrawing from the study prior to Month 30 
include but not limited to: 
 AEs 


 
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 Note 1: If considered necessary, as per Investigator’s discretion, IMP may be 
interrupted (e.g., in case of AE, hospitalization or procedure), however IMP 
should be resumed as soon as practically possible, unless there are safety 
concerns. Investigators are encouraged to discuss such cases with a Medical 
Monitor. 
 Note 2: If a subject prematurely discontinues from the IMP because of an AE, the 
study center personnel must record the AE as the reason for discontinuation. (An 
AE that occurs more than 30 days after the last dose of IMP is not considered a 
treatment-emergent adverse event [TEAE].) 
 Death 
 Protocol deviation(s) 
 If it is discovered after randomization that the subject did not meet protocol entry 
criteria, and continued participation would present unacceptable risk to subject’s 
health 
 Non-compliance with study treatment or protocol procedures 
 Subject’s decision to discontinue study drug or withdraw from the study assessments.  
 Withdraw of consent 
 Note 3: Subjects may withdraw consent at any time for any reason without 
prejudice to future treatment. In the event of withdrawal of consent, the ET 
procedures should occur as a final visit. Note: All participating subjects will be 
asked to consent to determination of vital status (dead, alive, heart transplant, 
receiving CMAD) at Month 30, either via direct contact or through public records, 
regardless of discontinuation or withdrawal status. Unless precluded by governing 
law or regulation, consent for determination of vital status may not be withdrawn. 
 Note 4: Withdrawal of consent should be distinguished from discontinuation of 
IMP. Subjects who discontinue IMP permanently will receive phone calls as 
specified by the protocol to assess vital status, heart transplant or CMAD 
implantation. 
 Received heart or liver transplant or received CMAD at any time during the trial 
 Need for medications prohibited during the study 
 Lost to follow-up 
 Pregnancy at any time after signing the ICF. Study therapy should be discontinued 
immediately, and pregnancy reported (Section 3.11.6) 
 Study terminated by Sponsor 
 Site closed by Sponsor 
 Subject’s treatment assignment unblinded to the Investigator (Section 3.7.9) 


 
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All dosed subjects who prematurely discontinue from the IMP permanently or 
discontinue/withdraw from the study, regardless of cause, will be asked to complete an Early 
Termination (ET) Visit and a safety follow up visit 30 days after the last dose (Schedule of 
Assessments [SoA], Appendix A). 
A safety follow-up visit 30 days post last dose per SoA will be conducted. If a subject is refusing 
to come into the study center for an ET Visit, or who cannot be reached must be requested in 
writing to come into the study center and to return any unused IMP. A copy of the registered 
letter will be kept by the study center with source documentation. 
For subjects who refused to come in for a safety follow-up 30 days after the last dose, a phone 
call to document the adverse events should be made. 
Reason for permanent discontinuation of IMP (end of treatment) and/or withdrawal from the 
study will be recorded on the appropriate CRF(s). Investigator should evaluate the possible 
contribution of an adverse event to permanent discontinuation of IMP. In this case, adverse event 
information will be documented accordingly in the CRF. 
In subjects who permanently discontinued IMP, every effort should be made to continue monthly 
phone contacts for vital status for subjects who discontinue IMP for up to Month 30 by 
completing monthly contact for vital status or until withdrawal of consent. 
Vital status will be determined for all subjects at Month 30, either via direct contact or through 
public records, regardless of discontinuation or withdrawal status. Unless precluded by 
governing law or regulation, consent for determination of vital status through public records may 
not be withdrawn. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. If a subject withdraws 
from the study, he/she may request destruction of any samples taken and not tested, and the 
investigator must document this in the site study records. If allowed by law, samples that have 
already been collected may continue to be stored and used to meet legal and regulatory 
obligations. 
3.4.1. 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Before a subject is deemed lost to 
follow-up, the investigator or designee must make every effort to regain contact with the subject 
(where possible, 3 telephone calls, and if necessary, a registered letter to the subject’s last known 
mailing address or local equivalent methods). These contact attempts should be documented in 
the subject’s medical record. Should the subject continue to be unreachable, he/she may be 
considered to have withdrawn from the study. 
3.5. 
Contraception and Pregnancy Avoidance 
Female subjects of childbearing potential who engage in heterosexual intercourse must agree to 
use a highly effective method of contraception (CTFG guidance v.1.1) beginning with 
randomization and continuing for 30 days after the last dose of IMP as follows: 


 
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 If heterosexually active, must be using a highly effective method of birth control such 
as hormonal oral contraceptives, intravaginal hormonal contraceptive, contraceptive 
injections/implant, contraceptive patch, intrauterine device, or bilateral tubal 
occlusion before subject randomization and must agree to continue to use a highly 
effective method of birth control throughout the study and for 30 days after the last 
dose of IMP, consistent with local regulations regarding use of birth control methods 
for subjects participating in clinical studies. 
 Female subjects using oral contraceptives must agree to use an additional birth 
control method. 
 While not considered highly effective, a double-barrier method (e.g., condoms, 
diaphragm, or cervical cap with spermicidal foam, cream, or gel) is acceptable. 
 Not heterosexually active (practices complete abstinence). Sexual abstinence is 
considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire study and for 30 days after the last dose of IMP. 
A female subject is considered of childbearing potential (i.e., fertile), following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause and has to be 
confirmed with plasma follicle-stimulating hormone (FSH). 
Subjects will be provided with information on method(s) of contraception acceptable for the 
study as a part of informed consent and will confirm that they understand the requirement to 
avoid pregnancy during the study and continuing for 30 days after the last dose of IMP.  
Pregnancy tests will be performed during the study according to the Schedule of Assessments 
(Appendix A), and subjects will receive guidance on avoidance of pregnancy throughout the 
study. Subjects will be instructed to contact their physician immediately if they become pregnant 
or suspect they may be pregnant. Subjects who become pregnant during the study will be 
withdrawn from study therapy, and their pregnancy will be followed to term (Section 3.11.6) 
A male subject who is sexually active with a female of childbearing potential and has not had a 
vasectomy must agree to use a double-barrier method of birth control such as a condom with 
spermicidal foam/gel/cream. 
If a male subject’s partner becomes pregnant any time between the start of IMP and 30 days after 
the last dose, the male subject must inform the Investigator as soon as possible. Follow-up 
information regarding the outcome of the pregnancy and any post-natal sequelae in the infant 
will be required. 
Study subjects should be reminded at the study visits regarding consistent and correct use of 
protocol-specified contraception methods. 
3.6. 
End of Study Definition 
The end of the study for reporting purposes is defined as the latest date of the following: last visit 
of the last subject or the last vital status assessment of the last subject in the study globally. 


 
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Subjects are considered to have completed the study if they have completed all periods of the 
study including the follow-up period, except for subjects who enroll in Study AG10-304 on the 
same day as the Month 30 visit in Study AG10-301. Completion of the follow-up period is 
defined as completion of the follow-up visit 30 days after the last dose of IMP. Subjects who 
enroll in Study AG10-304 on the same day as the Month 30 visit in Study AG10-301 will be 
considered to have completed the study when they have completed the double-blind treatment 
period including the Month 30 visit. 
3.7. 
Treatments 
3.7.1. 
Treatments Administered 
Subjects who meet eligibility criteria listed in Section 3.3 will be randomized in a 2:1 manner 
(acoramidis:placebo) to receive the following treatment arms in a double-blind fashion: 
 800 mg acoramidis hydrochloride (HCl) BID, orally (two 400 mg acoramidis HCl 
tablets (equivalent to 356 mg acoramidis), BID) 
 Matching placebo BID, orally (two matching placebo tablets, BID) 
3.7.2. 
Identity of Investigational Products 
Acoramidis HCl tablets (400 mg) and matching placebo tablets will be supplied by Eidos 
Therapeutics, Inc. The excipients of acoramidis HCl (400 mg) tablets or matching placebo 
tablets include microcrystalline cellulose, croscarmellose sodium, silicon dioxide, lactose 
monohydrate, and magnesium stearate, coated with Opadry. 
3.7.3. 
Packaging 
The IMP will be provided as blinded randomized kits assigned to subjects using a randomization 
code. The kits will be labeled as required by regulations in the countries where the trial is being 
performed. 
Full details regarding IMP packaging are provided in the Investigator’s Brochure and Pharmacy 
Manual. 
3.7.4. 
Storage, Dispensing, and Return of Investigational Product 
The Sponsor will provide the study center with IMP supplies. Full details regarding IMP storage 
are provided in the Pharmacy Manual. 
The site research pharmacist or delegated personnel will maintain an accurate record of the 
receipt of the IMP shipped by the Sponsor, including the date and quantity received. In addition, 
an accurate drug accountability record will be kept that specifies the amount of IMP, date 
dispensed to each subject, amount of IMP, and date returned by the subject. This inventory 
record must be available for inspection at any time, and copies of this record will be provided to 
the Sponsor at the conclusion of the study. 
It is the Investigator’s responsibility to ensure that subjects return their unused IMP at each visit. 
All unused IMP must be returned to the Sponsor or destroyed on-site throughout the course of 
the study after IMP accountability is completed and with approval by the Sponsor. If unused IMP 


 
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is not returned to the Sponsor and destroyed on-site, proof of destruction must be provided to the 
Sponsor. 
3.7.5. 
Method of Assigning Subjects to Treatment Groups 
Screening numbers will be assigned consecutively (e.g., 1, 2, 3,…) through an Interactive Web 
Response System (IWRS) portal after the subject signs the ICF. Subjects who meet eligibility 
criteria will be randomized using permuted blocks into the study and assigned a unique subject 
number through the IWRS. Subjects will be stratified at randomization based on whether they 
have ATTRm-CM or ATTRwt-CM with a targeted minimum of 20% of subjects with 
ATTRm-CM. Subjects will also be stratified according to NT-proBNP level (≤ 3000 vs 
> 3000 pg/mL) and renal function defined by eGFR (≥ 45 vs < 45 mL/min/1.73 m2) at Screening. 
3.7.6. 
Selection of Dosages in the Study 
The acoramidis HCl dose of 800 mg chosen for this study is based on nonclinical PK studies, 
data from the Phase 1, first-in-human, single ascending dose (SAD) and multiple ascending dose 
(MAD) Study AG10-001 conducted in healthy adult volunteers, and the Phase 2, repeat dose, 
dose-ranging, safety, tolerability, PK and PD Study AG10-201 in ATTR-CM subjects with 
NYHA Class II-III heart failure. Further details on these studies can be found in the acoramidis 
Investigator’s Brochure. 
3.7.7. 
Selection and Timing of Dose for Each Subject 
Dosing should be administered BID, once in the morning and once in the evening. Acoramidis 
can be taken with or without food. Additional information on dosing instructions can be found in 
the study Pharmacy Manual. 
3.7.8. 
Blinding 
Blinding of study treatment is critical to the integrity of this clinical trial and every effort will be 
made to protect the blind. If a subject’s treatment assignment is disclosed to the Investigator, the 
subject will have study treatment discontinued (Section 3.4). The Sponsor or a designated safety 
representative may independently unblind cases for expedited reporting of suspected unexpected 
serious adverse reactions (SUSARs). 
However, regardless of any unblinding, accidental or due to Investigator request in the context of 
an AE, all subjects will be followed until study completion unless consent to do so is specifically 
withdrawn by the subject (see Section 3.4). Note: all participating subjects will be asked to 
consent to determination of vital status (e.g., alive, death, heart transplant, receiving CMAD) at 
Month 30, either via direct contact or through public records, regardless of discontinuation or 
withdrawal status. Unless precluded by governing law or regulation, consent for determination of 
vital status through public records may not be withdrawn. 
Blinding for Part A and Part B 
Analysis for Part A will be performed by a team within an independent data reporting center who 
will be unblinded after the last enrolled subject in Part A has completed 12 months of treatment. 
Subject level CV-related hospitalizations data will not be available to the Sponsor Part A team; 


 
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however, the aggregated overall summary without treatment group information may be available 
to the Sponsor Part A team. 
A separate Part B team within the independent data reporting center will remain blinded to 
Part A subject level data prior to and following unblinding of Part A. 
Blinding to individual subject treatment allocation will be maintained for the subjects, 
Investigators, Clinical Events Committee (CEC), and Sponsor designated site monitoring 
personnel throughout the study to completion. The operational details of maintaining the blind 
and data access will be described and the process will be governed by a Data Access 
Management Plan. 
3.7.9. 
Emergency Unblinding 
Unblinding by Investigator should occur only if the knowledge of IMP assignment is required to 
enable urgent clinical decision making. In this situation, the decision to unblind a subject’s 
treatment assignment rests with the Investigator who has access to IWRS treatment assignment. 
The Investigator should attempt to contact the Medical Monitor (or designee) to discuss options 
prior to unblinding, unless the urgency of the subject’s medical situation prevents this. Detailed 
instructions for IMP unblinding will be provided in a Study Procedures Manual. In the event of 
emergency unblinding of a subject’s IMP assignment, a full written explanation of events 
requiring IMP unblinding should be provided to the Medical Monitor within 24 hours of 
occurrence. 
3.7.10. 
Prior and Concomitant Therapy 
At all visits, study center personnel will ask each subject specifically about all prior and 
concomitant medications and record the medication, dosage, and duration of use in the 
appropriate CRF. 
3.7.11. 
Prohibited Medications 
 Use of patisiran, inotersen, tafamidis (see Note below) or any other approved or 
investigational agent for the treatment of ATTR-CM is prohibited during the study. 
 Use of marketed drug products lacking a labeled indication for ATTR-CM (e.g., 
diflunisal, doxycycline) or of natural products or derivatives used as unproven 
therapies for ATTR-CM (e.g., green tea extract, tauroursodeoxycholic acid 
[TUDCA]/ursodiol) is prohibited. 
 Use of calcium channel blockers with conduction system effects (e.g., verapamil, 
diltiazem) is prohibited. Use of dihydropyridine calcium channel blockers is allowed. 
The use of digitalis will only be allowed if required for management of atrial 
fibrillation with rapid ventricular response. 
Note: If, during participation in the study, tafamidis becomes available for the indication of 
ATTR-CM and subjects have access to it, subjects will be permitted to initiate therapy with 
tafamidis as a concomitant medication if they have completed at least 12 months of blinded 
study therapy. (Currently, tafamidis is approved for the treatment of ATTR-CM in some 
regions.) Subjects initiating therapy with tafamidis indicated for ATTR-CM must have 


 
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completed the Month 12 visit. If a subject plans to initiate therapy with tafamidis more than 7 
days after the Month 12 visit or a later scheduled visit, they should have an unscheduled visit 
with study assessments prior to initiation of the concomitant therapy. 
3.7.12. 
Treatment Compliance 
IMP compliance will be closely monitored by counting the amount of IMP dispensed and 
returned at each study visit. Before dispensing new IMP at each visit, study center personnel will 
make every effort to collect all unused IMP. 
3.8. 
Study Procedures 
3.8.1. 
Schedule of Assessments 
The schedule of study procedures and assessments are tabulated by study day in the Schedule of 
Assessments in Appendix A. The descriptions of the procedures to be performed throughout the 
study are provided below. 
3.8.2. 
Screening (Day -35 to Day -1) 
Screening will be performed within ≤ 35 days before administration of the first dose of IMP. The 
following procedures will be performed at Screening: 
 Informed consent administration 
 Review Inclusion/Exclusion criteria to confirm subject is eligible 
 Confirm genotype either through existing documentation or testing during Screening. 
Genotyping must be confirmed prior to randomization.  
 Submission of source documents required for the Diagnostic Confirmation 
Committee (DCC) should be completed as early as possible during the Screening 
period and must include either: 
 endomyocardial biopsy report with confirmatory TTR amyloid typing by either 
mass spectrometry, immunoelectron microscopy, or immunohistochemistry; 
OR 
 positive 99mTc-PYP or -bisphosphonate (DPD or HMDP/HDP) scan, 
 AND clinical laboratory evidence excluding the diagnosis of AL amyloidosis 
(based on both IFE of serum and urine, and sFLC analysis); 
 Subjects with concurrent MGUS may require confirmation of the diagnosis of 
ATTR-CM by tissue biopsy with confirmatory TTR amyloid typing by either 
mass spectrometry, immunoelectron microscopy, or immunohistochemistry. 
 Medical and surgical history assessment 
 NYHA Class assessment (Appendix F) 


 
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 Physical examination including body weight and height measurements 
(Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG (in a supine position after a 5-minute rest) (Section 3.11.10) 
 Resting transthoracic ECHO or CMR, if LV wall (interventricular septum or LV 
posterior wall) thickness not documented in medical history within 10 years of 
Screening based on ECHO or CMR (Section 3.3) 
 6MWT, two assessments > 24 hours to ≤ 3 weeks apart. If one of the first two tests is 
not ≥ 150 m or the first two tests are not within 15% of distance walked, a third test 
must be conducted ≤ 3 weeks of the first test. If the third test is still not ≥ 150 m or 
within 15% of one of the first two tests, the subject will not be eligible for 
participation (Section 3.10.1) 
 Blood sample collection for hematology, serum chemistry (including circulating 
biomarkers), urinalysis (Section 3.11.8) 
 Blood sample collection for serum and plasma exploratory tests 
 Urine pregnancy test, for female subjects of childbearing potential only 
 Prior and concomitant medication use assessment 
3.8.3. 
Treatment Days 
Study procedures are listed below by study day, ideally performed in the order listed below, for 
each day. 
Screening safety assessments completed on the same day as Day 1 (e.g., physical exam, vital 
signs, ECG, clinical laboratory tests) may be used as Day 1 assessments at the investigator’s 
discretion provided that they are predose. 
3.8.4. 
Day 1 and Repeated Assessments 
These assessments will occur in-clinic at Day 1 and Months 3, 6, 9, 15, 18, 21, 24, and 27 
(±7 Days): 
 Review Inclusion/Exclusion criteria to confirm subject is eligible (Day 1) 
 Randomize subject to treatment arm and assign randomization number (Day 1) 
 NYHA Class assessment (Appendix F) 
 Physical examination including body weight measurement (Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG (in a supine position after a 5-minute rest) (Section 3.11.10) 
 KCCQ (Schedule of Assessments in Appendix A and Section 3.10.2) 
 EQ-5D-5L (Schedule of Assessments in Appendix A and Section 3.10.3) 


 
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 6MWT (Schedule of Assessments in Appendix A and Section 3.10.1) 
 Blood sample collection for hematology, serum chemistry (including circulating 
biomarkers), urinalysis (Section 3.11.8) 
 Urine pregnancy test, for female subjects of childbearing potential only 
 PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD 
substudy (Section 3.9.2) 
 PK blood sample collection (predose) in PK-PD substudy (Section 3.9.1) 
 Prealbumin blood sample collection (predose) (Section 3.9.3) 
 Dispense/collect and administer IMP with designated witness (i.e., site personnel) 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
 IMP compliance assessment (all visits except Day 1) 
3.8.5. 
Day 28 (±3 Days) 
 NYHA Class assessment (Appendix F) 
 Physical examination including body weight measurement (Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG at predose (in a supine position after a 5-minute rest) and at 1-
hour postdose (Section 3.11.10) 
 Blood sample collection for hematology, serum chemistry (including circulating 
biomarkers), urinalysis (Section 3.11.8) 
 Urine pregnancy test, for female subjects of childbearing potential only 
 PD blood sample collection for analysis of TTR stabilization (predose and at 1-hour 
postdose) in PK-PD substudy (Section 3.9.2) 
 PK blood sample collection (predose and at 1-hour postdose) in PK-PD substudy 
(Section 3.9.1) 
 Prealbumin blood sample collection (predose) (Section 3.9.3) 
 Dispense/collect and administer IMP with designated witness (i.e., site personnel) 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
 IMP compliance assessment 
3.8.6. 
Month 12 (±7 Days) 
 NYHA Class assessment (Appendix F) 


 
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 Physical examination including body weight measurement (Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG (in a supine position after a 5-minute rest) (Section 3.11.10) 
 KCCQ (Section 3.10.2) 
 EQ-5D-5L (Section 3.10.3) 
 6MWT (Section 3.10.1) 
 Blood sample collection for hematology, serum chemistry (including circulating 
biomarkers), urinalysis (Section 3.11.8) 
 Urine pregnancy test, for female subjects of childbearing potential only 
 PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD 
substudy (Section 3.9.2) 
 PK blood sample collection (predose) in PK-PD substudy (Section 3.9.1) 
 Prealbumin blood sample collection (predose) (Section 3.9.3) 
 Dispense/collect and administer IMP with designated witness (i.e., site personnel) 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
 IMP compliance assessment 
3.8.7. 
Monthly Telephone Contact (±7 Days) 
These telephone contacts will occur during months without scheduled in clinic visits (e.g., 
Months 2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, and 29): 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
 IMP compliance assessment 
Subjects who discontinue IMP may be asked to continue monthly phone contacts and 
determination of vital status at Month 30. 
3.8.8. 
Month 30 (±7 Days)  
 NYHA Class assessment (Appendix F) 
 Physical examination including body weight measurement (Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG (in a supine position after a 5-minute rest) (Section 3.11.10) 
 KCCQ (Section 3.10.2)  


 
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 EQ-5D-5L (Section 3.10.3) 
 6MWT (Section 3.10.1) 
 Blood sample collection for hematology, serum chemistry (including circulating 
biomarkers), urinalysis (Section 3.11.8) 
 Urine pregnancy test, for female subjects of childbearing potential only 
 PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD 
substudy (Section 3.9.2) 
 PK blood sample collection (predose) in PK-PD substudy (Section 3.9.1) 
 Prealbumin blood sample collection (predose) (Section 3.9.3) 
 Collect IMP with designated witness (i.e., site personnel) 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
 IMP compliance assessment 
Subjects who complete the 30-months of double-blinded study treatment and the Month 30 visit 
assessments, may be eligible to enroll into the OLE study (AG10-304). Subjects who are 
planning to enroll in Study AG10-304 should take the evening dose of IMP the day before the 
Month 30 visit and should not take the morning dose on the day of the Month 30 visit. 
3.8.9. 
Unscheduled Visit 
Unscheduled visits can be performed at any time during the study according to the Investigator’s 
judgment (e.g., if needed to assess or to follow up on an AE) or prior to initiation of tafamidis for 
ATTR-CM in subjects who complete at least 12 months of the study and the Month 12 visit 
study assessments. If a subject plans to initiate therapy with tafamidis more than 7 days after the 
Month 12 visit or a later scheduled visit, they should have an unscheduled visit with study 
assessments prior to initiation of the concomitant therapy. 
For any unscheduled visit, the date and reason for the unscheduled visit must be recorded in the 
source documentation, concomitant medications reviewed, and adverse events evaluated. 
If the unscheduled visit is for assessment or follow up of an AE, only procedures and 
assessments deemed necessary by the Investigator (e.g., physical exam, vital signs, 12-lead 
resting ECG, clinical laboratory assessments, and urine pregnancy test) need to be conducted. 
Other procedures (e.g., KCCQ, EQ-5D-5L, 6MWT) may not be needed. 
Any subject initiating therapy with tafamidis for the treatment of ATTR-CM and remaining in 
the trial must have completed the Month 12 visit. If a subject plans to initiate therapy with 
tafamidis more than 7 days after the Month 12 visit or a later scheduled visit, they should have an 
unscheduled visit with study assessments performed prior to initiation of tafamidis including but 
not necessarily limited to: 
 NYHA Class assessment (Appendix F) 


 
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 Physical examination including body weight measurement (Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG (in a supine position after a 5-minute rest) (Section 3.11.10) 
 KCCQ (Section 3.10.2)  
 EQ-5D-5L (Section 3.10.3) 
 6MWT (Section 3.10.1) 
 Blood sample collection for hematology, serum chemistry (including circulating 
biomarkers), urinalysis (Section 3.11.8) 
 Urine pregnancy test, for female subjects of childbearing potential only 
 PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD 
substudy (Section 3.9.2) 
 PK blood sample collection (predose) in PK-PD substudy (Section 3.9.1) 
 Prealbumin blood sample collection (predose) (Section 3.9.3) 
 Dispense/collect and administer IMP with designated witness (i.e., site personnel) 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
 IMP compliance assessment 
3.8.10. 
Follow-up 30 days After Last Dose of IMP (± 7 Days) 
Subjects who complete the Month 30 visit will have a visit 30 days (± 7 days) after the last dose 
of IMP. Subjects who choose to enroll in the OLE Study (AG10-304) the same day as 
completing the Month 30 visit in AG10-301 will not be required to have the 30-day follow-up 
visit (in Study AG10-301). The following procedures will be performed: 
 NYHA Class assessment (Appendix F) 
 Physical examination including body weight measurement (Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG (in a supine position after a 5-minute rest) (Section 3.11.10) 
 Blood sample collection for hematology, serum chemistry, urinalysis (Section 3.11.8) 
 Urine pregnancy test, for female subjects of childbearing potential only 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
Any clinically relevant findings obtained during the final examination, including clinically 
relevant laboratory abnormalities and the manner in which they are treated, will be followed until 


 
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the condition returns to pre-study status, has resolved or stabilized, or has been determined to be 
unrelated to the IMP. 
3.8.11. 
Early Termination (ET) 
All dosed subjects who prematurely discontinue study treatment permanently and/or 
discontinue/withdraw from the study, regardless of cause, will be asked to complete the ET Visit 
(Section 3.4) including the following assessments and procedures: 
 NYHA Class assessment (Appendix F) 
 Physical examination including body weight measurement (Section 3.11.11) 
 Vital signs assessment (Section 3.11.9) 
 12-lead resting ECG (in a supine position after a 5-minute rest) (Section 3.11.10) 
 KCCQ (Section 3.10.2) 
 EQ-5D-5L (Section 3.10.3) 
 6MWT (Section 3.10.1) 
 Blood sample collection for hematology, serum chemistry (including circulating 
biomarkers), urinalysis (Section 3.11.8) 
 Urine pregnancy test, for female subjects of childbearing potential only 
 PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD 
substudy (Section 3.9.2) 
 PK blood sample collection (predose) in PK-PD substudy (Section 3.9.1) 
 Prealbumin blood sample collection (predose) (Section 3.9.3) 
 Concomitant medication use assessment 
 AE/Vital status assessment/Hospitalization determination (Section 3.4) 
 Collect unused IMP 
 IMP compliance assessment 
If a subject discontinues IMP or discontinues/withdraws from the study, subjects will be asked to 
complete an ET visit and associated assessments and procedures. All participating subjects will 
be asked to consent to determination of vital status (e.g., alive, death, heart transplant, receiving 
CMAD) at Month 30, either via direct contact or through public records, regardless of 
discontinuation or withdrawal status. Unless precluded by governing law or regulation, consent 
for determination of vital status through public records may not be withdrawn (refer to 
Section 3.4 for further details). 


 
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3.9. 
Drug Concentration Measurements 
3.9.1. 
PK Blood Draw Schedule 
In a subgroup of subjects at participating sites, PK samples will be collected at the following 
times to determine acoramidis plasma concentrations: 
 Day 1: Predose 
 Day 28: Predose and 1-hour postdose 
 Months 3 - 27: Predose 
 Month 12: Predose 
 Month 30: Predose 
 ET 
 Unscheduled visit (e.g., Investigator’s discretion) 
3.9.2. 
PD Blood Draw Schedule 
In a subgroup of subjects at participating sites, PD properties of acoramidis will be assessed by 
established assays of TTR stabilization, including fluorescent probe exclusion (FPE) assay and 
Western blot. Sampling will be done at the following times to perform these PD assays: 
 Day 1: Predose 
 Day 28: Predose and 1-hour postdose 
 Months 3 - 27: Predose 
 Month 12: Predose 
 Month 30: Predose 
 ET 
 Unscheduled visit (e.g., Investigator’s discretion) 
3.9.3. 
Prealbumin Blood Sampling Procedures 
To measure prealbumin concentrations, blood sampling will be done at the following times: 
 Day 1: Predose 
 Day 28: Predose  
 Months 3 - 27: Predose 
 Month 12: Predose 
 Month 30: Predose 
 ET 
 Unscheduled visit (e.g., Investigator’s discretion) 


 
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3.10. 
Efficacy Assessments at Scheduled Visits 
For details on timings, refer to the Schedule of Assessments in Appendix A. 
3.10.1. 
Six-Minute Walk Test (6MWT) 
Prior to randomization, two 6MWTs will be conducted > 24 hours to ≤ 3 weeks apart. The 
walking distances must be ≥ 150 meters and the distance walked must be within 15% on two 
tests on different days. If one of the first two tests is not ≥ 150 m or the first two test results are 
not within the 15% of distance walked, a third test must be conducted ≤ 3 weeks of the first test. 
If the third test is still not ≥ 150 m or within 15% of one of the first two tests, the subject will not 
be eligible for participation. 
If the subject has a need for a walking aid (e.g., cane) or supplemental oxygen at baseline, it must 
be used consistently at each subsequent 6MWT throughout the study. If a subject develops a 
need for a walking aid (e.g., cane) or supplemental oxygen after baseline, it must be used 
consistently at each subsequent 6MWT throughout the study. 
The 6MWT should be conducted after completion of the KCCQ and EQ-5D-5L at the visits 
where required. 
The 6MWT with Borg Scale will be conducted based on the guidelines of the American Thoracic 
Society with appropriate modifications for the subject population. Complete details on the 
procedures for the 6MWT are provided in a Study Procedures Manual. 
3.10.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The KCCQ is a 23-item questionnaire developed to measure health status and health-related 
quality of life (QoL) in subjects with heart failure. Items include heart failure symptoms, impact 
on physical and social functions, and how their heart failure impacts their quality of life. It 
should be completed by the subject at predose. Complete details are provided in a Study 
Procedures Manual. 
3.10.3. 
EuroQoL 5-Dimensions 5-Level Health Outcomes Assessment (EQ-5D-5L) 
EQ-5D-5L is a brief, self-administered generic health status instrument that takes about 
5 minutes to complete and should be conducted after completion of the KCCQ. The instrument 
includes two parts. In the first part, respondents are asked to rate their current health state on 
5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) 
with each dimension having five levels of function (1-no problem, 2-slight problem, 3-moderate 
problem, 4-severe problem, and 5-extreme problem). The second part is a respondent’s self-
rating of current health status on a EuroQol-Visual Analog Scale (EQ VAS) with endpoints 
labeled “best imaginable health state” (score of 100) and “worst imaginable health state” (score 
of 0). The scores from the 5 dimensions may be used to calculate a single index value, also 
known as a utility score. Complete details administration and scoring are provided in a Study 
Procedures Manual. 


 
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3.11. 
Safety Assessments 
Subjects must be seen by a physician or an appropriately trained health professional at every 
in-clinic visit. The evaluation must be documented. The procedures discussed in this section will 
be assessed at every in-clinic visit beginning from the time the subject signs the ICF. The clinical 
relevance of any abnormal findings found in the physical examination, clinical laboratory 
evaluations, vital sign assessments, and ECGs must be evaluated and documented by the 
Investigator. For clinical laboratory tests, the Investigator will assess and document the clinical 
relevance of any values outside the reference ranges provided by the clinical laboratory.  
3.11.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an IMP and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product (ICH E2A). 
It is the responsibility of the Investigator to document all AEs that occur during the study. AEs 
should be elicited by asking the subject a nonleading question (e.g., “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”). AEs will be reported on 
the AE CRF. 
For the purpose of data collection for this study, any untoward event that is reported from the 
time that the subject signs the ICF until 30 days after the last dose of IMP is to be considered an 
AE (refer to Section 3.11.5 or further details). 
Examples of AEs are as follows: 
 Changes in the general condition of the subject that represents a decline in health or 
functional status 
 Symptoms offered by or elicited from the subject 
 Objective signs observed by the Investigator or other study personnel 
 All diseases that occur after the start of the study, including a worsening, excluding 
minor fluctuations, in the nature, severity, frequency, or duration of a pre-existing 
condition. Any medical condition present at Screening and which does not deteriorate 
should not be reported as an AE. However, any pre-existing medical condition that 
deteriorates during the study should be reported as an AE. 
An AE does not include: 
 A medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or 
transfusion); an AE is the underlying condition that leads to the procedure 
 Pre-existing diseases or conditions present or detected before start of IMP 
administration that do not worsen or increase in severity or frequency after the 
administration of IMP 


 
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 Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery for a condition that has not worsened on study, 
social and/or convenience admissions to grant families a respite in caring for a 
patient) 
 Overdose of either IMP or concomitant medication without any signs or symptoms 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis will be documented as the AE and 
not the individual signs/symptoms. If a diagnosis is not available, the sign/symptom may be 
reported as the AE. 
All clinically relevant abnormalities in laboratory values or clinically relevant physical findings 
that occur during the study should be reported as an AE. A clinically relevant laboratory value or 
physical finding is one associated with signs and symptoms and/or requires medical intervention. 
3.11.2. 
Causality Assessment 
The Investigator must assess the relationship of the event to the IMP. The causal relationship of 
the AE is assessed using a binary system, and AEs are classified as either ‘Related’ or 
‘Not Related’ as defined below. 
Related: The available evidence suggests the adverse event is most likely due to the IMP. For 
example, a temporal relationship exists between the AE onset and administration of the IMP that 
cannot be readily explained by the subject’s clinical state, concurrent disease or concomitant 
therapies. 
Not related: The available evidence suggests the adverse event is most likely related to factors 
other than the administration of the IMP. Such other factors may include the underlying disease 
state, comorbidities, an intercurrent illness, concomitant medication(s) or procedures. 
The causality assessment evaluates the likelihood that the event was caused by the drug, the 
underlying disease, comorbidities, intercurrent illness or other factors, and determines which 
factor is the most likely cause of the event. Causality assessment is not an assessment of whether 
or not the study drug can be ruled out. 
The Investigator must assess and report the relationship of an SAE to the IMP within 24 hours of 
when the site first becomes aware of the event. 
The Investigator may change the causality assessment at any time based on new accumulated 
information. 
An AE with causal relationship not initially determined will require follow-up to assign 
causality. 
3.11.3. 
Severity Assessment 
The Investigator will provide an assessment of the severity of each AE by recording a severity 
rating on the appropriate AE reporting page of the subject’s CRF. Severity, which is a description 
of the intensity of manifestation of the AE, is distinct from seriousness, which implies a subject 


 
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outcome or AE-required treatment measure associated with a threat to life or functionality. 
Severity will be assessed according to the following scale: 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research subject. 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
3.11.4. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life threatening; i.e., in the opinion of the Investigator, the AE places the subject at 
immediate risk of death from the event as it occurred; it does not include a reaction 
that, had it occurred in a more severe form, might have caused death. 
 Results in subject hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity, or 
 Results in a congenital anomaly or birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
Emergency room visits that do not result in hospitalization should be evaluated for one of the 
other seriousness outcomes to determine whether they qualify as SAEs. 
Preplanned hospitalizations (e.g., elective procedures for preexisting conditions that did not 
worsen) are excluded from SAE reporting. 
Note that death is an outcome of an AE and not an AE in itself. The event that was the proximate 
cause of death should be reported as the AE term. 
3.11.5. 
Reporting Adverse Events and Serious Adverse Events 
Any untoward event that is reported from the time that the subject signs the ICF until 30 days 
after the last dose of IMP must be collected. Thus, any untoward medical occurrences or 
unfavorable and unintended signs, symptoms, or diseases that occur in the pretreatment, 


 
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treatment, or posttreatment period are to be considered AEs (and SAEs if appropriate), and 
consequently recorded and reported as such. 
Subjects are to be queried regarding any AEs or SAEs at the time of each vital sign assessment, 
as well as at each visit, according to the Schedule of Assessments (Appendix A). Subjects will be 
asked to volunteer information with a nonleading question such as, “How do you feel?” Study 
center personnel will then record all pertinent information in the subject’s CRF. 
All AEs and SAEs reported by the subject (or subject representative) or observed or otherwise 
identified by the Investigator (or other study center personnel) at a defined study visit or during 
any communication with the subject (or subject representative) occurring outside a defined study 
visit (from the time the subject signs the ICF to 30 days after the last dose of IMP) must be 
documented. 
All AEs must be recorded on the appropriate AE reporting page of the subject’s CRF whether or 
not they are considered causally related to the IMP. 
For every AE, the Investigator must: 
 Provide an assessment of the severity, causal relationship to the IMP, and seriousness 
of the event (i.e., whether it is an SAE) 
 Document all actions taken with regard to the IMP 
 Detail any other treatment measures taken for the AE 
 Document outcome of the AE (with or without sequelae); ongoing; or lost to 
follow-up. 
3.11.6. 
Reporting of Pregnancies Occurring During the Study 
Study center personnel must report every pregnancy from the time a female subject signs the ICF 
until 30 days after the last dose of IMP. Within 24 hours of learning of the pregnancy, study 
center personnel must report the event to the Sponsor on the Clinical Trial Pregnancy Form, even 
if no AE has occurred. 
The pregnancy must be followed to term and the outcome reported by completing a follow-up 
Clinical Trial Pregnancy Form. If the pregnancy is associated with an SAE (e.g., if the female 
subject is hospitalized for hemorrhage), a separate SAE Form must be completed (in addition to 
the Pregnancy Form) as described in Section 3.11.6, with the appropriate serious criterion 
(e.g., hospitalization) indicated. 
In the event that a female subject becomes pregnant, the Investigator is required to contact the 
Medical Monitor within 24 hours of awareness. 
If a female subject becomes pregnant, administration of the IMP must be discontinued 
immediately. 
If a male subject’s partner becomes pregnant any time between the start of acoramidis and 30 
days after the last dose, the study investigator should be informed as soon as possible. 
Completion of the “Pregnant Partner ICF” will be requested at that time. Follow-up information 
regarding the outcome of the pregnancy will be requested. 


 
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3.11.7. 
Immediate Reporting of Serious Adverse Events and Events of Clinical Interest 
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet specific 
criteria. Therefore, the Sponsor must be notified immediately regarding any SAE that occurs 
after informed consent is obtained. 
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the study center 
personnel must report the event to the Sponsor or its designated representative on the SAE Form. 
In addition, SAEs that are assessed by the Investigator as related to IMP and occurring after 
30 days post the last dose of IMP will also be reported to the Sponsor within 24 hours of when 
the site first becomes aware of the event. 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, 
that AE should be recorded as a new SAE. 
The study center personnel must transmit the SAE Form to the Sponsor within 24 hours of when 
the site first becomes aware of the event. Even if the site has discussed the event with a Sponsor 
representative, the study center personnel must complete the SAE Form with all available details 
and transmit the form within 24 hours of when the site first becomes aware of the event. 
Supplemental information related to the SAE shall be submitted as soon as available and may 
include laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and death 
certificates. 
The Investigator is expected to take all therapeutic measures necessary to treat and promote 
resolution of the SAE. Any medications or procedures necessary for treatment of the SAE must 
be recorded on the appropriate pages of the subject’s CRF. The study center personnel must 
follow all SAEs until resolution or until the SAE is deemed stable. The Sponsor may contact the 
study center to solicit additional information or follow-up on the event. 
A CV-related hospitalization is defined as a non-elective admission to an acute care setting for 
CV-related morbidity that results in ≥ 24 hours stay (or a date change if the time of 
admission/discharge is not available). 
Events of clinical interest (EOCI) are defined as medical visits (e.g., emergency 
department/ward, urgent care clinic, day clinic, etc.) of < 24 hours where diagnosis and 
interventions indicate that the purpose of the visit was for intravenous diuretic therapy for 
management of decompensated heart failure. EOCI are considered as part of the efficacy 
endpoint of CV-related hospitalizations. 
Mortality, heart transplant, CMAD, and CV-related hospitalizations are endpoints for Part B of 
the trial but the events that lead to death or hospitalization will be reported as Serious Adverse 
Events on the SAE Form to the Sponsor throughout the trial. 
The Investigator is responsible for ensuring potential study endpoints, including dates of 
admissions and discharge, are collected and well documented for adjudication purposes (this 
includes but is not limited to: admission notes describing signs and symptoms, cardiology or 
other relevant clinical notes, hospital discharge summary); for providing Investigator assessment 
whether the hospitalization is CV-related; and for submitting the SAE Form for all AEs that 
result in deaths or hospitalizations. 




 
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Hematology 
Hemoglobin, hematocrit, white blood cell (WBC) count, platelet count, 
complete blood count (CBC), and differential 
Chemistry 
Sodium, potassium, chloride, carbon dioxide (bicarbonate), glucose, 
blood urea nitrogen (BUN), creatinine, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), total protein, albumin, 
prealbumin, retinol-binding protein (RBP), free thyroxine (FT4), 
alkaline phosphatase, calcium, phosphorus, total and fractionated 
(indirect or direct) bilirubin, uric acid, thyroid-stimulating hormone 
(TSH), troponin I, creatine kinase (CK), creatine kinase-MB fraction 
(CK-MB), and NT-proBNP 
Urinalysis 
Complete urinalysis (specific gravity, pH, glucose, protein, 
hemoglobin, leukocyte esterase, and nitrite). Additionally, albumin to 
creatinine ratio and a microscopic urinalysis will be performed on every 
specimen and will specifically look for casts, bacteria, white blood 
cells, epithelial cells, and red blood cells 
Others 
FSH only to confirm post-menopausal status at Screening in female 
subjects who do not have menses for at least 12 months and are not 
using hormonal contraception or hormone replacement therapy 
(Section 3.5). 
Pregnancy 
test 
Highly sensitive urine test at all visits as outlined in the Schedule of 
Assessments (Appendix A) (female subjects of childbearing potential 
only) 
 
Samples will be collected, processed, and stored according to the instructions provided in the 
supplementary Laboratory Manual. 
Clinical laboratory test data will be reviewed by the Investigator or qualified Sub-Investigator. If 
the test is considered inaccurate based on the subject’s medical history or is an error from the 
Central Laboratory, clinical laboratory tests may be repeated at the Investigator’s or qualified 
Sub-Investigator’s discretion. 
The Investigator or qualified Sub-Investigator will review all laboratory results for clinical 
relevance. Any laboratory result deemed clinically relevant (e.g., is associated with signs and 
symptoms and/or requires medical intervention) will be recorded as an AE as described in 
Section 3.11.1. 
3.11.9. 
Vital Signs 
Vital signs will be assessed at the times detailed in the Schedule of Assessments (Appendix A). 
Study center personnel will assess vital signs predose after a 5-minute rest. The investigator will 
determine whether abnormal vital signs are clinically relevant. Any abnormal vital sign that is 
deemed clinically relevant by the Investigator (e.g., is associated with symptoms and/or requires 
medical intervention) will be recorded as an AE as described in Section 3.11.1. 


 
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3.11.10. 
Electrocardiograms 
A standard 12-lead ECG will be assessed at the times detailed in the Schedule of Assessments in 
Appendix A. ECGs will be performed in the supine position after a 5-minute rest at predose and 
1-hour postdose on Day 28. 
The Investigator or qualified Sub-Investigator will review all ECG interpretations and interval 
duration measurements for clinical relevance. Any ECG interpretation deemed to be clinically 
relevant (e.g., is associated with symptoms and/or requires medical intervention) will be reported 
as an AE as described in Section 3.11.1. 
3.11.11. 
Physical Examinations 
At the times detailed in the Schedule of Assessments in Appendix A, subjects will undergo a 
complete physical examination (PE) including body weight and height measurements, which is 
to be completed by a physician or an appropriately trained health professional. Any abnormal 
physical examination finding that is deemed clinically relevant by the Investigator (e.g., is 
associated with symptoms and/or requires medical intervention) will be recorded as an AE as 
described in Section 3.11.1. 
3.11.12. 
Definition of Cardiac Mechanical Assist Device, Cardiovascular-related 
Hospitalization and Events of Clinical Interest 
In this study, CMAD and heart transplant are included in the “All-cause mortality” component of 
the primary endpoint for Part B, and therefore should be collected for all randomized patients 
even if they discontinued treatment permanently or withdrew consent (see also Section 3.4). 
CMAD is defined as a durable CMAD implanted in a patient with end-stage heart failure as a 
bridge to transplant or as a destination therapy. Temporary cardiac mechanical support (i.e., 
those interventions that can only be employed in the inpatient setting, e.g., Intra-Aortic Balloon 
Pump [IABP], Impella, or Extra-corporeal membrane oxygenation [ECMO]) are not considered 
CMAD. In addition, other cardiac interventions such as pacemaker, implantable cardioverter 
defibrillator (ICD), cardiac resynchronization therapy (CRT), percutaneous coronary intervention 
(PCI), coronary artery bypass surgery (CABG), valvular percutaneous intervention or surgery are 
not considered CMAD. 
A CV-related hospitalization is defined as a non-elective admission to an acute care setting for 
CV-related morbidity that results in ≥ 24 hours stay (or a date change if the time of 
admission/discharge is not available). 
EOCI (Section 3.11.7) re defined as medical visits (e.g., emergency department/ward, urgent 
care clinic, day clinic, etc.) of < 24 hours where diagnosis and interventions indicate that the 
purpose of the visit was for intravenous diuretic therapy for management of decompensated heart 
failure. EOCI are considered as part of the efficacy endpoint of Part B CV-related 
hospitalizations. 
The Investigator is responsible for ensuring potential study endpoints, including dates of 
admissions and discharge, are collected and well documented for adjudication purposes (this 
includes but is not limited to: admission notes describing signs and symptoms, cardiology or 
other relevant clinical notes, hospital discharge summary); for providing Investigator assessment 




 
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Efficacy analyses will adjust for randomization stratification factors. Adjustments for additional 
covariates, if any, will be mentioned separately for different endpoints. 
3.13.2. 
Determination of Sample Size 
The primary analysis population will include subjects with baseline eGFR ≥ 30 mL/min/1.73 m2 
(i.e., subjects with baseline eGFR < 30 mL/min/1.73 m2 will be excluded from the primary 
analysis population). It is estimated that approximately 10% of subjects will have baseline eGFR 
< 30 mL/min/1.73 m2. Sample size calculations are based on two-sided alphas = 0.01 for Part A 
and 0.04 for Part B.  
Part A: 
The primary endpoint of Part A is the change from baseline in the distance achieved in the 
6MWT following 12 months of double-blind study treatment.  
The sample size calculation for the primary endpoint in Part A is based on the following 
assumptions: two-sided alpha = 0.01, power = 0.9, normally distributed data per group, equal 
within group standard deviations. Based on the ATTR-ACT study (Maurer 2018), it is estimated 
that the between group mean change from baseline is 30 meters with an estimated within group 
standard deviation of 70 meters. Under these assumptions, with a t-test, a total sample size of 
approximately 365 subjects will provide 90% power to reject the null hypothesis of no mean 
difference between groups. To allow for the possibility that approximately 20% of subjects may 
not complete the Month 12 6MWT, and that approximately 10% of subjects will have baseline 
eGFR < 30 mL/min/1.73 m2 the adjusted sample size is approximately 510 subjects 
(340 allocated to acoramidis and 170 allocated to placebo). 
Part B: 
The power for Part B was originally estimated based on the primary endpoint of a hierarchical 
combination of All-cause mortality and CV-related hospitalizations over a 30-month treatment 
period. The test statistic for the combined endpoint is Finkelstein and Schoenfeld’s (Finkelstein 
1999) adaptation of the generalized Gehan Wilcoxon test (and will be referred to as the 
Finkelstein-Schoenfeld test). Simulations based on estimates of mortality and CV-related 
hospitalizations from ATTR-ACT result in greater than 90% power with two-sided alpha = 0.04 
with total N = 460 (= 0.9*510, i.e., after excluding 10% of subjects with baseline eGFR 
< 30 mL/min/1.73 m2) for the Finkelstein-Schoenfeld test to reject the null hypothesis that 
neither All-cause mortality nor CV-related hospitalizations is different between acoramidis and 
placebo. Simulations assumed an All-cause mortality rate of 40% for placebo with a hazard ratio 
of 0.7, mean number of CV-related hospitalizations by Month 30 of 1.15 and 0.75 in the placebo 
and acoramidis groups, respectively.  
The primary endpoint is a hierarchical combination of All-cause mortality, cumulative frequency 
of CV-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 
6MWT over a 30-month fixed treatment duration.  
The number of subjects who will initiate, and when they will initiate, tafamidis after Month 12 is 
unknown and is not possible to estimate with any precision. Simulations to assess power for the 
four-component hierarchical endpoint (All-cause mortality, cumulative frequency of CV-related 
hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT) were 


 
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conducted under various scenarios taking into consideration potential tafamidis use and 
potentially missing data. The estimated power across the various scenarios remains above 80%. 
3.13.3. 
Timing of Analyses 
Part A analyses will occur following the last subject completing the Month 12 visit. For Part B 
analyses, when final in-clinic visits and safety follow-up visits have been completed for all 
subjects and all data is entered, the database will be cleaned and locked, randomized treatment 
assignments will be obtained, and safety analyses will be performed. 
3.13.4. 
Analysis Sets and Analysis Conventions 
The modified intent-to-treat (ITT) population will be primary for efficacy endpoints. The ITT 
population is defined as all randomized subjects who have received at least one dose of IMP and 
have at least one post baseline efficacy evaluation. The modified ITT (mITT) population will 
exclude subjects with baseline eGFR < 30 mL/min/1.73 m2. For both Parts A and B, the primary 
efficacy analysis will be performed on the mITT population. The per-protocol (PP) population 
will be secondary for the primary and key secondary endpoints. The PP population will include 
all subjects from the mITT set who did not have one of a pre-defined list of important protocol 
deviations. The list of subjects with one of these important protocol deviations will be identified 
prior to unblinding the Part A and Part B, respectively. For safety, the analysis population will 
include all subjects who received at least one dose of IMP. 
Unless otherwise specified, baseline values are defined as the last measurement obtained before 
the first dose of IMP. 
3.13.5. 
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment. 
3.13.6. 
Extent of Exposure and Treatment Compliance 
The Investigator must maintain exact records of the amount of IMP dispensed to each subject by 
recording the following information: 
 Subject randomization number 
 Date(s) and visit number when IMP was dispensed 
 Amount of IMP dispensed 
 Date of return of IMP 
 Amount of IMP returned 
An accountability log will be maintained at the study site to record IMP compliance for each 
subject. 
Additional details about IMP dispensing can be found in the study specific Pharmacy Manual. 
3.13.7. 
Efficacy Analyses 
The alpha for Part A is 0.01 and 0.04 for Part B. 


 
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Part A 
Primary Efficacy Analysis 
The primary efficacy endpoint will be analyzed using a mixed model repeated measures 
(MMRM). The model will include terms for randomization stratification factors, treatment, time, 
treatment by time interaction. An unstructured variance-covariance model will be used. 
Analysis of Secondary Endpoints 
The key secondary endpoint will be analyzed similarly. The secondary endpoint of change from 
baseline in TTR level will also be analyzed similarly at Month 12. To control alpha, KCCQ-OS 
and change from baseline in TTR level will be formally tested sequentially in this order at 
significance level of 0.01 if the primary endpoint is statistically significant at the 0.01 level. The 
proportion of subjects who achieve TTR stabilization at Month 12 will be analyzed by the 
Cochran-Mantel-Haenszel test. 
Part B 
Primary Efficacy Analysis 
The primary analysis will use a hierarchical combination of the Finkelstein-Schoenfeld method 
(Finkelstein 1999) applied to All-cause mortality, cumulative frequency of CV-related 
hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT at the 
last available visit over the 30-month fixed treatment duration. In this study, “All-cause 
mortality” includes death due to any cause, heart transplant, or CMAD (see Section 3.11.12). 
The test is based on the principle that each subject is compared to every other subject in each 
stratum in a pair-wise manner. The hierarchical approach recognizes the greater importance of 
the mortality endpoint. Vital status data (dead, alive, heart transplant, receiving CMAD) will be 
obtained for subjects who discontinue from the IMP and or/study procedures prior to Month 30 
either via direct contact or through public records, regardless of discontinuation or withdrawal 
status. Unless precluded by governing law or regulation, consent for determination of vital status 
may not be withdrawn (Section 3.4) For CV-related hospitalizations, change from baseline in 
NT-proBNP, and change from baseline in 6MWT, missing data will not be imputed for the 
Finkelstein-Schoenfeld method. 
The null hypothesis is that all of the four components of All-cause mortality, cumulative 
frequency of CV-related hospitalization, change from baseline in NT-proBNP, and change from 
baseline in 6MWT are the same between placebo and acoramidis groups. Rejection of the null 
hypothesis implies that at least one of the four components of the primary endpoint is different 
between the treatment groups. 
Analysis of Secondary Endpoints 
The key secondary endpoints adjusted for alpha are: 
a. Change from baseline to Month 30 in the distance walked during the 6MWT 
b. Change from baseline to Month 30 on the KCCQ-OS 
c. Change from baseline to Month 30 in serum TTR level 


 
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d. All-Cause Mortality by Month 30, including death due to any cause, heart transplant, 
or CMAD 
To control alpha at the 0.04 level, the key secondary endpoints will be formally tested 
sequentially in the order shown above if the primary endpoint is statistically significant at the 
0.04 level. Change from baseline in 6MWT, KCCQ-OS and serum TTR level will be analyzed 
using an MMRM with an unstructured covariance matrix. The model will include additional 
terms for randomization stratification factors, visit, and treatment by visit interaction. The time to 
All-Cause mortality will be analyzed using a stratified Cox proportional hazards model that 
includes treatment as an explanatory factor along with baseline 6MWT. 
Additional secondary endpoints (not adjusted for alpha) include: 
 A hierarchical combination of All-cause mortality and cumulative frequency of CV-
related hospitalization over a 30-month fixed treatment duration 
 A hierarchical combination of All-Cause mortality, cumulative frequency of CV-
related hospitalization, and change from baseline in 6MWT over a 30-month fixed 
treatment duration 
 Change in NT-proBNP from baseline to Month 30 of treatment  
 Cumulative frequency of CV-related hospitalization by Month 30 
 CV mortality by Month 30 
 TTR stabilization measured in established ex-vivo assays (FPE and Western blot) in 
the PK-PD substudy 
TTR stabilization measured in established ex-vivo assays (FPE and Western blot) in the PK-PD 
substudy. The components of the combined endpoint will also be analyzed separately. Mortality 
will be analyzed by the Mantel-Haenszel test. All-cause mortality will also be analyzed by a Cox 
regression model adjusting for stratification factors. Similar analyses will be performed for CV 
mortality. 
The cumulative frequency of CV-related hospitalization will be analyzed by: (a) negative 
binomial regression. An offset term will be included. The offset will be the log of each subject’s 
study duration; (b) Cochran-Mantel-Haenszel row means scores tests. 
Subgroups 
Subgroup analyses will be conducted for randomization stratification factors for the primary 
endpoint, the components of the primary endpoint, and for the key secondary endpoints. 
Missing Data 
Following the conclusion of Part A and Part B, sensitivity and supplementary analyses will be 
conducted with adjustments for missing data. Imputation details on handling of missing data will 
be described in the SAP.  


 
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3.13.8. 
Pharmacokinetic Analyses 
Population PK (PopPK) analysis will be conducted for both Part A and Part B in the PK-PD 
substudy according to a separate analysis plan. 
3.13.9. 
Pharmacodynamic Analyses 
TTR stabilization will be measured serially as described in the Schedule of Assessments 
(Appendix A) for subjects in the substudy. At each time point, each of these parameters will be 
summarized by treatment. In addition, these parameters will be plotted vs plasma drug 
concentration and the concentration response may be modeled as appropriate. 
3.13.10. 
Exploratory Analyses 
Change from baseline in EQ-5D-5L will be analyzed similarly as the key secondary endpoints. 
Troponin I will be summarized descriptively. Details of these and other exploratory analyses will 
be provided in the SAP. 
3.13.11. 
Safety Analyses 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
The incidence of each treatment-emergent AE will be summarized by system organ class, 
preferred term and treatment assignment. Multiple AEs mapped to the same preferred term will 
be counted once per subject. Concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary with generic term and Anatomical Therapeutic Chemical 
(ATC) code and summarized by ATC code, WHO generic name, and treatment. Safety 
laboratory findings, vital signs, and 12-lead ECGs will be summarized descriptively and listed by 
treatment assignment and visit. Values and changes from baseline at scheduled time points will 
be summarized. Laboratory data will be listed and values and changes from baseline at each visit 
will be summarized. An additional listing of treatment-emergent laboratory abnormalities will be 
provided. 
3.13.12. 
Adverse Events 
An AE (classified by preferred term) that occurs during the treatment period will be considered a 
TEAE if it was not present before the first dose of IMP or if it was present before the first dose 
of IMP but increased in severity during the treatment period. If more than 1 AE is reported 
before the first dose of IMP and is coded to the same preferred term, the AE with the greatest 
severity will be used as the benchmark for comparison with the AEs that were also coded to that 
preferred term and that occurred during the period. An AE that occurs more than 30 days after 
the last dose of IMP will not be counted as a TEAE. 
3.13.13. 
Interim Analysis 
No interim analysis is planned for this study. 
 


 
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4. 
REFERENCES 
Clinical Trials Facilitation and Coordination Group (CTFG). Recommendations related to 
contraception and pregnancy testing in clinical trials. Version 1.1. September 2020. 
Finkelstein DM and Schoenfeld DA. Combining mortality and longitudinal measures in clinical 
trials. Stat Med. 1999;18:1341-54. doi: 10.1002/(sici)1097-0258(19990615)18:11<1341:aid-
sim129>3.0.co;2-7. PMID: 10399200. 
Fox, J.C, et al. First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent 
Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, 
Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers. 
Clinical pharmacology in Drug Development. 2019;00 (0):1-15.  
Judge DP, Heitner SB, Falk RH, et al. Transthyretin Stabilization by AG10 in Symptomatic 
Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2019;74(3):285-295. doi: 
10.1016/j.jacc.2019.03.012. Epub 2019 Mar 15. PMID: 30885685. 
Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with 
transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379:1007-10. doi: 
10.1056/NEJMoa1805689. Epub 2018 Aug 27. PMID: 30145929. 
 


 
 
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APPENDIX A. SCHEDULE OF ASSESSMENTS 
 
Screening Period 
Treatment Period 
Follow-up1 
ET1 
Unscheduled 
Visit2 
 
(within 35 days of 
Day 1) 
Day 1 
Day 28 
(± 3 Days) 
Monthly 
Phone 
Contact 
(± 7 Days)3 
Month 3 – 27 
(Every 3 Months 
[± 7 Days])4 
Month 12 
(± 7 Days) 
Month 30  
(±7 Days)5 
30 days 
postdose 
(± 7 Days) 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
Review 
X 
X 
 
 
 
 
 
 
 
 
Confirm genotype6 
X 
 
 
 
 
 
 
 
 
 
Source documents submission to 
DCC 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
                                                 
1 All dosed subjects who prematurely discontinue from the IMP or discontinue/withdraw from the study, regardless of cause, will be asked to complete an Early Termination (ET) Visit and a safety 
follow up visit 30 days after the last dose as soon as possible and to return any unused IMP. 
2 Subjects who complete ≥ 12 months of blinded study therapy and initiate therapy with tafamidis for ATTR-CM must have completed the Month 12 visit. If a subject plans to initiate therapy with 
tafamidis more than 7 days after the Month 12 visit or a later scheduled visit, they should complete an unscheduled visit with all study assessments performed prior to initiation of tafamidis. For an 
assessment or follow up of an AE, only procedures and assessments deemed necessary by the Investigator need to be performed (e.g., physical exam, vital signs, 12-lead resting ECG, clinical 
laboratory assessments, and urine pregnancy test) [Section 3.7.11]. 
3 Telephone contact will occur during months without scheduled in clinic visits (e.g., Months 2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, and 29). 
4 In-clinic visits will occur at Month 3, and every 3 months up to Month 27. 
5 Subjects who complete the Month 30 visit will have a visit 30 days (± 7 days) after the last dose of IMP. Subjects who choose to enroll in the OLE Study (AG10-304) the same day as completing the 
Month 30 visit in AG10-301 will not be required to have the 30-day follow-up visit (in Study AG10-301). Subjects not entering the OLE (Study AG10-304) will be required to have the follow-up 
visit. 
6 Confirm genotype either through existing documentation or testing during Screening. Genotyping must be confirmed prior to randomization. 


 
 
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Screening Period 
Treatment Period 
Follow-up1 
ET1 
Unscheduled 
Visit2 
 
(within 35 days of 
Day 1) 
Day 1 
Day 28 
(± 3 Days) 
Monthly 
Phone 
Contact 
(± 7 Days)3 
Month 3 – 27 
(Every 3 Months 
[± 7 Days])4 
Month 12 
(± 7 Days) 
Month 30  
(±7 Days)5 
30 days 
postdose 
(± 7 Days) 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
NYHA Class Assessment 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical Exam7 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital Signs8 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
12-lead resting ECG9 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Resting transthoracic ECHO or 
CMR10 
X 
 
 
 
 
 
 
 
 
 
KCCQ11 
 
X 
 
 
X 
X 
X 
 
X 
X 
EQ-5D-5L12 
 
X 
 
 
X 
X 
X 
 
X 
X 
6MWT13 
X 
 
 
X 
X 
X 
 
X 
X 
Clinical laboratory assessments 
(Section 3.11.8) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
                                                 
7 Full PE with body weight measurement at all visits; height measurement at Screening only. 
8 Study center personnel will assess vital signs predose after a 5-minute rest. 
9 ECGs will be obtained in supine position after a 5-minute rest at predose and Investigator or qualified Sub-Investigator will review at all visits. On Day 28 an additional ECG will be obtained at 1-
hour postdose (Section 3.11.10) 
10 Resting transthoracic ECHO or CMR will be performed at Screening and read locally, if LV wall (interventricular septum or LV posterior wall) thickness not documented in medical history within 
10 years of Screening based on ECHO or CMR. 
11 KCCQ will be obtained on Day 1, M6, M9, M12, M18, M24, and M30. 
12 EQ-5D-5L will be obtained on Day 1, M6, M9, M12, M18, M24, and M30. 
13 Two 6MWTs prior to randomization will be conducted >24 hours to ≤3 weeks apart. (Section 3.10.1). 6MWT will be obtained on M6, M9, M12, M18, M24, and M30 and should be conducted after 
completion of KCCQ and EQ-5D-5L. 


 
 
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Screening Period 
Treatment Period 
Follow-up1 
ET1 
Unscheduled 
Visit2 
 
(within 35 days of 
Day 1) 
Day 1 
Day 28 
(± 3 Days) 
Monthly 
Phone 
Contact 
(± 7 Days)3 
Month 3 – 27 
(Every 3 Months 
[± 7 Days])4 
Month 12 
(± 7 Days) 
Month 30  
(±7 Days)5 
30 days 
postdose 
(± 7 Days) 
 
 
Exploratory blood collection 
(serum, plasma) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test14 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
PD assays15 
 
X 
X 
 
X 
X 
X 
 
X 
X 
PK sample collection15 
 
X 
X 
 
X 
X 
X 
 
X 
X 
Prealbumin collection 
 
X 
X 
 
X 
X 
X 
 
X 
X 
IMP dosing during visit 
 
X 
X 
 
X 
X 
X16 
 
 
X 
Prior/Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events/ 
Vital status/ Hospitalization 
determination17 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect IMP 
 
X 
X 
 
X 
X 
X18 
 
X 
X 
IMP compliance assessment 
 
 
X 
X 
X 
X 
X 
 
X 
X 
                                                 
14 For females of childbearing potential: urine pregnancy test at all visits. 
15 In a subgroup of subjects at participating sites in the PK-PD substudy, PK and PD samples will be collected at predose and 1-hour postdose at Day 28; predose at all other visits.  
16 Subjects who are planning to enroll in Study AG10-304 should take the evening dose of IMP the day before the Month 30 visit and should not take the morning dose on the day of the Month 30 
visit. 
17 For the purpose of data collection for this study, any untoward event that is reported from the time that the subject signs the ICF until 30 days after the last dose of IMP is to be considered an AE. 
18 To collect IMP only and no IMP dispensing will occur. 
 


 
 
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APPENDIX B. ETHICS 
Ethical Conduct of the Study 
The trial will be conducted in accordance with the International Council on Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, US Title 21 CFR Parts 11, 50, 54, 56, and 312; the EU 
Clinical Trials Directive (and Clinical Trial Regulation when in effect); principles enunciated in 
the Declaration of Helsinki; and all human clinical research regulations of the countries where 
the trial is conducted. 
The Investigator(s) and the Sponsor will sign the protocol and study contract, to confirm 
agreement. The Investigator(s) will not implement any amendment (deviation or changes of the 
protocol) without agreement by the Sponsor and IRB/IEC approval, except where necessary to 
eliminate immediate hazard(s) to study subjects, or when change(s) involve only logistical or 
administrative aspects of the study. 
Protocol deviations will only be recognized and assessed for ethical, medical, scientific, and 
regulatory implications and for impact on the subject’s participation in the study and will be 
documented. 
Records that may reveal the identities of subjects must be well protected, with consideration 
given to confidentiality and the right to privacy of subjects. 
Institutional Review Board or Independent Ethics Committee 
It is the responsibility of the Investigator to obtain the approval of the Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) before the start of the study. During the course of 
the study, the Investigator will provide timely and accurate reports to the IRB/IEC on the 
progress of the study at appropriate intervals not to exceed 1 year and at the completion of the 
study. The Investigator will notify the IRB/IEC of serious adverse events (SAEs) or other 
significant safety findings if appropriate according to local requirements. The study protocol and 
amendments, informed consent form (ICF), information sheet, advertisements, will be approved 
by the IRB/IEC at each study center in conformance with requirements of the controlling 
regulatory authority. 
Subject Information and Consent 
At screening, the subject will read the ICF and after being given an explanation of the study. 
Before signing the ICF and the HIPAA form (if applicable), subjects will have an opportunity to 
discuss the contents of these forms with study center personnel. Subjects must assent 
understanding of and voluntarily sign these forms. Subjects will be made aware that they may 
withdraw from the study at any time. 
The ICF contains all the elements of informed consent listed in this protocol. Signed copies of 
the ICF will be given to the subject, and both documents will be placed in the Investigator’s 
study files. The Sponsor will review the ICF before it is submitted to the IRB/IEC. 


 
 
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APPENDIX C. DATA QUALITY ASSURANCE 
Data Monitoring 
Before the first subject is dosed in the study, a representative of the Sponsor will meet with the 
Investigator and the Investigator’s personnel to review the procedures for conducting the study 
and to train the personnel on recording the data on the CRFs using the electronic data capture 
(EDC) system. The Sponsor representative will periodically monitor the progress of the study by 
conducting on-site visits thereafter. The Sponsor representative will also be able to review query 
statuses remotely, which may warrant more frequent communication with the Investigator and 
his or her personnel. The Investigator will make available to the Sponsor representative the 
source documents, the signed consent forms, and all other study-related documents. The 
Investigator will be responsible for reviewing CRFs, resolving data queries generated by the 
Sponsor representative via the system, providing missing or corrected data, approving all 
changes performed on the data, and endorsing the subject data within the EDC system. This 
approval method will include applying an electronic signature, a uniquely assigned username and 
a password that together will represent a traditional handwritten signature. 
Data Audit 
Members of the Sponsor Quality Assurance department or designee may conduct an audit of a 
clinical site at any time before, during, or after completion of the study. The Investigator will be 
informed if an audit is to take place and advised as to the scope of the audit. Representatives of 
the FDA or other Regulatory Agencies may also conduct an inspection of the study. If informed 
of such an inspection, the Investigator should notify the Sponsor immediately. The Investigator 
will ensure that the auditors have access to the study site facilities, investigational products, 
original source documentation, and all study files. 
Data Recording and Documentation 
Data collection will involve the use of an EDC system, to which only authorized personnel will 
have access. In addition to periodic monitoring occurring within the system by the Sponsor 
personnel and/or authorized Sponsor representatives, programmatic edit checks will be used to 
review the data for completeness, logic, and adherence to study protocol. As a result of this 
monitoring and these checks, queries may be issued electronically to the clinical study center and 
answered electronically by that study center. The identifying information (assigned username, 
date, and time) for both the originator of the query (if created during the monitoring process) and 
the originator of the data change (if applicable), as well as the Investigator’s approval of all 
changes performed on his or her subjects’ data, will be collected. 
All data collected in the context of this study will be stored and evaluated according to regulatory 
requirements and applicable guidance for electronic records. Data will be stored and evaluated in 
such a way as to guarantee subject confidentiality in accordance with the legal stipulations 
applying to confidentiality of data. Study records (e.g., copies of CRFs, regulatory documents) 
will be retained at the study center, along with adequate source documentation, according to 
local regulatory requirements and ICH requirements. All study records must be available for 
inspection by the Sponsor, its authorized representatives, and regulatory officials. 


 
 
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APPENDIX D. STUDY SPONSORSHIP 
Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a specific study center at 
any time and for any reason. 
Reporting and Publication 
All data generated in this study will be the property of the Sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study. 
Publication of the results by the Investigator will be subject to agreement between the 
Investigator and the Sponsor. 


 
 
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APPENDIX E. INVESTIGATOR OBLIGATIONS 
Documentation 
The Investigator must provide the following to the Sponsor before the start of the study: 
 A written and signed document verifying the Investigator has the experience and 
background needed to conduct the trial and that it will be done in a way that is ethical 
and scientifically sound. The document should be comparable to the US FDA Form 
1572. 
 A fully executed contract 
 The curricula vitae and licensure for the Investigator and all Sub-Investigators, as well 
as for the Clinical Laboratory Director 
 A copy of the initial IRB/IEC/REB approval for conducting the study. If the study is 
ongoing, renewals must be submitted at yearly intervals. All subsequent 
modifications must be submitted and approved by the IRB/IEC/REB, as described in 
the protocol. 
 A copy of the IRB/IEC/REB-approved ICF 
 A list of the IRB/IEC/REB members 
 A copy of the clinical laboratory certifications and reference ranges 
 The Investigator’s Statement page in this protocol signed and dated by the 
Investigator 
 A financial disclosure statement completed and signed by the Investigator and all 
Sub-Investigators listed on the US FDA Form 1572, or comparable document. If 
applicable, the Investigator and all Sub-Investigators will provide an updated 
financial disclosure statement to the Sponsor during the study and for one year after 
the completion of the study. 
Performance 
The Investigator must demonstrate reasonable efforts to obtain qualified subjects for the study. 
Use of Investigational Materials 
The Investigator will acknowledge that the drug supplies are investigational and as such must be 
used strictly in accordance with the protocol and only under the supervision of the Investigator. 
After receipt of the documentation package, the Sponsor will arrange for the shipment of IMP. 
The IMP must be stored in a safe and secure place. At study initiation, a representative from the 
Sponsor will inventory the IMP at the study center. 
The Investigator must ensure adequate records are maintained documenting the receipt and 
disposition of all study supplies. The Sponsor will supply forms on which to record the date and 
amount of IMP received and the lot number of the IMP. 


 
 
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All unused IMP must be returned to the Sponsor or destroyed on-site throughout the course of 
the study, after IMP accountability is completed and with approval by the Sponsor. If unused 
IMP is not returned to the Sponsor and destroyed on-site, proof of destruction must be provided 
to the Sponsor. The Investigator will be responsible for ensuring that subjects return their IMP. 
Case Report Forms, Laboratory Data, and Other Vendor Data 
All data relating to the study will be recorded in the CRF. The CRFs are to be completed in a 
timely manner. The Investigator will be responsible for verifying that all data entries in the CRFs 
are accurate. The Investigator must sign the completed CRF upon notification from the Sponsor. 
The laboratory data must be transferred to the Sponsor in electronic format acceptable to the 
Sponsor specifications. 
Retention and Review of Records 
The Investigator must maintain the documentation relating to this study. If the Sponsor or any 
regulatory authority wishes to review any documentation relating to the study, the Investigator 
must permit access to such records. 
The Investigator must retain a copy of all records that support CRFs for this study (e.g., ICFs, 
clinical laboratory reports, source documents, IMP dispensing records) for a period of at least 
15 years after study completion unless local regulations or study center policies require a longer 
retention period or otherwise notified in writing by the Sponsor. 
If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a suitable alternate custodian employee 
of the study center or to a suitably qualified and responsible third party. The Sponsor must be 
notified in writing of the name and address of the new custodian before such transfer is made. 
No study records shall be destroyed without notifying the Sponsor and giving the Sponsor the 
opportunity to arrange long-term storage for such study records or to authorize in writing the 
destruction of records after the required retention period. 
Subject Confidentiality 
All subject records will only be identified by subject initials and subject number. Subjects’ 
names are not to be transmitted to the Sponsor. The Investigator will keep a master subject list on 
which the subject number and the full name, address, and telephone number of each subject are 
listed. 


 
 
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APPENDIX F. NEW YORK HEART ASSOCIATION (NYHA) 
FUNCTIONAL CLASSIFICATION 
Class 
Description 
I 
Patients have cardiac disease, but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, dyspnea, palpitations or anginal pain. 
II 
Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity results in fatigue, dyspnea, palpitations or anginal pain. 
III 
Patients have cardiac disease with marked limitations of physical activity. They are comfortable at 
rest. Less than ordinary physical activity causes fatigue, dyspnea, palpitations or anginal pain. 
IV 
Patients have cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is increased. 
 


 
 
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APPENDIX G. SUMMARY OF CHANGES 
CHANGE 
RATIONALE 
SECTIONS AFFECTED 
Original Protocol vs Amendment 1.0 
Statements clarifying contraception 
requirements and acceptable methods were 
added in several places in the protocol. 
To be consistent with the Clinical 
Trial Facilitation Group (CTFG) 
requirements. 
 
Synopsis 
 
Section 3.3 
 
Section 3.5 
Amendment 1.0 vs Amendment 2.0 
Changed address 
Administrative change 
 
Cover page 
Designation for acoramidis changed to 
“acoramidis HCl”  
To clarify the strength of 
acoramidis is in the hydrochloride 
form. 
 
Synopsis 
 
Section 3.6 
Simplified text in the Introduction 
Because up-to-date information is 
provided in the Investigator’s 
Brochure, the current simplified 
Introduction provides the major 
findings from prior investigations. 
 
Section 1 
Exploratory endpoints for circulatory 
biomarkers and EQ-5D-5L were changed 
change from baseline. 
To allow for analysis at the end of 
both Parts A and B. 
 
Synopsis 
 
Section 2 
Clarified the ability to use tafamidis after at 
least 24 months of double-blind treatment 
during the study. 
The change was needed due to the 
recent approval of tafamidis in 
some regions. 
 
Synopsis 
 
Section 3 
Removed the statement to encouragement 
subjects to remain in the trial. 
To clarify that the subjects are 
allowed to withdraw at any time. 
 
Synopsis 
 
Section 3 
Clarified that the 35th day will be included 
in the Screening period. 
For additional clarification only. 
 
Section 3 Figure 1 
Deleted ability to grant exceptional 
approval for subjects who refuse genetic 
testing. 
The change was in response to 
regulatory authorities and to 
ensure that all subjects have 
documented genotyping prior to 
the randomization. 
 
Synopsis 
 
Section 3.2.1 
 
Appendix A 
Inclusion Criteria: 
 
#3 1: clarified Screening criteria for 
ATTR-CM with addition of mass 
spectrometry or immunoelectron 
microscopy 
 
#3 2 clarified that IFE of serum and 
urine is needed. 
 
Confirmation of diagnosis by central 
review of clinical data was deleted.  
 
 
#8 6MWT to be completed ≥ 150 m 
on the 6MWT on 2 tests 
 
 
To allow for immune electron 
microscopy for diagnosis of 
ATTR-CM 
 
 
To be consistent with the 
clinical practice based on 
feedback from DCC. 
 
Clarified the timeframe for 
confirmation of diagnosis by 
DCC in Section 3.11.3 
 
To clarify that the 2 6MWT 
do not need to be consecutive. 
 
Synopsis 
 
Section 3.3.1 
 
Section 3.7.2 
Exclusion Criteria: 
 
#2: TIA is excluded 
 
#7: changed Screening NT-proBNP to 
≥8500 pg/mL from≥7000 pg/mL 
 
 
 
Based on feedback from 
advisors, the threshold was 
changed to allow for 
 
Synopsis 
 
Section 3.3.2 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
 
 
#10: removed reference to any 
investigational agent  
 
#11: clarified exclusion of calcium 
channel blockers was for those with 
conduction system effects and 
allowed for use of dihydropyridine 
and limit the use of digoxin. 
risk/benefit assessments at 
higher levels of NT-proBNP 
 
Exclusion of investigational 
drug is covered in EC#14. 
 
The changes in concomitant 
medications changed based 
on advisors’ feedback and 
current medical practice. 
Simplified the section and refer to the Data 
Access Management Plan for Details. 
 
For additional clarification 
only. 
 
Synopsis 
 
Section 3.6.8 
Subjects should be discontinued if 
treatment assignment has been unblinded to 
the investigator. The reason for 
discontinuation is to be recorded in the 
CRF. 
 
To harmonize with other parts 
of the protocol. 
 
Section 3.4 
Treatment compliance will be monitored 
by recording drug accountability.  
 
To be consistent with deletion 
of drug dosing diaries. 
 
Section 3.6.4 
 
Clarified exclusion of calcium channel 
blockers with conduction system 
effects and allowed for use of 
dihydropyridine. And limit the use of 
digoxin. 
 
Clarified that tafamidis for indication 
of ATTR-CM will be allowed after at 
least 24 months of blinded study 
therapy. 
 
To be consistent with 
Exclusion criteria 
 
 
 
 
To clarify that tafamidis use is 
to be for indication of ATTR-
CM 
 
Section 3.6.11 
Deleted the use of study drug dosing 
diaries during the study. 
 
Prior to study initiation, a 
decision was made to monitor 
drug use by drug 
accountability. 
 
Section 3.6.12 
Clarified need for medical history of 
ECHO or CMR to be within 10 years of 
Screening. 
 
To be consistent with IC #10 
 
Synopsis 
 
Section 3.7.2 
 
Appendix A 
 
Renamed header from “Day 1 and 
Every 3 Months (±7 Days to “Day 1 
and Repeated Assessments” 
 
Refer to the Schedule of Assessments 
for 6MWT 
 
Changed to better characterize 
the contents of the section 
 
 
To clarify the assessment 
schedule for 6MWT is 
different from other repeated 
assessments. 
 
Section 3.7.4 
Clarified the collection of vital status for 
subjects who discontinue study drug and 
study assessments continue up to month 30. 
 
For additional clarification 
only. 
 
Section 3.7.7 
Revised header for Section 3.9 from 
Efficacy Assessments to Efficacy 
Assessments at Scheduled Visits. 
 
Clarification due to the 
content of this section. 
 
Section 3.9 
To clarify that a third 6MWT if needed 
should be repeated within 24 hours to 1 
week of last 6MWT. 
 
To clarify the time frame for a 
third test, if required. 
 
Section 3.9.1 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
Provided further clarity for the events of 
clinical interest. 
 
Added that CV-related hospitalizations will 
not be included in periodic safety reporting. 
 
To provide additional 
clarification for the definition 
of events of clinical interest 
 
To clarify that the study 
endpoint of CV-related 
hospitalizations will not be 
included in the periodic safety 
reporting  
 
Section 3.10.7 
Clarification of single repeat of clinical 
laboratory tests and additional repeat test 
was added. 
 
For additional clarification 
only. 
 
Section 3.10.8 
Vital signs will be assessed at predose only 
and not at pre and postdose. 
 
Post-dose vital signs are 
included in error, as it is not 
indicated in this Phase 3 trial. 
 
Section 3.10.9 
 
Appendix A 
Definition of CV-related hospitalization 
was clarified. 
 
For additional clarification 
only. 
 
Section 3.10.12 
Clarified that review and confirmation by 
DCC may occur after randomization but 
not later than Day 28. 
 
For additional clarification 
only. 
 
Section 3.11.3 
Clarified Primary Analysis is for efficacy.  
The per-protocol population will include 
subjects in the modified ITT set. 
 
For additional clarification 
only. 
 
Section 3.12.4 
Additional secondary endpoint analyses 
will include Cox regression model 
adjusting for stratification factors. 
 
Inclusion of an additional 
analysis method 
 
Section 3.12.7 
“Exploratory Analyses” section was added 
to statistical analyses. 
 
To harmonize with the listed 
endpoints. 
 
Section 3.12.10 
Reference added for use of contraception in 
clinical trials. 
 
To provide a source for the 
contraceptive use during the 
trial 
 
Section 4 
 
Row added for “confirm genotype” in 
Schedule of Assessments 
 
Reference to Section 3.9.1 was added 
for 6MWT 
 
For consistency 
 
 
For additional clarification 
only 
Appendix A 
Other minor editorial changes. 
 
For accuracy with no change 
to details or study design. 
Throughout the document 
Amendment 2.0 vs Amendment 3.0 
Clarified that tafamidis approved for 
indication of ATTR-CM will be allowed as 
a concomitant medication after at least 12 
months of blinded study therapy. 
 
To allow subjects that 
complete Part A and gain 
access to tafamidis approved 
for ATTR-CM as part of their 
routine care, to be eligible to 
remain in the trial (as opposed 
to discontinuing the study). 
 
Synopsis 
 
Exclusion criteria #10 
 
Section 3.1 
 
Section 3.6.11 
Increased number of centers worldwide. 
 
To update current number of 
centers worldwide 
 
Synopsis 
6MWT: Added distance walked must be 
within 15% on two tests. If one of the first 
two tests is not ≥ 150 m or the first two 
 
To align inclusion criteria 8 
with Section 3.9.1 6MWT of 
 
Synopsis 
 
Section 3.3.1 
 
Section 3.7.2 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
tests are not within 15% of distance 
walked, a third test must be conducted and 
must meet the inclusion criteria. 
the protocol, with no change 
to the inclusion criteria 
 
Section 3.9.1 
 
Appendix A 
6MWT: Two tests and the third test (if 
needed) must be conducted within 3 weeks. 
 
Simplified the time frame for 
all three tests based on 
feedback from Investigators to 
align with subjects’ standard 
of care visits. 
 
Synopsis 
 
Section 3.3.1 
 
Section 3.7.2 
 
Section 3.9.1 
 
Appendix A 
Added guideline for walking aid or 
supplemental oxygen at subsequent 6MWT 
after baseline. 
 
To standardize 6MWT after 
baseline 
 
Section 3.9.1 
Clarified acceptable diagnostic method of 
ATTR-CM includes endomyocardial 
biopsy with immunohistochemistry.  
Subjects with concurrent MGUS may 
require confirmation of diagnosis of 
ATTR-CM by tissue biopsy with 
confirmatory TTR amyloid typing. 
 
Based on advisors’ feedback 
and current medical practice 
 
Synopsis 
 
Section 3.3.1 
 
Section 3.7.2 
 
Section 3.11.3 
Revised frequency of KCCQ and EQ-5D-
5L administration. 
 
To be consistent with 6MWT 
visits 
 
Appendix A 
Deleted adjustment to 400 mg. 
 
To be consistent with current 
Investigator’s Brochure, with 
no change to the risk/benefit 
of acoramidis 
 
Section 3.6.1 
Other minor editorial and template 
changes. 
 
For accuracy, with no change 
to study design. 
 
Throughout the 
document 
Amendment 3.0 vs Amendment 4.0 
 
Corrections, clarifications, 
administration changes  
 
Administrative updates have 
been made throughout for 
consistency (e.g., minor 
changes to grammar, 
punctuation, or formatting) 
 
Throughout the 
document 
 
Incorporated acoramidis where AG10 
is mentioned 
 
Incorporated acoramidis as 
international nonproprietary 
name (INN) for AG10 
 
Throughout the 
document 
 
Updated Key Sponsor contacts 
 
Addition of new Sponsor 
contacts. 
 
Cover page 
 
Section 3.10.7 
 
Inclusion criteria ≥18 to ≤ 90 years of 
age: Added at time of randomization 
 
For additional clarification 
only; included in Protocol 
Amendment 3.0 Clarification 
Letter dated 23 Sep 2020 
 
Synopsis 
 
Section 3.2.1 
 
Section 3.3.1 
 
Added abbreviation PYP and HDP 
 
Corrected abbreviation HMPD to 
HMDP 
 
pyrophosphate (PYP) 
or -bisphosphonate (DPD or 
HMDP/HDP); these 
abbreviations appear to be 
used interchangeably in 
current medical practice 
 
Synopsis 
 
Section 3.3.1 
 
Section 3.7.2 


 
 
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CHANGE 
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SECTIONS AFFECTED 
 
Transposition error corrected, 
with no change to study 
design 
 
Clarified barrier method as double-
barrier method 
 
For consistent use throughout 
the protocol 
 
Synopsis 
 
Section 3.3.1 
 
Section 3.5 
 
Added abbreviations AL, ATTRm, 
ATTRwt, CK, CK-MB, CRF, DPD, 
EOCI, EQ VAS, FAP, HCl, HDP, 
HMDP, IWRS, IFE, IXRS, KCCQ, 
MGUS, PE, PYP, sFLC, SSA, TIA, 
TSH, 99mTc 
 
Updated list of abbreviations  
 
List of Abbreviations 
 
Removed Voice from abbreviation 
IXRS and replaced with IWRS 
 
Interactive Voice not currently 
used in study; Only Interactive 
Web Response System 
 
List of Abbreviations 
 
Section 3.6.5 
 
Removal of acoramidis high oral 
bioavailability and binding selectivity 
in all animal species 
 
Current information included 
in Investigator’s Brochure 
 
Section 1.1 
 
Insertion of exploratory objective: To 
evaluate the effects of acoramidis on 
circulating biomarkers of myocardial 
wall stress and microvascular ischemia 
in subjects with symptomatic ATTR-
CM 
 
Text present in Synopsis but 
missing from Section 2; Text 
reinserted with no change to 
study design 
 
Section 2 
 
Added list of excipients of acoramidis 
or placebo 
 
For additional clarification 
only 
 
Section 3.6.2 
 
Added IMP returns to Sponsor for 
destruction or on-site destruction can 
occur upon authorization from the 
Sponsor and throughout the course of 
the study 
 
For additional clarification 
only; included in Protocol 
Amendment 3.0 Clarification 
Letter dated 23 Sep 2020 
 
Section 3.6.4 
 
Appendix E 
 
Added guidance on genotyping 
 
For additional clarification 
only  
 
Section 3.7.2 
 
Appendix A 
 
Added guidance on collection of ECGs 
after a 5-minute rest in a supine 
position 
 
For additional clarification 
only 
 
Section 3.7.2 
 
Section 3.7.4 
 
Section 3.7.5 
 
Section 3.7.6 
 
Section 3.7.8 
 
Section 3.7.9 
 
Section 3.7.10 
 
Section 3.7.11 
 
Section 3.7.12 
 
Section 3.7.13 
 
Added guidance on when telephone 
contacts should occur 
 
For additional clarification 
only 
 
Section 3.7.7 
 
Appendix A 


 
 
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SECTIONS AFFECTED 
 
Added guidance on visit window for 
subjects who initiate tafamidis after 
Month 12 or a later visit 
 
For additional clarification 
only; included in Protocol 
Amendment 3.0 Clarification 
Letter dated 23 Sep 2020 
 
Section 3.6.11 
 
Section 3.7.11 
 
Appendix A 
 
Added guidance on ET visit 
 
For additional clarification 
only 
 
Section 3.7.13 
 
Added guidance on walking aid for 
6MWT 
 
Added to reflect existing 
procedures and guidance on 
conduct of 6MWT 
 
Section 3.9.1 
 
Documentation of outcome of AE is 
requested for safety reporting, rather 
than resolution of AE 
 
For additional clarification, as 
AE may not resolve at time of 
safety reporting 
 
Section 3.10.5 
 
Added events of clinical interest 
(EOCI) negatively adjudicated by CEC 
will be considered as adverse events  
 
No change to original intent or 
to study conduct, wording was 
missing previously 
 
Section 3.10.7 
 
Added clarification that EOCI are 
considered as part of the efficacy 
endpoint of CV-related 
hospitalizations 
 
For additional clarification 
 
Section 3.10.7 
 
Section 3.10.12 
 
Removal of language around PK-PD 
relationship to QTc  
 
The removed sentences refer 
to actions the Sponsor might 
take under hypothetical future 
circumstances not to current 
or planned/committed to study 
conduct or analyses 
 
Section 3.10.10 
 
Removed “If immunohistochemistry is 
employed for TTR amyloid typing, the 
analyzing pathology laboratory’s 
methodology and reagents must be 
reviewed by the Diagnostic 
Confirmation Committee as meeting 
acceptable standards of sensitivity and 
specificity” and requirement by Day 
28 for confirmation of ATTR-CM by 
DCC 
 
Function of DCC is to provide 
an independent review of 
submitted diagnostic data 
supporting diagnosis of 
ATTR-CM; This independent 
review can provide the basis 
for an assessment of clinical 
consistency and robustness of 
diagnosis in a global clinical 
trial of ATTR-CM. The 28-
day timeframe is not required 
since review can be completed 
after randomization, and this 
requirement was removed 
 
Section 3.11.3 
 
Updated language to be consistent with 
language used in the synopsis 
 
For additional clarification 
only 
 
Section 3.12.9 
 
Added additional footnotes to clarify 
timing of assessments 
 
For additional clarification 
only 
 
Appendix A 
 
Specified procedure for Sponsor audit 
of clinical sites 
 
Added to reflect existing 
procedure 
 
Appendix C 
Amendment 4.0 vs Amendment 5.0 
 
Corrections, clarifications, 
administration changes  
 
Administrative updates have 
been made throughout for 
 
Throughout the 
document 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
consistency (e.g., address 
changes, minor changes to 
grammar, punctuation, or 
formatting, etc.) 
 
Added “change from baseline in 
6MWT” to the key primary 
objective/endpoint for component of 
Part B  
 
Initiation of tafamidis after 
Month 12 is expected to 
reduce the power of 
Finkelstein-Schoenfeld test for 
the hierarchical combination 
of All-cause mortality and 
CV-related hospitalizations. 
To compensate for the 
reduction in power, the 
primary endpoint was changed 
to a hierarchical combination 
of All-cause mortality, CV-
related hospitalization, and 
change from baseline in 
6MWT 
 
Synopsis 
 
Section 2 
 
Section 3.1 
 
Section 3.13.2 
 
Section 3.13.7.2.1 
 
Updated power estimate for Part B 
analysis 
 
To update power estimate as 
the primary endpoint was 
changed to a hierarchical 
combination of All-cause 
mortality, CV-related 
hospitalization, and change 
from baseline in 6MWT 
 
Synopsis 
 
Section 3.13.2 
 
 
Added “A hierarchical combination of 
All-Cause mortality and CV-related 
hospitalization over a 30-month 
period” 
 
Added to align with the 
secondary objective for Part B  
 
Synopsis 
 
Section 2 
 
Section 3.13.7.2.1 
 
Removed “mutations” from TTR and 
added “variants” for exploratory 
endpoints for Part A and B 
 
Harmonized with variants 
described in IB.  
 
Synopsis 
 
Section 2 
 
 
 
 
Revised the open-label extension 
(OLE) throughout the protocol 
 
A separate protocol (AG10-
304) is being developed for 
those subjects who rollover 
into the OLE study  
 
Synopsis  
 
Section 3.1 
 
Section 3.2.2 
 
Section 3.6 
 
Section 3.8.8 
 
Section 3.8.10 
 
Appendix A 
 
Removed “and established ex vivo 
assays of….” And added “measured in 
established ex-vivo assays (fluorescent 
probe exclusion ([FPE)] and Western 
blot) at Day 28 and subsequent visits 
in the PK-PD substudy” for Part A and 
Part B Secondary endpoints 
 
This is a substudy and added 
for consistency with other 
endpoints that will be assessed 
only in the substudy 
population 
 
Synopsis 
 
Section 2 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
 
Moved PK/PD correlation to 
exploratory objective/endpoint “To 
describe the PD properties and the 
pharmacokinetic (PK)-PD relationship 
of acoramidis as assessed by 
circulating prealbumin (transthyretin, 
TTR) concentration as an in vivo 
biomarker of stabilization and by 
established ex vivo assays of TTR 
stabilization, and correlated with 
acoramidis PK” and “Describe the PK-
PD relationship of acoramidis in adult 
subjects with symptomatic ATTR-CM 
in the PK-PD substudy” 
 
PK PD correlation analysis 
will be exploratory 
 
Synopsis 
 
Section 2 
 
Updated PK-PD substudy 
 
Clarified that PK-PD samples 
will be collected in the PK-PD 
substudy and the PopPK and 
PD measures analyses will be 
separate analyses 
 
Synopsis 
 
Section 2 
 
Section 3.8.4 
 
Section 3.8.5 
 
Section 3.8.6 
 
Section 3.8.8 
 
Section 3.8.9 
 
Section 3.8.11 
 
Appendix A  
 
Added “To describe the population PK 
(PopPK) of acoramidis in subjects with 
ATTR-CM” and “PopPK analysis of 
acoramidis in the PK-PD substudy” for 
Part A and B objectives/endpoints 
 
PopPK analysis will be 
exploratory in the PK-PD 
substudy 
 
Synopsis 
 
Section 2 
 
Section 3.13.8 
 
Added “If a subject chooses to initiate 
treatment with another therapy, 
including tafamidis in the first 12 
months of the study, they will be asked 
to complete an ET visit and associated 
procedures prior to discontinuation/ 
withdrawal.” 
 
Clarification if subjects decide 
to initiate treatment with 
another therapy, they need to 
complete an ET visit  
 
Synopsis 
 
Section 3.1 
 
Added “If a subject plans to initiate 
therapy with tafamidis more than 7 
days after the Month 12 visit or a later 
scheduled visit” and removed “…if it 
has been more than 7 days since the 
Month 12 visit or a later visit” 
 
Clarify when an unscheduled 
visit should occur if the 
subject initiates therapy with 
tafamidis 
 
Synopsis 
 
Section 3.1 
 
Section 3.7.11 
 
Section 3.8.9 
 
Appendix A 
 
Changed the statement from ‘will’ to 
‘may’ in “Subject level CV-related 
hospitalization data will not be 
available to the Sponsor Part A team; 
however, the aggregated overall 
summary without treatment group 
information ‘may’ be available to the 
Sponsor Part A team.” 
 
To accurately reflect data 
summary and access plan 
 
Synopsis 
 
Section 3.7.8 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
 
Added “Subjects who choose to enroll 
in the OLE Study (AG10-304) the 
same day as completing the Month 30 
visit in AG10-301 will not be required 
to have the 30-day follow-up visit (in 
Study AG10-301).” 
 
The Open-label portion of this 
study has been removed as the 
OLE is now a separate study 
(AG10-304)  
 
Synopsis 
 
Section 3.8.10 
 
Appendix A 
 
 
Removed from Part A Efficacy 
Analyses “To control alpha, the key 
secondary endpoint will be formally 
tested if the primary endpoint is 
statistically significant at the 0.01 
level.” 
 
To reflect the update in alpha-
control plan 
 
 
Synopsis 
 
Section 3.13.7.1.1 
 
Added to Efficacy Analyses “The 
secondary endpoint of change from 
baseline in TTR level will also be 
analyzed similarly at Month 12. To 
control alpha, KCCQ-OS and change 
from baseline in TTR level will be 
formally tested sequentially in this 
order at significance level of 0.01 if 
the primary endpoint is statistically 
significant at the 0.01 level.” 
 
To reflect the alpha control of 
the TTR level in the 
secondary endpoint  
 
Synopsis 
 
Section 3.13.7.1.1 
 
Updated text on Discontinuation of 
IMP, and Withdrawal from the study; 
change was made to the title of the 
section “assessments” to “withdrawal 
from the study” 
 
To align with the language 
across the protocols in 
cardiomyopathy and 
polyneuropathy programs 
 
Synopsis 
 
Section 3.4 
 
Category of “Death” is added to 
harmonize with the categories captured 
in the case report form 
 
Added clarification on 
discontinuation of therapy  
or withdrawal from the study 
and to harmonize with the 
categories captured in the case 
report form 
 
Section 3.4 
 
Added “All participating subjects will 
be asked to consent to determination of 
vital status (alive, death, heart 
transplant, receiving CMAD) at Month 
30, either via direct contact or through 
public records, regardless of 
discontinuation or withdrawal status. 
Unless precluded by governing law or 
regulation, consent for determination 
of vital status through public records 
may not be withdrawn.” 
 
Update guidance on vital 
status during the study  
 
Synopsis 
 
Section 3.1 
 
Section 3.4 
 
Section 3.7.8 
 
Section 3.8.11 
 
Section 3.13.7.2.1 
 
Added a statement, “(Terms KCCQ 
overall score and KCCQ overall 
summary score are interchangeably 
used in this document)” 
 
Added for the clarity of terms 
used 
 
Section 3.1 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
 
Added a statement, “All dosed subjects 
who prematurely discontinue from the 
IMP or discontinue/withdraw from the 
study, regardless of cause, will be 
asked to complete an Early 
Termination (ET) Visit and a safety 
follow up visit 30 days after the last 
dose” 
 
Added for clarification and 
consistency across sections 
 
Section 3.4 
 
Appendix A 
 
Added section on “Lost to Follow-up” 
 
To define if a subject is lost to 
follow-up 
 
Section 3.4.1 
 
Added “CTFG guidance v.1.1” and 
“bilateral tubal occlusion” 
 
To clarify the CTFG guidance 
and effective method of birth 
control 
 
Section 3.5 
 
Added a new section ‘End of Study 
Definition”  
 
Added for clarification and 
align with the protocol 
template 
 
Section 3.6 
 
Added “(equivalent to 356 mg 
acoramidis)”  
 
To introduce free base 
strength for acoramidis 
 
Section 3.7.1 
 
Added “Screening safety assessments 
completed on the same day as Day 1 
(e.g., physical exam, vital signs, ECG, 
clinical laboratory tests) may be used 
as Day 1 assessments at the 
investigator’s discretion provided that 
they are predose.” 
 
Clarification on safety 
assessments at Screening can 
be completed at Day 1 
 
Section 3.8.3 
 
Added “Subjects who complete the 30 
months of double-blinded study 
treatment and the Month 30 visit 
assessments, may be eligible to enroll 
into the OLE Study (AG10-304).” 
“Subjects who are planning to enroll in 
AG10-304 should take the evening 
dose of IMP the day before the 
Month 30 visit and should not take the 
morning dose on the day of the Month 
30 visit.” 
 
Clarification on completion of 
Month 30 visit assessments 
 
To align across sections 
 
Section 3.8.8 
 
Appendix A 
 
 
Added “e.g., Investigator’s discretion” 
to the unscheduled visit 
 
Clarification that the 
investigator can conduct an 
unscheduled visit at their 
discretion  
 
Section 3.9.1 
 
Section 3.9.2 
 
Section 3.9.3 
 
Removed “The Sponsor’s Medical 
Monitor may also be notified by 
telephone.” 
 
Protocol template has been 
updated to remove this 
information  
 
Section 3.11.7 
 
Revised the following paragraph “The 
study center personnel must transmit 
the SAE Form to the Sponsor within 
24 hours of when the site first becomes 
aware of the event. Even if the site has 
discussed the event with a Sponsor 
 
Clarification only  
 
Section 3.11.7 


 
 
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CHANGE 
RATIONALE 
SECTIONS AFFECTED 
representative, the study center 
personnel must still complete the SAE 
Form with all available details and 
send the form within 24 hours of when 
the site first becomes aware of the 
event.”  
 
Added “The investigator will 
determine whether abnormal vital 
signs are clinically relevant.” 
 
Clarification on determining 
abnormal vital signs  
 
Section 3.11.9 
 
Updated the section on Analysis of 
Secondary Endpoints 
 
To clarify the specific 
statistical test used 
 
Section 3.13.7.1.1 
 
Section 3.13.7.1.2 
 
Removed “… will be considered 
censored at the time of subject 
discontinuation from the study” and 
added “missing data will not be 
imputed for the Finkelstein-Schoenfeld 
method” 
 
Clarification on missing data 
 
Section 3.13.7.2.1 
 
Added clarification on the conduct of 
the study and information on 
Declaration of Helsinki 
 
Added “and Council for International 
Organizations of Medical Sciences 
(CIOMS) international ethical 
guidelines” 
 
Added Research Ethics Board 
 
Clarification on Ethical 
conduct of the study 
 
Appendix B 
Amendment 5.0 vs Amendment 6.0 
 
Updated Key Sponsor contacts 
 
Addition of new Sponsor 
contacts. 
 
Cover page 
 
Revised the Primary Endpoint in Part B to 
reflect addition of NT-proBNP: 
 
A hierarchical combination of All-
Cause mortality, cumulative frequency 
of CV-related hospitalization, change 
from baseline in NT-proBNP, and 
change from baseline in 6MWT over a 
30-month fixed treatment duration 
 
 
 
Blinded data review suggested 
that the initial design 
assumptions were not being 
met. To maintain the original 
anticipated power of the study, 
the primary analysis approach 
for Part B was modified as 
described.  
 
 
 Synopsis, (Objectives and 
endpoints; Study design 
and Investigational plan; 
Statistical methodology) 
 Section 2 
 Section 3.1 
 Section 3.13.2 (Part B) 
 Section 3.13.7.2.1 
Primary Efficacy 
Analysis; Analysis of 
secondary endpoints 
Key Secondary Objectives/Endpoints, Part 
B: 
Promoted two Secondary 
objectives/endpoints to Key Secondary 
objectives/endpoints  
 
Change from baseline to Month 30 in 
serum TTR (prealbumin) level (an in 
vivo measure of TTR stabilization)  
 
All-Cause Mortality by Month 30 
including death due to any cause, heart 
transplant, or CMAD  
 
 
 
To reflect the change of 
analytical approach made in 
SAP Part B Version 2.0 
(Effective Date 13 December 
2021) that was finalized prior 
to Part A unblinding. 
 
 
 Synopsis, (Objectives and 
endpoints; Statistical 
methodology) 
 Section 2 
 Section 3.11.7 
 Section 3.13.7.2.1  


 
 
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Secondary Objectives/Endpoints, Part B: 
Revised Secondary objectives and 
associated endpoints:  
 
Moved key primary endpoint “A 
hierarchical combination of All-Cause 
mortality, cumulative frequency of 
CV-related hospitalization, and change 
from baseline in 6MWT over a 30-
month fixed treatment duration” and 
the associated objective to the 
secondary endpoint/objective section  
 
Promoted exploratory endpoint 
“Change in NT-proBNP from baseline 
to Month 30 of treatment” and 
associated objective to secondary 
objective/endpoint section 
 
 
 
 
 
 
Previous primary objective/ 
endpoint in Amendment 5.0, 
moved to secondary endpoint.  
 
Previous exploratory endpoint 
promoted to secondary 
endpoint 
 
 
 
 
 
 
 
 
 
 Synopsis, (Objectives and 
endpoints; Study design 
and Investigational plan; 
Statistical methodology). 
 Section 2 
 Section 3.1 
 Section 3.13.2 (Part B) 
 Section 3.13.7.2.1  
 
Exploratory Objectives/Endpoints, Part A: 
 
Separated the Part A exploratory 
objective/endpoint evaluating the 
effects of acoramidis on circulating 
biomarkers (NT-proBNP and TnI)  
 
For clarification only 
 Synopsis, (Objectives and 
endpoints) 
 Section 2 
 
Statistical methodology: Sample size for 
Part B: 
 
Added new text summarizing changes 
in primary endpoint “is a hierarchical 
combination of All-cause mortality, 
cumulative frequency of CV-related 
hospitalization, change from baseline 
in NT-proBNP, and change from 
baseline in 6MWT over a 30-month 
fixed treatment duration.”   
 
 
Revised the text to align with 
the revised objectives and 
endpoints 
 
 Synopsis, (Statistical 
methodology- Sample size 
for Part B 
 Section 3.13.2 
Discontinuation of Subjects from Therapy 
or Withdrawal from the Study 
 
For AEs, added “Note 1: If considered 
necessary, as per Investigator’s 
discretion, IMP may be interrupted 
(e.g., in case of AE, hospitalization or 
procedure), however IMP should be 
resumed as soon as practically 
possible, unless there are safety 
concerns. Investigators are encouraged 
to discuss such cases with a Medical 
Monitor.” 
 
Previous AE “Note” numbered to 
“Note 2”  
 
Previous Withdrawal of Consent bullet 
numbered to “Note 3”  
 
Added “Note 4: Withdrawal of consent 
should be distinguished from 
discontinuation of IMP. Subjects who 
 
 
 
For additional clarification 
only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For additional clarification 
only 
 
 
 
 Section 3.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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discontinue IMP permanently will 
receive phone calls as specified by the 
protocol to assess vital status, heart 
transplant or CMAD implantation.”  
 
Added the word “permanently” to 
clarify the language on early 
termination of study treatment. 
 
Added text “Investigator should 
evaluate the possible contribution of an 
adverse event to permanent 
discontinuation of IMP. In this case, 
adverse event information will be 
documented accordingly in the CRF.”  
 
 
 
 
 
 
For additional clarification 
only 
 
 
For additional clarification 
only 
 
 
 
 
 
Section 3.8.11 
 
 
Immediate Reporting of SAEs and EOCIs 
Definition of Cardiac Mechanical Assist 
Device, Cardiovascular-related 
Hospitalization and Events of Clinical 
Interest 
 
Added text “for adjudication purposes 
(this includes but is not limited to: 
admission notes describing signs and 
symptoms, cardiology or other relevant 
clinical notes, hospital discharge 
summary)”  
 
 
 
Clarification on Investigator 
responsibility 
 
 
 Section 3.11.7 
 Section 3.11.12 
 
 
Changed section title.  
 
Added “In this study, CMAD and heart 
transplant are included in the “All-
cause mortality” component of the 
primary endpoint for Part B, and 
therefore should be collected for all 
randomized patients even if they 
discontinued treatment permanently or 
withdrew consent (see also Section 
3.4). CMAD is defined as a durable 
CMAD implanted in a patient with 
end-stage heart failure as a bridge to 
transplant or as a destination therapy. 
Temporary cardiac mechanical support 
(i.e., those interventions that can only 
be employed in the inpatient setting, 
e.g., Intra-Aortic Balloon Pump 
[IABP], Impella, or Extra-corporeal 
membrane oxygenation [ECMO]) are 
not considered CMAD. In addition, 
other cardiac interventions such as 
pacemaker, implantable cardioverter 
defibrillator (ICD), cardiac 
resynchronization therapy (CRT), 
percutaneous coronary intervention 
(PCI), coronary artery bypass surgery 
(CABG), valvular percutaneous 
 
 
Defined CMAD 
 
Section 3.11.12 


 
 
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intervention or surgery are not 
considered CMAD.”   
 
Added text clarifying that an 
independent CEC will review and 
adjudicate “heart transplant, CMAD” 
to determine whether they meet the 
definition of protocol-specified 
efficacy endpoints for Part B. 
 
For additional clarification 
only 
 
 Section 3.12.2 
 

SAP_001.pdf: 
CONFIDENTIAL 
Part B Statistical Analysis Plan 
(ATTRibute-CM)
Page 1 of 58
 
Version 3.0, 03 August 2022 
 
 
 
Statistical Analysis Plan 
Study AG10-301 (Part B) 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety 
of Acoramidis (AG10) in Subjects with Symptomatic Transthyretin Amyloid 
Cardiomyopathy (ATTRibute-CM Trial) 
Version: 3.0 Effective: 03 August 2022 
Protocol Date: 16 June 2022   Version: Amendment 6.0 
Sponsor: Eidos Therapeutics, Inc. 
 
 
 
 


CONFIDENTIAL
Part B Statistical Analysis Plan 
(ATTRibute-CM)
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Version 3.0, 03 August 2022
Prepared by:
Reviewed by:
                                                                  Date
________________________________________
Date
Date
Date
Date










CONFIDENTIAL 
Part B Statistical Analysis Plan 
(ATTRibute-CM)
Page 7 of 58
 
Version 3.0, 03 August 2022 
 
Table of Contents 
1.
LIST OF ABBREVIATIONS......................................................................................................5 
List of Tables ......................................................................................................................................9 
List of Figures ...................................................................................................................................10 
2.
INTRODUCTION .....................................................................................................................11 
2.1 Objectives of Part B of the Study ..........................................................................................11 
2.1.1 
Primary ....................................................................................................................... 11 
2.1.2 
Key Secondary ........................................................................................................... 11 
2.1.3 
Other Secondary......................................................................................................... 11 
2.1.4 
Exploratory ................................................................................................................ 11 
2.2 Study Design ..........................................................................................................................12 
2.3 Study Population and Stratification .......................................................................................14 
2.4 Sample Size Determination....................................................................................................14 
2.5 Blinding..................................................................................................................................14 
2.6 Interim Analyses ....................................................................................................................15 
3.
GENERAL ANALYSIS CONSIDERATIONS ........................................................................16 
3.1 Analysis Populations ..............................................................................................................17 
3.1.1 
Intention-to-Treat (ITT) Analysis Population ............................................................ 17 
3.1.2 
Modified Intention-to-Treat (mITT) Analysis Population ......................................... 17 
3.1.3 
Per-Protocol (PP) Analysis Population ...................................................................... 17 
3.1.4 
Safety Analysis Population ........................................................................................ 17 
3.2 Study Day Derivation ............................................................................................................18 
3.3 Visit Windows for Analysis ...................................................................................................18 
3.4 Data Included in Part B Analyses ..........................................................................................21 
3.5 Handling of Dropouts and Missing data ................................................................................21 
4.
SUBJECT DISPOSITION .........................................................................................................21 
5.
PROTOCOL DEVIATIONS .....................................................................................................21 
6.
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................21 
6.1 Demographic Variables .........................................................................................................21 
6.2 Baseline Characteristics .........................................................................................................22 
7.
MEDICAL AND SURGICAL HISTORY ................................................................................22 
8.
ATTR-CM DIAGNOSIS AND HISTORY ...............................................................................22 
9.
PRIOR AND CONCOMITANT MEDICATIONS ...................................................................23 
9.1 Permitted Concomitant Tafamidis 12 Months .....................................................................23 
10. EXTENT OF EXPOSURE TO IMP ..........................................................................................23 
11. EFFICACY EVALUATIONS ...................................................................................................24 
11.1 Primary Efficacy Endpoint ....................................................................................................24 
11.1.1 
Primary Efficacy Analysis ......................................................................................... 24 
11.1.2 
Sensitivity Analyses of the Primary Endpoint ........................................................... 28 
11.1.2.1 F-S Test with Different Thresholds for the Difference in CFB in NT-proBNP ........ 28 
11.1.2.2 Imputation for Missing Data in CFB NT-proBNP and CFB 6MWT ........................ 28 
11.1.2.3 Multiple Imputation Methods for CV-related hospitalization ................................... 29 
11.1.3 
Supplementary Analyses of the Primary Endpoint .................................................... 29 
11.1.3.1 Hypothetical Strategy................................................................................................. 30 
11.1.3.2 Principal Stratum Strategy ......................................................................................... 30 
 


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11.1.4 
Supportive Analyses in the Per-Protocol Population ................................................. 30 
11.2 Key Secondary Endpoints ......................................................................................................30 
11.2.1 
Change from Baseline to Month 30 in Distance Walked During 6MWT ................. 31 
11.2.2 
Change from Baseline to Month 30 of treatment in the (KCCQ-OS) ....................... 33 
11.2.3 
Change from baseline in TTR (prealbumin) (an in vivo measure of TTR 
stabilization) at Month 30 ......................................................................................................... 33 
11.2.4 
All-Cause Mortality by Month 30.............................................................................. 34 
11.2.5 
Sensitivity Analyses of the Key Secondary Endpoint(s) ........................................... 34 
11.2.6 
Supplementary Analyses of the Key Secondary Endpoint(s) .................................... 36 
11.3 Other Secondary Endpoints ...................................................................................................36 
11.3.1 
Hierarchical combination of All-Cause Mortality, CV-related hospitalization and 
CFB in 6MWT over a 30-month period ................................................................................... 36 
11.3.2 
Hierarchical combination of All-Cause Mortality and CV-related hospitalization over 
a 30-month period ..................................................................................................................... 36 
11.3.3 
Cardiovascular mortality by Month 30 ...................................................................... 37 
11.3.4 
Cumulative frequency of cardiovascular-related hospitalization by Month 30 ......... 37 
11.3.5 
TTR Stabilization Measured in Established Ex-Vivo Assays (Fluorescent Probe 
Exclusion (FPE) and Western Blot (WB)) in the PK-PD substudy .......................................... 37 
11.3.6 
Change from baseline in N-terminal pro-Brain-type Natriuretic Peptide (NT-
proBNP) 38 
11.3.7 
Supplementary Analyses for Other Secondary Endpoints ......................................... 38 
11.4 Exploratory Endpoints ...........................................................................................................39 
11.4.1 
Change from baseline in Troponin I (TnI) ................................................................. 39 
11.4.2 
Change from baseline in the EuroQol Health Outcomes Assessment tool (EQ-5D-5L)
 
39 
11.4.3 
PK-PD Analysis ......................................................................................................... 40 
11.4.4 
PK Analysis ............................................................................................................... 40 
11.4.5 
Other Exploratory Endpoints ..................................................................................... 40 
11.5 Multiplicity Adjustment .........................................................................................................40 
12. SAFETY EVALUATIONS .......................................................................................................41 
12.1 Adverse Events ......................................................................................................................41 
12.2 Physical Exam, Vital Signs, ECG, Clinical Laboratory Parameters......................................42 
12.3 Covid-19 Related ...................................................................................................................44 
12.4 Database Sources ...................................................................................................................44 
13. SUBGROUP ANALYSIS .........................................................................................................44 
14. SUMMARY OF CHANGES FROM PROTOCOL ..................................................................45 
15. REFERENCES ..........................................................................................................................46 
16. APPENDICES ...........................................................................................................................47 
Appendix 1.1. Statistical Analysis Summary ...................................................................................47 
Appendix 1.2 Finkelstein-Schoenfeld Scoring Algorithm (Primary Efficacy Endpoint) .................51 
Appendix 1.3 Generic algorithm from Carpenter et al. (2013) .........................................................53 
Appendix 1.4 Sample SAS codes for key secondary and other endpoints. ......................................54 
Appendix 1.5 Missing Date Handling ..............................................................................................56 
1.  Missing Date Information for Adverse Events .................................................................... 56 
2. Missing Date Information for Prior or Concomitant Medications ....................................... 58 


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LIST OF TABLES 
Table 1 
Analysis Visit Windows for Assessments except KCCQ, EQ-5D-5L, and 
6MWT Distance ........................................................................................................19 
Table 2 
Analysis Visit Windows for KCCQ .........................................................................20 
Table 3  
Analysis Visit Windows for 6MWT Distance and EQ-5D-5L ..............................20 
Table 4 
Intercurrent Events and Handling Rules for Primary Analysis ..........................25 
Table 5 
Intercurrent Events and Handling Rules for Key Secondary Analysis ...............33 
Table 6 
Categories of Liver Test Elevations ........................................................................43 
 


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LIST OF FIGURES 
Figure 1     Study Schematic: ATTRibute-CM Trial ................................................................13 
Figure 2 
Finkelstein-Schoenfeld Scoring Algorithm .............................................................27 
 
 
 


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2. 
INTRODUCTION  
The AG10-301 ATTRibute-CM Trial (A Phase 3, Randomized, Double-blind, Placebo-Controlled 
Study of the Efficacy and Safety of Acoramidis in Subjects with Symptomatic Transthyretin 
Amyloid Cardiomyopathy) examines an investigational drug, acoramidis, in the treatment of 
transthyretin amyloid cardiomyopathy (ATTR-CM). This document describes study objectives, 
data analysis methods, and data summaries for Part B of this clinical study protocol (CSP). 
Screening and randomization will be followed by a total of 30 months of blinded, placebo-
controlled treatment. 
Analysis approaches detailed within this document take precedence if different from the analyses 
and summaries presented in the protocol. 
2.1 
Objectives of Part B of the Study 
2.1.1 
Primary 
To determine the efficacy of acoramidis in the treatment of subjects with symptomatic ATTR-CM 
by evaluating the difference between the acoramidis and placebo groups in the combined endpoint 
of All-Cause Mortality, the cumulative frequency of cardiovascular (CV)-related hospitalization, 
change from baseline in the NT-proBNP, and change from baseline in the Six-Minute Walk Test 
(6MWT).  
2.1.2 
Key Secondary 
 To evaluate the effects of acoramidis on 6MWT.  
 To evaluate the effects of acoramidis on health-related Quality of Life (QoL) as measured 
by a heart failure (HF)-specific instrument (KCCQ) in subjects with symptomatic 
ATTR-CM.  
 To assess the pharmacodynamic (PD) effects of acoramidis by assessing circulating 
prealbumin (transthyretin, TTR) concentration as an in vivo biomarker of stabilization. 
 To assess the effect of acoramidis on all-cause mortality. 
2.1.3 
Other Secondary 
 To determine the efficacy of acoramidis treatment as measured by the individual 
components of the primary endpoint and hierarchical combinations thereof. 
 To determine the efficacy of acoramidis in reducing CV mortality in subjects with 
symptomatic ATTR-CM. 
 To evaluate the safety and tolerability of acoramidis administered for 30 months in subjects 
with symptomatic ATTR-CM. 
 To assess the pharmacodynamic (PD) effects of acoramidis as assessed by established ex 
vivo assays of TTR stabilization. 
2.1.4 
Exploratory 
 To evaluate the effects of acoramidis on circulating biomarkers of microvascular ischemia 
in subjects with symptomatic ATTR-CM. 
 
 
 
 
 
 
 
 
 


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 To characterize the pharmacokinetics (PK) of acoramidis (and its predominant metabolite) 
when acoramidis-HCI 800 mg is administered orally twice daily (BID) in subjects with 
symptomatic ATTR-CM.  
 To describe the population PK (PopPK) of acoramidis in subjects with ATTR-CM. 
 To describe the PD properties and the PK-PD relationship of acoramidis as assessed by 
circulating prealbumin (TTR) concentration as an in vivo biomarker of stabilization and by 
established ex vivo assays of TTR stabilization, and correlation with acoramidis PK (PK-
PD substudy). 
 To evaluate the effects of acoramidis on health related QoL as measured by EuroQoL 
Health Outcomes Assessment tool (EQ-5D-5L) in subjects with symptomatic ATTR-CM. 
 To assess the ability of acoramidis to bind and stabilize a diverse array of pathogenic and 
likely pathogenic variant TTR tetrameric species, representing amino acid substitutions 
located throughout the sequence of TTR that are responsible for a spectrum of clinical 
presentations, from sera and/or plasma of subjects with ATTR-CM (Additional assays). 
2.2 
Study Design 
This prospective, Phase 3, randomized, multicenter, parallel-group study will evaluate the efficacy 
and safety of acoramidis in symptomatic subjects compared to placebo, administered on a 
background of stable heart failure therapy. Screening and randomization will be followed by a total 
of 30 months of blinded, placebo-controlled treatment. At the end of 12 months of treatment (Part 
A) efficacy of acoramidis will be assessed through analyses of the functional (6MWT) and health-
related QoL (as measured by HF-specific instrument KCCQ) endpoints. At the end of 30 months 
of treatment (Part B) efficacy of acoramidis will be further assessed through analysis of All-Cause 
Mortality, cumulative frequency of CV-related hospitalization, change from baseline in NT-
proBNP, and change from baseline in 6MWT.  
This Statistical Analysis Plan (SAP) addresses Part B of the study. Part A has a separate document 
specifying its planned analyses. The study schematic for the ATTRibute-CM trial is shown in 
Figure 1. See Section 2.2 for criteria for conclusion of Part B of the study. 
 
 
 
 
 
 
 


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Figure 1     Study Schematic: ATTRibute-CM Trial  
 
Approximately 510 eligible subjects will be randomized in a 2:1 ratio to acoramidis 800 mg or 
matching placebo administered orally BID. Part B of the study will conclude after the last subject 
enrolled has concluded the last visit of the study or is not expected to complete that visit (e.g. 
subject has died or withdrawn from the study). After that milestone, all data collected in the study 
database will be used for the analysis of Part B efficacy and safety outcomes to be presented in the 
Part B Clinical Study Report (CSR).   
Subjects who complete the Month 30 visit will have a visit 30 days (± 7 days) after the last dose of 
investigational medicinal product (IMP). Subjects who complete the 30-months of double-blinded 
study treatment and the Month 30 visit assessments, may be eligible to enroll into the OLE study 
(AG10-304) with its own protocol and a separate SAP. Subjects who choose to enroll in the OLE 
Study (AG10-304) the same day as completing the Month 30 visit in AG10-301 will not be 
required to have the 30-day follow-up visit (in Study AG10-301). 
Blinding to treatment allocation will be maintained for the subjects, Investigators, Clinical Events 
Committee (CEC), and Sponsor designated site monitoring personnel throughout the study until 
the final subject has completed the expected Month 30 or follow-up visit. Upon Part A unblinding, 
the Part A team conducting the analysis will not be involved in conduct or analysis of Part B prior 
to the Part B unblinding. The Part B statistical team conducting the analysis will not be involved in 
unblinded analysis of Part A. The operational processes and procedures that will be executed in 
conjunction with the Part B analysis to preserve confidentiality and blinding of the entire trial will 
be governed by a 
 finalized before Part A unblinding.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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2.3 
Study Population and Stratification 
 (at time of randomization) with 
chronic, stable, symptomatic (NYHA Class I-III) ATTR-CM will be randomized in a 2:1 ratio 
(340 subjects to active treatment, 170 to matching placebo) in the study. Randomization will be 
stratified according to whether subjects have ATTRm-CM or ATTRwt-CM with a targeted 
minimum of 20% of subjects with ATTRm-CM. Randomization will also be stratified according to 
NT-
mL/min/1.73 m2) at screening. For statistical analyses, the stratification factor levels used during 
randomization in the Interactive Web Response System (IWRS) will be utilized. If the overall mis-
stratification proportion is greater than 10% of subjects, a sensitivity analysis on the primary and 
key secondary endpoints using actual stratification factors will be performed. 
2.4 
Sample Size Determination 
2 
(i.e., subjects with baseline eGFR < 30 mL/min/1.73 m2 will be excluded from the primary 
analysis population). It is estimated that approximately 10% of subjects will have baseline eGFR 
< 30 mL/min/1.73 m2. Sample size calculations are based on two-sided alphas = 0.01 for Part A 
and 0.04 for Part B.  
The power for Part B was originally estimated based on the primary endpoint of a hierarchical 
combination of All-Cause Mortality and CV-related hospitalizations over a 30-month treatment 
period. The test statistic for the combined endpoint is 
(Finkelstein 1999) adaptation of the generalized Gehan Wilcoxon test (and will be referred to as 
the Finkelstein-Schoenfeld (F-S) test). Simulations based on estimates of mortality and CV-related 
hospitalization from ATTR-ACT result in greater than 90% power with two-sided alpha = 0.04 
with total N = 460 (= 0.9*510, i.e., after excluding 10% of subjects with baseline eGFR < 30 
mL/min/1.73 m2) for the Finkelstein-Schoenfeld test to reject the null hypothesis that neither All-
Cause Mortality nor CV-related hospitalization is different between acoramidis and placebo. 
Simulations assumed an All-Cause Mortality rate of 40% for placebo with a hazard ratio of 0.7, 
mean number of CV-related hospitalizations by Month 30 of 1.15 and 0.75 in the placebo and 
acoramidis groups, respectively.  
The primary endpoint is a hierarchical combination of all-cause mortality, cumulative frequency of 
CV-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 
6MWT.  
The number of subjects who will initiate, and when they will initiate tafamidis after Month 12 is 
unknown and is not possible to estimate with any precision. Simulations to assess power for the 
four-component hierarchical endpoint (All-Cause Mortality, cumulative frequency of CV-related 
hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT) were 
conducted under various scenarios taking into consideration potential tafamidis use and potentially 
missing data. The estimated power across the various scenarios remains above 80%. 
2.5 
Blinding  
As noted in Section 2.2, a Data Access Management Plan will be documented prior to the 
unblinding of Part A of the study. Briefly, the Part B team will be blinded to treatment through 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 


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Part B data base lock. They will not participate in any unblinded analyses including subject-level 
information on treatment assignment, PK and PD or review of Part A. 
2.6 
Interim Analyses  
No interim analysis is planned for this study. Part A analyses will occur following the last subject 
completing the Month 12 visit.  
An independent Data Monitoring Committee (DMC) will provide independent reviews of data 
relevant to the safety, efficacy, outcomes and conduct of the ongoing trial. The DMC will operate 
in agreement with its charter, which was drafted in accordance with the March 2006 Food and 
Drug Administration Guidance document on the Establishment and Operation of Clinical Trial 
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3. 
GENERAL ANALYSIS CONSIDERATIONS 
This report will utilize subject data through their end of study participation. This includes 
scheduled, unscheduled, early termination visit dates, data from public records (for mortality) and 
telephone contacts.   
All continuous variables will be summarized as means (standard deviations), medians (25th and 
75th percentiles), minimum and maximum. The number and percentage of subjects in each 
category will be presented for categorical variables. 
Unless otherwise specified, all hypothesis tests will be two-sided. 
Alpha recycling rule 
B): B will be 0.05 for the primary and key secondary endpoints if the p-
value for the alpha-controlled sequentially-tested endpoints in Part A (change from baseline 
(CFB) in 6MWT, CFB in KCCQ score and CFB in TTR at 12 months) is <0.01, allowing us to 
re-use the 0.01 alpha for Part B. This is effectively a fallback procedure (Wiens 2005). B will 
be 0.04 otherwise. Any further mention of the controlled type 1 error in this document will be 
denoted by B.  
All CFB values are calculated as the respective (post baseline value  baseline value) for the 
measure of interest. 
Analysis approaches for primary and secondary efficacy endpoints are detailed in Section 11 
while analyses for safety are outlined in Section 12. Formal statistical tests of the primary and 
select secondary efficacy analyses will be controlled at an alpha level of 
B sequentially as 
specified in Section 11. For other variables of interest uncontrolled for type 1 error, statistical 
comparisons will use a two-sided significance test evaluated at alpha level of 0.05. 
All analyses for primary, secondary and exploratory endpoints will adjust for the 
randomization stratification factors unless specified otherwise. 
Survival status response collected through the end of the study will be used for mortality in the 
efficacy analyses. For any analyses on All-Cause Mortality, receiving a heart transplant or a 
cardiac mechanical assist device (CMAD) will be treated as death. Survival status response 
the eCRF page, subjects will be censored at the date they are last known alive or the upper 
bound of the Month 30 visit analysis window, whichever is earlier.  
For efficacy analyses, CV-related hospitalizations are those that were adjudicated as CV 
related and non-elective by the CEC including Events of clinical interest (EOCI). The 
adjudicated CV-related hospitalizations occurring up to when the survival status eCRF page is 
filled out will be included in the analysis. For subjects who complete the 30-month study, 
CV-related hospitalization frequency is calculated for the period of (assessment date from 
survival status eCRF page - first dose of IMP date +1). For subjects who prematurely 
discontinue from the IMP or discontinue/withdraw from the study, CV- related hospitalization 
frequency is calculated relative to (30 days after last dose date - first dose of IMP date +1).  
Event rates per 100 patient-years by each of the treatment groups through 30 months will be 
calculated for the following endpoints: All-Cause Mortality, CV death, CV-related 
hospitalization and composite of All-Cause Mortality or first CV-related hospitalization. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 


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Kaplan Meier (KM) curves and cumulative incidence function (CIF) by treatment groups will 
be plotted for All-Cause Mortality, CV death, time to first CV-related hospitalization and time 
to All-Cause Mortality or first CV-related hospitalization. The number of subjects at risk, 
number of events and number of censored observations through 30 months will be summarized 
.  
All the descriptive summaries for the endpoints will also be repeated for the following 
concomitant tafamidis grouping: 
o acoramidis only: subjects who received any acoramidis and did not receive any tafamidis   
o placebo only: subjects who received only placebo and did not receive any tafamidis,  
o acoramidis+tafamidis: subjects who received any acoramidis and any tafamidis   
o placebo+tafamidis: subjects who received placebo and any tafamidis. 
Analyses will be performed using SAS software version 9.4 or higher 
 
. 
3.1 
Analysis Populations  
Analysis Population and Analysis Set are used interchangeably in this document.  
3.1.1 
Intention-to-Treat (ITT) Analysis Population 
The ITT population (ITT) is defined as all randomized subjects who have received at least one 
dose of IMP and have at least one post baseline efficacy evaluation. Subjects in this population will 
be analyzed according to their assigned randomized treatment. 
3.1.2 
Modified Intention-to-Treat (mITT) Analysis Population 
The modified ITT population (mITT) will be the primary analysis population for efficacy 
endpoints. The mITT population includes subjects who meet the definition of ITT and have a 
baseline eGFR > 30 mL/min/1.73 m2. Subjects in this population will be analyzed according to 
their assigned randomized treatment. 
3.1.3 
Per-Protocol (PP) Analysis Population 
The per-protocol population will be a subset of the mITT population based on a pre-identified list 
of important protocol deviations. The list of subjects with such deviations from the protocol will be 
identified prior to unblinding Part A and Part B of the study. The PP population analysis will be 
considered as supportive of the mITT analyses for the primary efficacy and key secondary 
endpoints. Subjects will be analyzed according to their assigned randomized treatment. If the PP 
analyses set makes up a large fraction (>90%) of the mITT then the PP analysis will not be 
conducted. 
3.1.4 
Safety Analysis Population 
For safety, the analysis population will include all randomized subjects who received at least one 
dose of IMP. Safety analyses will be presented by actual treatment received.  
 
 
 
 
 
 
 
 
 


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3.2 
Study Day Derivation 
The day of the study is the day relative to randomization date. The study day is defined as the 
(assessment/event date  randomization date) if the assessment/event date is prior to the 
randomization date and as (assessment/event date  randomization date) + 1 if the 
assessment/event date is on/after the date of randomization. Using this derivation, the day of 
randomization will be considered study day 1. There is no study day 0. Negative days indicate 
assessments prior to randomization. Positive days indicate assessments on or after randomization. 
A month is defined as 30.4375 days and a year is defined as 365.25 days. Study day will be used 
for all efficacy and other analyses unless stated otherwise. 
The day of treatment is the day relative to first dose of IMP. The treatment day is defined as the 
(assessment/event date  first IMP dose date) if the assessment/event date is prior to the first IMP 
dose date. If the assessment/event date is on/after the date of the first IMP dose date, then the 
treatment day relative to first dose of IMP is defined as (assessment/event date  first IMP dose 
date) + 1. Using this derivation, the day of the first IMP dose date will be considered treatment day 
1. There is no treatment day 0. Negative days indicate assessments/events prior to the first IMP 
dose date. Positive days indicate assessments/events on or after the first IMP dose date. A month is 
defined as 30.4375 days and a year is defined as 365.25 days. Treatment day will be used for 
safety summaries where identified. 
3.3 
Visit Windows for Analysis 
Visit windows for presentation of results will be derived from date of the assessment (or visit date 
if assessment date was not collected or is missing) relative to the randomization date unless otherwise 
specified. Visit windows will be contiguous and are presented in Table 1, Table 2 and Table 3 
based on assessment specific scheduled visits. Visit windows for assessments except KCCQ, 
6MWT distance, and EQ-5D-5L are presented in Table 1. KCCQ is not assessed at Day 28 and will 
utilize the visit windows as shown in Table 2. 6MWT distance and EQ-5D-5L are not assessed at 
Day 28 and Month 3 so they have different window thresholds exhibited in Table 3. 
 
 
 
 
 
 
 
 
 


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Table 1 
Analysis Visit Windows for Assessments except KCCQ, EQ-5D-5L, and 
6MWT Distance 
Double-Blind Treatment Period 
 
Visit 
Target Study Day 
Analysis Window Study Day 
Low 
High 
Baseline 
< 1* 
<1* 
1* 
Day 28 
28 
2* 
59 
Month 3 
91 
60 
136 
Month 6 
183 
137 
228 
Month 9 
274 
229 
319 
Month 12 
365 
320 
410 
Month 15 
457 
411 
502 
Month 18 
548 
503 
593 
Month 21 
639 
594 
684 
Month 24 
731 
685 
776 
Month 27 
822 
777 
867 
Month 30 
913 
868 
958 
 
*: The day of treatment is used, unless if the first IMP dose is taken on a later date of the protocol 
scheduled Day 1 visit, for which both time and date of the first IMP dose will be used as the 
window threshold. 
 


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Table 2 
Analysis Visit Windows for KCCQ 
Double-Blind Treatment Period 
 
Visit 
Target Study Day 
Analysis Window Study Day 
Low 
High 
Baseline 
< 1* 
< 1* 
1* 
Month 3 
91 
2* 
136 
Month 6 
183 
137 
228 
Month 9 
274 
229 
319 
Month 12 
365 
320 
410 
Month 18 
548 
411 
594 
Month 24 
731 
595 
867 
Month 30 
913 
868 
958 
*: The day of treatment is used, unless if the first IMP dose is taken on a later date of the protocol 
scheduled Day 1 visit, for which both time and date of the first IMP dose will be used as the 
window threshold. 
Table 3  
Analysis Visit Windows for 6MWT Distance and EQ-5D-5L 
Double-Blind Treatment Period 
*Day 1 = Randomization date 
Visit 
Target Study Day 
Analysis Window Study Day 
Low 
High 
Baseline 
< 1* 
< 1* 
1* 
Month 6 
183 
2* 
228 
Month 9 
274 
229 
319 
Month 12 
365 
320 
410 
Month 18 
548 
411 
594 
Month 24 
731 
595 
867 
Month 30 
913 
868 
958 
*: The day of treatment is used, unless if the first IMP dose is taken on a later date of the protocol 
scheduled Day 1 visit, for which both time and date of the first IMP dose will be used as the 
window threshold. 
 
Results presented by visit will use the visit record data closest to the scheduled (target) visit day. If 
two visits occur equidistant from the scheduled (target) visit day, the most recent visit record date 
(i.e., later of the 2 visits) will be used.   
Shift tables from baseline to worst post-baseline will utilize all records for a subject, even if there 
are multiple visits within a derived visit window. Listings will present data from all visits attended. 
Unless otherwise specified, baseline values are defined as the last measurement obtained on or 
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the first IMP dose if taken on a later date. For subjects randomized and not treated, the baseline 
value will be the last measurement prior to randomization. When there is a missing baseline 
assessment, it will not be imputed, thus, subjects are excluded from any CFB analyses for which 
they have a missing baseline value. 
3.4 
Data Included in Part B Analyses 
All data included in the study database will be used for Part B analyses.  
3.5 
Handling of Dropouts and Missing data 
Imputation of missing values for efficacy analyses is detailed in Section 11. The robustness of the 
primary and key secondary efficacy analyses to missing data assumptions will be explored as 
detailed in Section 11. Missing dates for Adverse Events and Prior or Concomitant Medication will 
be handled as described in Appendix 1.5. 
4.        SUBJECT DISPOSITION 
The number of subjects screened (i.e., signed informed consent) and the number of subjects 
randomized will be reported overall. Reasons for screen failures will be summarized. 
The number and percentage of randomized subjects that received IMP, discontinued IMP early, 
failed to complete the study and the reason for discontinuation of IMP and from the study will be 
presented by treatment group and overall. 
Any subjects randomized but not treated with any IMP will be presented in a separate listing. 
5.          PROTOCOL DEVIATIONS  
A listing of subjects with important protocol deviations will be provided. A listing of prespecified 
subset of important protocol deviation leading to exclusion from PP population will be identified 
prior to database freeze for Part A and prior to database lock for Part B and reported. Subjects 
excluded from Part A PP population will not necessarily be excluded from Part B unless they also 
meet Part B subset of important protocol deviations.    
6.          DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Variables to be presented as reported at baseline are detailed in the remainder of Section 6. These 
variables will be summarized for the mITT and safety populations. 
6.1 
Demographic Variables 
Demographic characteristics collected are: 
 
Age in years (quantitative and qualitative) variable:  
a) Continuous variable  
b) 
 
c) 
 
Gender (Male, Female) 
 
 
 
 
 
 
 
 
 
 


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Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, Not reported) 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
6.2 
Baseline Characteristics 
Baseline characteristics collected and to be summarized are: 
Baseline height (cm) 
Baseline weight (kg) 
Baseline Body Mass Index (BMI) (kg/m2) 
ATTR-CM type (ATTRm-CM vs ATTRwt-CM) 
Stratification factors (from IWRS based on data at screening):  
a) ATTR-CM type (ATTRm-CM vs ATTRwt-CM) 
b) Baseline NT-
 
c) 
2) 
2) as calculated at baseline using the Modification of 
Diet in Renal Disease (MDRD) equation using the central laboratory data from
 
 
 This will be presented for Safety Population only as 
this is part of the criteria for mITT population.  
7.        MEDICAL AND SURGICAL HISTORY 
Medical and surgical history will be coded using the version of Medical Dictionary for  
Regulatory Activities (MedDRA) currently in effect at the time of Part B database lock. Medical 
and surgical history will be summarized by system organ class (SOC) and preferred term (PT). 
These summaries will be produced for the safety population. 
8.       ATTR-CM DIAGNOSIS AND HISTORY  
ATTR-CM diagnosis and history variables to be reported at baseline include: 
Genetic status and if mutant, genotype 
Zygosity 
Clinical basis for diagnosis and if non-invasive, type of assessment 
History of atrial fibrillation and type 
History of thromboembolic event or stroke/ Transient Ischemic Attack (TIA)/ Reversible 
Ischemic Neurological Deficit (RIND) 
Permanent pacemaker placed 
Implantable cardioverter-defibrillator (ICD) placed 
Presence of amyloid polyneuropathy and if present, stage 
Diagnosis of renal disease 
Prior carpal tunnel release surgery 
Prior spinal stenosis surgery 
History of heart failure 
History of prior congestive heart failure (CHF) hospitalizations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical evidence of heart failure 
Heart failure symptoms that required or require ongoing treatment with a diuretic 
LV wall (interventricular septum or LV posterior wall) thickness 
Other relevant cardiovascular history 
o Active coronary artery disease 
o Prior valve surgery 
o Prior pericarditis, pericardial surgery or pericardiocentesis 
o Prior aortic surgery 
o Other prior arterial intervention (e.g., femoral-popliteal bypass or stent) 
9.  
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be coded according to the AG10-301 Coding Conventions 
using the World Health Organization Drug Dictionary (WHODrug). Prior medications are those 
medications with a start date prior to the first day of IMP. For those that never received IMP, prior 
medications are those received prior to randomization. Concomitant medications are those taken 
on or after the day of first dose of IMP, including those started prior to IMP and continued past 
initiation of IMP. If no IMP is administered, concomitant mediations are those taken on or after the 
date of randomization. Note that medications that started prior to randomization and continued or 
stopped after randomization will be summarized as both prior and concomitant medications. 
Additionally, subjects initiating tafamidis and the time to initiation of tafamidis will be 
summarized separately. 
Prior and concomitant medication use will be separately summarized by Anatomical Therapeutic 
Classification (ATC) medication class (Level 4) and preferred name (i.e. generic medication 
name). A subject reporting the same medication more than once will be counted once when 
calculating the number and percentage of subjects who received that medication. 
These summaries will be produced for the safety population. 
9.1 
Permitted Concomitant Tafamidis 12 Months 
Number of subjects in acoramidis and placebo arms that initiate concomitant tafamidis, duration of 
exposure and their time to starting this concomitant medication will be summarized descriptively 
as raw rates and by using KM estimates and plots. The baseline characteristics for subjects with 
introduction of tafamidis will be generated to understand any inherent differences in the subjects 
that initiate this concomitant medication. A subject level listing will also be provided.  
10. 
   EXTENT OF EXPOSURE TO IMP 
The extent of IMP exposure and subject compliance will be assessed by several measures: the 
proportion of subjects receiving at least one dose, the proportion of tablets taken out of the 
scheduled number (i.e. ignoring dose reductions), and the number of months of exposure. Number 
of tablets taken is calculated as the number of tablets dispensed minus the number of tablets 
returned. In case any dispensed bottle is not returned by database lock, it is assumed for the 
purpose of last dose of IMP date that the subject has taken the drug per protocol up to the earlier 
date of the (1) last dose (if available 
) or (2) the date that bottle is 
 
 
 
 
 
 
 
 
 
 


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expected to be emptied assuming the subject has taken the drug (two tablets) twice daily or (3) end 
. 
 
The number of months of exposure will be defined as: (last dose of IMP date  first dose of IMP 
date +1) / 30.4375, regardless of intermittent discontinuations or dose reductions. Non-integer 
values will be rounded to one decimal place. The number of months of adjusted exposure will be 
defined as: (last dose of IMP date  first dose of IMP date  number of days reported on eCRF as 
no medication was taken +1) / 30.4375. Number of days where no medication was taken can be 
calculated by counting days wherever dose is not available or is missed based on the Drug 
Accountability eCRF page and/or the Exposure-Missed Doses eCRF page.    
 
Proportion of tablets taken of those scheduled will be calculated using the below formula. If there 
are unreturned bottles, the assumption is that the patient took the treatment per protocol during the 
period of when the bottle is not returned. Algorithm for Part B last dose of IMP date is defined 
earlier within this section.  
 
Proportion =
  
11.     EFFICACY EVALUATIONS 
11.1 
Primary Efficacy Endpoint 
The primary endpoint for Part B is the hierarchical combination of All-Cause Mortality, 
cumulative frequency of CV-related hospitalization as adjudicated by the clinical events committee 
(CEC), change from baseline (CFB) in NT-proBNP, and CFB in 6MWT over the 30-month 
duration.  
Receiving a heart transplant or a cardiac mechanical assist device (CMAD) will be treated as 
death. For efficacy analyses, CV-related hospitalizations are those that were adjudicated as such by 
the CEC. A threshold of 500 pg/mL will be added in the comparison of CFB in NT-proBNP for 
each pair.   
11.1.1 
Primary Efficacy Analysis 
The estimand for the primary endpoint can be summarized in the following attributes: 
A) Population:  Subjects with symptomatic ATTR-CM and baseline eGFR  30 mL/min/1.73m2. 
B) Variable: A hierarchical combination of All-Cause Mortality, cumulative frequency of CV-
related hospitalization, CFB in NT-proBNP and CFB in 6MWT at the last available visit where 
both subjects have non-missing assessments.   
C) Intercurrent event: The treatment policy approach will apply for the primary efficacy analysis. 
Measurements of the components of the primary efficacy endpoint will be used as available 
regardless of whether or not subjects discontinue IMP or initiate concomitant tafamidis. Please 
refer to Table 4 for the data handling approach of intercurrent events identified for the third 
and fourth components (CFB in NT-proBNP and 6MWT) in the primary estimand. 
D) Population level summary: Sum of ranked scores (calculated within each randomization strata) 
by study treatment at Month 30.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 




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The pairwise comparison of CFB in NT-proBNP will be performed for the last available pair of 
subjects. Difference of CFB in NT-proBNP between two subjects needs to be  500 pg/mL or else 
remains a tie and go to next component. For example: If CFB in NT-proBNP for subject A is 900 
pg/mL and is 300 pg/mL for subject B, then subject B wins. If CFB in NT-proBNP for subject A is 
500 pg/mL and is 300 pg/mL for subject B, then the comparison remains a tie and goes to the next 
component. 
CFB in 6MWT will be compared between both subjects through 30 months using the last available 
pairs.  
 
 
 




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The pairwise comparisons as identified in Figure 2 are done within each stratum prior to 
calculating the sum of scores on which the test statistic is based. The three stratification factors 
resulting in a total of 8 strata (2X2X2) are identified below:  
 ATTRm-CM or ATTRwt-CM (with a targeted minimum of 20% of subjects with 
ATTRm-CM),  
 NT-
 
 
2) at Screening  
If there are 5 patients in any of the strata, the strata including ATTRm-CM will be combined and 
resulting in a total of 5 strata.  
The primary hypothesis is: 
H0 (null hypothesis): All of the four components of All-Cause Mortality, cumulative 
frequency of CV-related hospitalization, change in NT-proBNP, and change in 6MWT 
distance are the same between placebo and acoramidis treatment groups 
 Ha (alternative hypothesis): At least one component of All-Cause Mortality, cumulative 
frequency of CV-related hospitalization, change in NT-proBNP, and change in 6MWT 
distance is different between the placebo and acoramidis treatment groups   
The primary hypothesis will be formally tested (two-tailed) using 
B (Section 3). 
A table illustrating various scoring scenarios is included in Appendix 1.2 Finkelstein-Schoenfeld 
Scoring Algorithm. 
The p-value from F-S test will be presented. Win-Ratio (Pocock 2012) and its confidence intervals 
will be calculated to aid in interpretation of the results for primary efficacy analysis from the F-S 
scoring algorithm.  
 
The stratified non-matched Win-Ratio method will allocate all treated and placebo pairs within 
each stratum in the same hierarchical structure from F-S test. The win ratio (RW) will be calculated 
by adding all wins from treatment group and dividing it by all wins from placebo group. The 
standard error of log (RW) will be derived as: SE (log (RW)) = log (RW)/Z-score from F-S test. An 
approximate 95% CI of win ratio then can be estimated from confidence interval of log (RW).  
 
11.1.2 
Sensitivity Analyses of the Primary Endpoint 
11.1.2.1 F-S Test with Different Thresholds for the Difference in CFB in NT-proBNP  
To evaluate the impact of the preset threshold of the difference between subjects in CFB in NT-
proBNP comparison, the F-S test described in Section 11.1.1 will be repeated for mITT population 
using different thresholds that set to 250 pg/mL, 750 pg/mL and 1000 pg/mL.   
11.1.2.2 Imputation for Missing Data in CFB NT-proBNP and CFB 6MWT 
To evaluate sensitivity of the primary analysis result to the presence of missing CFB in NT-
proBNP and CFB in 6MWT data at 30 months, the missing values at 30 months will be imputed. 
The choice of imputation method will depend on the reason for missing data.  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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Note that All-Cause Mortality is included as first component of the primary hierarchical composite 
endpoint, any missing data after ACM event will not be imputed. All data available post tafamidis 
use will be used as collected.  The below imputation methods will be used for the subjects without 
ACM events and with missing measurements of 6MWT or NT-proBNP at 30 months: 
 If the subject did not discontinue the IMP early and had missing measurements due to CV-
related AE, then the missing measurements will be imputed by resampling from the bottom 
25% in the same arm at a given visit.   
 Any missing measurements due to early discontinuation of IMP will be imputed under 
MNAR using the Jump to Reference (J2R) method summarized in Section 11.2.1 below.  
 All other missing 30-month measurements due to protocol deviations or any other reasons 
will be imputed under MAR. 
 
The F-S method in primary analysis will be repeated on these imputed CFB NT-proBNP and CFB 
6MWT datasets respectively, one at a time. 
11.1.2.3 Multiple Imputation Methods for CV-related hospitalization 
A two-stage multiple imputation process that follows the procedure for monotone missing data 
(Rubin 1987) will be used to assess the sensitivity of primary analyses for any missing CV-related 
hospitalizations due to early study discontinuation. Missing CV-related hospitalization will not be 
imputed after ACM event. Subjects who die in an interval will be excluded from the imputation 
model estimation. The imputation models will be estimated for each IMP group in two phases as 
below: 
 
Models for CV-related hospitalization rates are estimated for each time interval (months 1-10 
(period1), months 11-20 (period2), and months 21-30 (period3)). Within each short time interval 
(10 months), a negative binomial regression model will be assumed for hospitalization counts. 
 No imputation is required for a subject who dies during the interval. All other subjects still 
in the study at the beginning of the interval are included in the model estimation. The 
reduced exposure of dropouts during the intervals is represented by an exposure multiplier 
(between 0-10) of the monthly hospitalization rate (McCullagh 1989). 
 The monthly hospitalization rate during the first period is a function of the baseline NT-
proBNP level, TTR genotype and renal function (eGFR).  
 The monthly hospitalization rate during the second period is a function of the baseline 
covariates and the hospitalization counts during the first period. The monthly 
hospitalization rate during the third period is a function of the baseline covariates, and the 
hospitalization counts during the first and second periods. 
The null hypothesis will then be tested using the complete-data as imputed above in step 1 using 
the same analytic method as for primary analyses (F-S test), any missing measurements for NT-
proBNP and 6MWT will not be imputed. The results will finally 
(Rubin 1987). 
11.1.3 
Supplementary Analyses of the Primary Endpoint 
Supplementary analyses of the primary endpoint will be conducted to address concomitant 
tafamidis, which is allowed after Month 12.  
 
 
 
 
 
 
 
 
 
 
 


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11.1.3.1 Hypothetical Strategy 
In this supplementary estimand, the hypothetical strategy will be applied to the intercurrent event 
of concomitant tafamidis instead, addressing the treatment effect in a hypothetical setting where 
concomitant tafamidis was not available to subjects.  
The F-S test as used for primary efficacy analyses will be repeated in the mITT population using 
observations without any concomitant tafamidis. For subjects who had any concomitant tafamidis, 
the observations after initiation of tafamidis will not be used in this analysis.   
11.1.3.2 Principal Stratum Strategy 
In this supplementary estimand, the principal stratum strategy will be applied to the intercurrent 
event of concomitant tafamidis. 
The F-S test as used for primary efficacy analyses will be repeated using the principal stratum 
strategy in which subjects from mITT population who initiate tafamidis are excluded (i.e., 
acoramidis only vs placebo only). The tafamidis grouping is defined in Section 3. 
11.1.4 
Supportive Analyses in the Per-Protocol Population 
The PP population analyses will be considered as supportive of the mITT analyses for the primary 
efficacy and key secondary endpoints. Only the main analyses of these endpoints will be 
performed (i.e., not any of the sensitivity/supplementary analyses). Subjects will be analyzed 
according to their randomized treatment. 
11.2 
 Key Secondary Endpoints 
The key secondary endpoint(s) of Part B are:   
1. Change from baseline to Month 30 in the distance walked during the 6MWT  
2. Change from baseline to Month 30 of the KCCQ Overall Score (KCCQ-OS)  
3. Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR 
stabilization) at Month 30 
4. All-cause mortality by Month 30, including heart transplant and CMAD 
To maintain the B for the key secondary endpoints, they will be formally tested per the 
multiplicity adjustment rule in Section 11.5.  
 
The estimand for the key secondary endpoints can be summarized in the following attributes: 
A) Population: Subjects with symptomatic ATTR-CM and baseline 
2. 
B) Variable: CFB in 6MWT, CFB in KCCQ-OS, CFB in TTR (prealbumin) level, ACM including 
heart transplant and CMAD to Month 30  
C)  Intercurrent event: The treatment policy approach will apply. For subjects who initiate 
tafamidis post 12 months, die or those who discontinue study treatment earlier than 30 months, 
their last available post baseline 6MWT distance/KCCQ-OS will be used in analyses as 
available. 
 
  
 
 
 


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D) Population level summary: Difference in mean change from baseline in distance walked during 
6MWT, difference in mean change from baseline in KCCQ-OS score, difference in mean 
change from baseline in TTR (prealbumin) level, difference in ACM including heart transplant 
and CMAD between acoramidis and placebo groups at Month 30.  
 
No other missing data will be imputed for the key secondary endpoints.  
11.2.1 
Change from Baseline to Month 30 in Distance Walked During 6MWT   
 
Change from baseline to Month 30 in distance walked during the 6MWT is one of the key 
secondary efficacy endpoints for Part B.  
For the subjects randomized, the baseline 6MWT is the average of the total distance walked by 
subject for the two qualifying 6MWTs that meet the protocol-defined criteria on or prior to the 
date of randomization. In case there are more than one pair of qualifying 6MWTs, the pair of two 
qualifying 6MWTs with most similar distance (percentage between each other relative to the larger 
distance walked and then absolute difference in distance if tied on percentage) walked will be 
utilized to calculate the baseline value. If such a pair (meeting all protocol-defined criteria) cannot 
be determined programmatically, then: 1) if there are only two 6MWTs within 35 days prior to 
randomization, these 6MWTs will be used to calculate the baseline; 2) if there are more than one 
pair of 6MWTs within 35 days prior to randomization, the pair with the most similar distance will 
be used; 3) If <2 6MWT results are available within 35 days of randomization, apply rules 1)-2) 
using all 6MWT data prior to randomization; 4) if only one 6MWT is available after step 3), the 
result of that test will be used as the baseline value. 
Subjects who prematurely discontinue the study will have the 6MWT administered at the time of 
discontinuation. 
 
Observed 6MWT distance values will be utilized if available at Month 30 regardless of 
intercurrent events such as IMP discontinuation, tafamidis initiation, and other protocol deviations. 
Missing data due to reasons other than IMP discontinuation and death will be handled by mixed 
model repeated measures (MMRM) without imputation. For missing data following death, the 
imputation would be performed by sampling with replacement (within treatment arm) from the 
bottom 5% of observed (non-missing) change from baseline values in each arm at a given visit.  
For missing data following IMP discontinuation before the Month 30 visit and while subjects are 
alive, the key secondary analysis will utilize the Jump to Reference (J2R) multiple imputation (MI) 
approach suggested by Carpenter et al. (Carpenter 2013). This method treats intermediate missing 
values separately from monotone missing values. A missing value is said to be intermediate if a 
later response is observed for that subject. The J2R approach imputes intermediate missing values 
under a randomized-arm missing at random (MAR) assumption. Missing values in the acoramidis 
arm for visits after IMP discontinuation will be imputed under the assumption of missing not at 
random (MNAR), utilizing the J2R approach. The J2R imputation will not be used to complete 
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In the J2R approach, the distribution of missing values in 6MWT distance in the acoramidis arm 
other words, missing values for the subjects due to IMP discontinuation in the acoramidis group 
group. In this discussion, the reference group 
is the group of subjects randomized to placebo. Missing data post IMP in the reference group are 
imputed under randomized-arm MAR.  
The generic algorithm utilized by Carpenter et al (Carpenter 2013) and references for SAS code to 
implement the J2R analysis is presented in Appendix 1.3. The model of interest will be based on a 
MMRM analysis. At least one thousand one hundred imputed datasets will be created. The number 
of imputed datasets may be increased above 1100 as needed to improve model performance. 
Analysis will be performed on the imputed 
rule (Rubin 1987). 
The key secondary efficacy endpoint of change from baseline in distance walked during the 
6MWT for the imputed datasets will be analyzed using a MMRM with an unstructured covariance 
matrix. Should the model not converge with an unstructured covariance approach, autoregressive 
(1), compound symmetry and independent covariance structures will be utilized and the approach 
will be change from baseline in 6MWT distance collected by visit. The model will include terms 
for randomization stratification factors (wild vs. mutant genotype, NT-proBNP group, and eGFR 
group), treatment group, time (i.e., visit), and treatment group by time interaction as fixed effects, 
and baseline 6MWT as a covariate. Time will be treated as a categorical variable (i.e., as visit). 
However, if more than 10% of the completed subject visits at Month 30 are outside the protocol 
specified visit window (-7 days), time will be modeled as a continuous measure (i.e., as days).  
Least square means will be displayed for each post-baseline study visit to summarize treatment 
effects over time.  
Details of the data handling method before MMRM is applied in the key secondary analysis is 
summarized in below Table 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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In addition, levels of serum TTR, change from baseline and percent change from baseline in serum 
TTR level will also be summarized by visit and ATTRwt-CM and ATTRm-CM genotype groups. 
Additionally, Box and whisker plots will be presented for serum TTR and percent change from 
baseline in serum TTR overall and by gene mutation genotype. 
 
The proportion of subjects whose TTR level is below 20 mg/dl and within the range of (20 mg/dl, 
40 mg/dl) and greater than 40 mg/dL will also be presented by visit. 
   
The mean of TTR will be plotted over visit using both absolute value of serum TTR and change 
from baseline in serum TTR for subjects whose baseline TTR level is below 20 mg/dl and subjects 
whose baseline TTR level is within the range of [20 mg/dl to 40 mg/dl], separately. 
11.2.4 
All-Cause Mortality by Month 30 
Any death, receiving a heart transplant or a cardiac mechanical assist device (CMAD) recorded up 
to the 30-month duration will be summarized and analyzed as a time to event endpoint in mITT. 
The number and percentage of subjects with All-Cause Mortality events will be summarized by 
treatment group and the subset of death, receiving a heart transplant or a CMAD will also be 
provided. 
The time to All-Cause Mortality will be analyzed using a stratified Cox proportional hazards 
model that includes treatment as an explanatory factor along with baseline 6MWT. P-values and 
confidence intervals for the HR will be based on the Wald statistic (Appendix 1.4). 
Prior to running the Cox proportional hazards model, the overall validity of proportional hazards 
assumption will be examined by graphical methods and model, such as: 
Log (-log) plots; if the assumption holds the curves should be approximately parallel to each 
other.  
Include treatment*log (time) as a factor in the model and test the interaction factor at the 0.05 
significance; non significance (p>0.05) of this factor would suggest proportionality. 
 
In case the stratified Cox model does not converge, then a regular Cox proportional hazards model 
will be used with stratification factors, treatment, and baseline 6MWT as explanatory variables. 
In addition, stratified log-rank test will be performed.  
Treatment differences in the proportion of subjects with All-Cause Mortality will be tested at 
Month 30 with the stratified Cochran-Mantel-Haenszel (CMH) test. 
Sample SAS code(s) are included in Appendix 1.4 
 
11.2.5 
Sensitivity Analyses of the Key Secondary Endpoint(s) 
Sensitivity analyses will be conducted for the key secondary endpoints to examine the impact of 
missing data on interpretation of results. Four approaches to sensitivity analysis will be used: 1) 
Copy increments in reference (CIR); 2) MMRM without imputation; 3) Tipping point analysis; 4) 
MMRM with imputation of missing values occurring during a CV-related hospitalization.  
 
 
 


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All participating subjects will be asked to consent to determination of vital status (alive, death, 
heart transplant, receiving CMAD) at Month 30. Sensitivity analyses will not be performed for 
All-Cause Mortality.  
11.2.5.1 Copy Increments in Reference (CIR) 
This approach utilizes the generic algorithm of Carpenter et al. (Carpenter 2013) as used for the 
key secondary analysis but uses a different assumption as to the trajectory of responses after the 
intercurrent event of discontinuation of IMP. After cessation of IMP, missing 6MWT distance and 
KCCQ score values of subjects in the acoramidis group track that of the mean profile of the 
placebo group, starting from the last value observed for each subject.  
11.2.5.2 MMRM without imputation 
The CFB 6MWT and KCCQ-OS at Month 30 efficacy endpoints will be analyzed using the 
MMRM from the key secondary analysis without imputation of missing values.  
11.2.5.3 Tipping Point Analysis 
If the key secondary analysis has a p-value > 
B for the effect of treatment, two sets of tipping 
point analyses will be conducted on the imputation of missing data due to discontinuation of IMP 
or due to death separately. For each set of the following tipping point analysis, the approaches 
descripted in the key secondary efficacy analysis will be applied except for the imputation method 
for the specific intercurrent event being examined. 
Discontinuation of IMP  
As the assumption of a conservative, immediate J2R in change in 6MWT distance and KCCQ-OS 
at IMP discontinuation is progressively lessened, this analysis will determine if and at which point 
the p-value becomes < 
B. The methodology of Carpenter et al. (Carpenter 2013) used in the key 
secondary analysis will be utilized. After imputation is completed, a fixed non-stochastic amount 
(the delta) is added onto the imputed observations.  
The magnitude of the treatment difference estimated with the J2R approach for each post-baseline 
visit (denoted by 
t, t = 6, 9, 12, 18, 24, 30) from the key secondary analysis will serve as the basis 
for delta adjustment. Subjects in the acoramidis arm with imputed values at visit t (t = 6, 9, 12, 18, 
24, 
t added to the imputed value. The values 
t will progressively increase 
t.  
A total of at least 1100 imputed datasets will be generated. Then, analysis will be performed on 
imputed datasets and the results will be combined using 
Rubin 1987).  
In a similar manner, if the key secondary analysis has a p-value < 
B for the effect of treatment, the 
t subtracted from the imputed values in the 
acoramidis arm. 
 
Death 
Tipping point analysis will also be carried out on imputation strategy for missing data due to death. 
If the p-value from the key secondary analysis has a p-value > 
B, the key secondary analysis will 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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be repeated with missing data following death being imputed by sampling with replacement 
(within treatment arm) from the bottom 10% up to all (in 5% increments) of the observed (non-
missing) change from baseline values in each arm at a given visit. A total of at least 1100 imputed 
datasets will be generated. 
11.2.5.4 Imputation of missing values occurring during a CV-related hospitalization 
In addition to the data handling approaches in the key secondary analysis, imputation of missing 
data due to CV-related hospitalization will be added by replacing missing values occurring during 
a CVH with observations sampled with replacement (within treatment arm) from the bottom 25% 
of the observed (non-missing) change from baseline values in each arm at a given visit. Missing 
data is considered during CVH if 
-missing assessment within the same analysis visit window. 
11.2.6 
Supplementary Analyses of the Key Secondary Endpoint(s) 
Supplementary analyses of the key secondary endpoint(s) will be conducted to address 
concomitant tafamidis permitted after 12 months. 
The key secondary efficacy analyses will be repeated in mITT set using both hypothetical strategy 
and principal stratum strategy, as defined in Section 11.1.3.1 and Section 11.1.3.2. 
11.2.6.1 Time Dependent Covariate Cox proportional hazards model for All-Cause Mortality  
To examine the introduction of tafamidis to the study treatments, cox proportional hazards model 
for the All-Cause Mortality with the randomized study treatment (acoramidis and placebo) will be 
performed, however, now with the addition of the time dependent covariate for introduction of 
tafamidis.  
11.2.6.2 Analyses on ITT Population  
The analyses planned for All-Cause Mortality will be repeated on the ITT population. 
11.3 
Other Secondary Endpoints 
Additional secondary endpoints, not adjusted for alpha are:  
11.3.1 
Hierarchical combination of All-Cause Mortality, CV-related hospitalization and 
CFB in 6MWT over a 30-month period 
The F-S method will be used as done for the primary efficacy endpoint to analyze the hierarchical 
combination endpoint of All-Cause Mortality, cumulative frequency of CV-related hospitalization, 
and CFB in 6MWT over the 30-month duration of the trial.  
The analyses will be conducted in mITT population. 
11.3.2 
Hierarchical combination of All-Cause Mortality and CV-related hospitalization 
over a 30-month period 
The F-S method will be used as done for the primary efficacy endpoint to analyze the hierarchical 
combination endpoint of All-Cause Mortality, and cumulative frequency of CV-related 
hospitalization over the 30-month duration of the trial.  
 
To evaluate the robustness of F-S test due to ties in pairwise comparison, Win Odds (Brunner, 
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The analyses will be conducted in mITT population. 
11.3.3 
Cardiovascular mortality by Month 30 
Any all-cause mortality adjudicated by the CEC as due to a cardiovascular or undetermined cause 
up to the 30-month duration will be summarized and analyzed as a time to event endpoint. For 
cardiovascular mortality, subjects who died for non-cardiovascular reasons will be designated as 
censored at the time of death. The same analytic methods as for All-Cause Mortality will be used. 
11.3.4 
Cumulative frequency of cardiovascular-related hospitalization by Month 30 
Cumulative frequency of CEC adjudicated CV-related hospitalization will be analyzed using 
negative binomial regression analysis with treatment, the three stratification factors and an offset 
cluded in the model. If the number of subjects 
with zero CV-related hospitalization is high, a zero inflated negative binomial model will be 
performed to provide further assurance of the results.  
Stratified Cochran-Mantel-Haenszel (CMH) row means scores tests will be used to analyze the 
frequency of CEC adjudicated cardiovascular-related hospitalizations by treatment. 
Sample SAS code is included in Appendix 1.4 
 
Additionally, CV-related hospitalization will be summarized by adjudicated attributed categories.  
11.3.5 
TTR Stabilization Measured in Established Ex-Vivo Assays (Fluorescent Probe 
Exclusion (FPE) and Western Blot (WB)) in the PK-PD substudy 
In the PK-PD sub-study, ex vivo TTR stabilization will be assessed through Fluorescent Probe 
Exclusion (FPE) percent stabilization and Western Blot (WB) percent stabilization. Only subjects 
with sufficient data to calculate TTR stabilization will be included in the following analyses. 
FPE is a competitive binding assay measuring occupancy of TTR's thyroxine (T4) binding site. For 
each sample, FPE reading is measured in triplicate for every 15 min up to 6 hours. The 
measurement points are pre-
78 data points). FPE data will be tabulated for time: Y=60 mins for all visits. FPE percent 
stabilization, at Day X will be derived as follows (using the mean of the triplicates): 
 
where Day 1 represents the last sample prior to first dose of study drug. 
The WB is a measure of a bound ligand's ability to prevent the accelerated dissociation of 
tetrameric TTR under acidic denaturing conditions. WB data will be tabulated for all visits. WB 
percent stabilization at Day X will be derived as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
    
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  


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Summary statistics of FPE and WB percent stabilization at each visit will be presented. Treatment 
differences in the FPE and WB percent stabilization at each visit will be presented in graphs for 
wild/mutant genotype TTR. The distribution of TTR stabilization (FPE and WB) at each visit will 
be displayed using box and whisker plots. At 
by treatment groups for wild/mutant TTR and overall. The FPE 
rate constant will be presented for each visit for each subject (Equation for deriving Rate Constant 
is shown in Section 11.4.3).  
summarized by visit and will be tested at Month 30 nominally (without alpha control) with the 
CMH statistic (2-sided, alpha = 0.05) adjusting for wild/mutant genotype TTR, NT-proBNP group, 
and eGFR group. In addition, the proportion of subjects who maintain > 90% stabilization at 
Month 30 after achieving >90% stabilization at Day 28 will be summarized descriptively by 
treatment group.  
Summary statistics of TTR stabilization will be presented for ATTRwt-CM and ATTRm-CM 
genotype groups. Summaries of quality control samples will be reported for FPE and Western Blot 
analyses.      
11.3.6 
Change from baseline in N-terminal pro-Brain-type Natriuretic Peptide (NT-
proBNP) 
The change from baseline in NT-proBNP to the Month 30 visit will be examined. The analytic 
method utilized in the analysis of the key secondary endpoint(s) will be repeated for NT-proBNP.  
If the normality assumption is violated, the log-transformed NT-proBNP will be used in the 
MMRM model. The estimated geometric means for the ratio of NT-proBNP to baseline levels and 
their 95% confidence intervals will also be provided based on the MMRM model. 
11.3.7 
Supplementary Analyses for Other Secondary Endpoints  
11.3.7.1 Hypothetical Strategy 
Supplementary analyses for other secondary endpoint(s) will be done to address concomitant 
tafamidis permitted after 12 months. The analytic method used for their primary analyses will be 
repeated, within the mITT set, using the hypothetical strategy as defined in Section 11.1.3.1. 
11.3.7.2 Principal Stratum Strategy  
Supplementary analyses for other secondary endpoint(s) to address concomitant tafamidis 
permitted after 12 months will also be done using the primary analyses methods along with 
principal stratum strategy as defined in Section 11.1.3.2 within the mITT set.  
11.3.7.3 Time Dependent Covariate Cox proportional hazards model for the cardiovascular 
mortality or first CV-related hospitalization 
To examine the introduction of tafamidis to the study treatments, cox proportional hazards model 
for the cardiovascular mortality or the first CV-related hospitalization with the randomized study 
treatment (acoramidis and placebo) will be performed, however, now with the addition of the time 
dependent covariate for introduction of tafamidis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.3.7.4 Analyses on ITT Population  
The analyses planned for cardiovascular mortality (Section 11.3.3) will be repeated on the ITT 
population. 
11.4 
Exploratory Endpoints 
11.4.1 
Change from baseline in Troponin I (TnI) 
TnI may be summarized descriptively and will be analyzed separately for each assay used. For 
subjects whose TnI results were obtained with the same assay for all time points starting with 
baseline, descriptive summaries of observed value and change from baseline may be provided. The 
proportion of subjects with Troponin I values not detectable (below the lower limit of 
quantification), and summary statistics for assays above that threshold will be presented. 
11.4.2 
Change from baseline in the EuroQol Health Outcomes Assessment tool (EQ-5D-
5L)  
The EQ-5D-5L is a brief, self-administered generic health status instrument that takes about 5 
minutes to complete and per protocol should be conducted after completion of the KCCQ. The 
instrument includes two parts. In the first part, respondents are asked to rate their current health 
state on 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or 
depression) with each dimension having five levels of function (1-no problem, 2-slight problem, 3-
moderate problem, 4-severe problem, and 5-
self-
cores 
from the 5 dimensions may be used to calculate a single index value, also known as a utility score. 
Complete details of administration and scoring are provided in the Study Procedures Manual. 
Data from the EQ-5D-5L will be examined in three ways: 
1. 
 
summarized descriptively as the proportion of subjects within a category. The approach of 
Devlin 2010 will be used. Health status change between time periods is classified into one 
of four categories based on the scores in each health state dimension over time: 
a. Their health state is better (i.e., better on at least one dimension and is no worse in 
any other dimension). 
b. Their health state is worse (i.e., worse in at least one dimension and no better in any 
other dimension). 
c. Their health state is exactly the same (i.e., same state on each dimension). 
d. 
 
2. Descriptive statistics for the VAS will be presented. The analysis utilized for the key 
secondary endpoint will be repeated for the change from baseline in the VAS response. 
3. Descriptive statistics for the index score will be presented. The analysis utilized for the key 
secondary endpoint will be repeated for the change from baseline in the index score 
response. 
For the VAS and the index score, the sensitivity analyses described for the key secondary endpoint 
(excluding the tipping point analysis) will be used to explore the sensitivity of conclusions to 
missing values.  
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.4.3 
PK-PD Analysis 
The FPE rate constant will be tabulated for each subject in the PK-PD substudy with sufficient 
data for analysis for all visits.   
The rate constant k is derived as follows: The mean values of the triplicate (duplicate when 
triplicate values are not available) of full 6hr FPE time course measurements Relative 
Fluorescence Units (RFU) are fitted with the following equation.  
Fluorescence (RFU) = offset + A(1  e(-k*t)) 
where: 
t is the time of fluorescence measurement, in minutes,  
k is the rate constant, expressed in 1/minutes, determined by the fit,  
A is the amplitude, expressed in RFU, determined by the fit, and 
Offset is determined by the fit, expressed in RFU. 
For PK-PD correlation analysis, the PD results (Serum TTR, FPE percent stabilization, FPE rate 
constant, and WB percent stabilization) will be plotted against PK measurements (plasma 
acoramidis concentration) overall and by genotype (ATTRwt-CM/ATTRm-CM). PK-PD 
correlation analysis will be done by wild/mutant genotype and overall. The FPE rate constant and 
the plasma acoramidis concentration will also be tabulated by subject by visit. In addition to the 
FPE rate constant, RFU will be evaluated by linear regression over the first hour for each subject. 
11.4.4 
PK Analysis 
Plasma concentration of acoramidis will be summarized at each timepoint by treatment group for 
subjects in the PK-PD substudy with sufficient data for analysis. In addition, plasma acoramidis 
concentration will be listed for individual subjects for each timepoint. Concentration will be 
reported for steady state predose except for the Day 28 1 hour post-dose measurement.   
11.4.5 
Other Exploratory Endpoints 
The analysis of the other exploratory endpoints will be performed outside of this statistical analysis 
and may be reported in a separate report. 
11.5 
Multiplicity Adjustment 
To control B, the following efficacy endpoints will be formally tested sequentially in the order 
specified below:  
 The primary efficacy endpoint  
 Change from baseline to Month 30 in 6MWT  
 Change from baseline to Month 30 in KCCQ-OS  
 Change from baseline to Month 30 in serum TTR level  
 All-Cause Mortality by Month 30 (stratified cox proportional hazard model) 
In this hierarchical approach, except for the primary efficacy endpoint, an endpoint will only be 
formally tested if the previous endpoint is statistically significant at the 
B level (p-
B). 
If an endpoint is not statistically significant at the 
B level (p-value is > B), the statistical tests 
corresponding to all subsequent endpoints will be considered not statistically significant. 
Multiplicity adjustment will apply to primary efficacy endpoint and key secondary endpoints only. 
The multiplicity procedure will be applied to the mITT analysis set only.  
 
 
 
 
 
 
 
 
 
 
  


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12. 
SAFETY EVALUATIONS 
One of the secondary objectives in Part B is to assess the safety and tolerability of acoramidis 
administered for 30 months in subjects with symptomatic ATTR-CM. Safety and tolerability of 
acoramidis will be assessed within the safety population unless stated otherwise. Safety parameters 
to be assessed include treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAEs 
leading to IMP discontinuation, abnormal physical exam findings of clinical relevance, abnormal 
vital signs of clinical relevance, abnormal electrocardiogram (ECG) parameters of clinical 
relevance, and changes in clinical safety laboratory parameters of clinical relevance. Safety 
analyses will be conducted in the safety analysis population by actual treatment received. A subject 
that takes at least one dose of acoramidis will be presented in the acoramidis actual treatment 
group.  
 
Analysis 
2) at screening will be conducted for 
summaries of TEAEs, clinical laboratory parameters, liver function tests, vital signs, and ECG.   
12.1 
Adverse Events  
Adverse event (AE) 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary (version 23.1 or newer). For 
the purpose of data collection for this study, any untoward event that is reported from the time that 
the subject signs the ICF until 30 days after the last dose of IMP is to be considered an AE.  
An AE (classified by preferred term (PT)) that occurs during the treatment period will be 
considered a TEAE if it was not present before the first dose of IMP or if it was present before the 
first dose of IMP but increased in severity during the treatment period. Conservatively, if an AE 
occurs in the same date as the first IMP date, then it will be considered a TEAE. All AEs included 
in the adverse event summaries are treatment emergent. 
A subject level summary table of TEAE characteristics by treatment will be presented. This table 
will include: 
Subjects who experienced at least one TEAE 
Serious TEAE: Subjects who had at least one treatment emergent serious adverse event (SAE) 
meeting a seriousness criterion (death, life threatening, requires or prolongs hospitalization, 
persistent or significant disability/incapacity, congenital anomaly or birth defect, important 
medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based on appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition). 
TEAE with fatal outcome: Subjects who had a TEAE with an outcome of death 
TEAE resulting in permanent IMP discontinuation: Subjects who had at least one TEAE with 
an action taken regarding IMP discontinuation 
TEAE related to IMP: Subjects who had at least one TEAE indicated as related to IMP as 
assessed by the investigator 
Severe TEAE: Subjects who had at least one TEAE with a severity of severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The incidence of each TEAE will also be summarized by system organ class (SOC), PT and 
treatment assignment. Additionally, the incidence of each TEAE will also be summarized by SOC, 
PT, severity, and treatment assignment. Multiple AEs mapped to the same PT will be counted once 
per subject though the number of events per PT may also be presented.  
The incidence table of TEAE, serious TEAE and related TEAEs by PT or SOC, respectively, in 
descending order will also be provided. A similar summary of most frequent TEAEs by PT will be 
provided. Appropriate summaries will be repeated for serious TEAEs, IMP related TEAEs, TEAEs 
leading to discontinuation of IMP and TEAEs leading to fatal outcome. Additionally, exposure-
adjusted (patient-years) event rate will be summarized for TEAE, Serious TEAE and related 
TEAEs by SOC, PT and treatment assignment.  
 
A listing displaying TEAEs leading to fatal outcome will be generated. TEAEs and non-treatment 
emergent AEs will be provided in a listing.  
 
Additionally, Kaplan Meier plot will be presented for TEAEs leading to fatal outcome. 
12.2 
 Physical Exam, Vital Signs, ECG, Clinical Laboratory Parameters  
Safety laboratory findings, vital signs, and 12-lead ECGs will be summarized (including figures) 
and listed by treatment group and visit. Values and changes from baseline at scheduled time points 
will be summarized.   
Descriptive summaries of observed values and changes from baseline will be provided for 
numerical laboratory assessments by visit based on International System of Units (SI). If a result 
2. If 
laboratory results will be summarized by frequency and percentage and by visit. 
Laboratory values will also be represented in shift tables from baseline to worst post-baseline and 
from baseline to last post-baseline values. An additional listing of laboratory abnormalities will be 
provided.   
The number and proportion of subjects with liver test elevations will be presented by treatment 
group. Liver test elevations are assessed by using post-baseline results for ALT, AST, ALP, and 
total bilirubin based on the definitions presented in the following table. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 




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Proportion of subjects with QRS duration >120 msec and change from baseline >25% (of baseline 
observed value) by treatment group and by timepoint/visit including Day 28 pre-dose and Day 28 
post dose. These will also be presented as worst post-baseline values. 
12.3 
Covid-19 Related 
Any important deviations from the protocol related to Covid-19 as reported will be summarized 
overall and by treatment.A listing will be generated including all protocol deviations related to 
COVID 19. COVID-19 impact on: visits, IMP and Study Completion, Six Minute Walk Test 
(6MWT) Assessments and Adverse Events of COVID-19 will be summarized overall and by 
treatment. Listings of all subjects recorded as impacted by COVID-19 (related to visit completion, 
early study or IMP discontinuation, inability to complete 6MWT, missed IMP doses, or any 
reported adverse events of COVID-19) will also be provided as appropriate. Standardized 
MedDRA Queries (SMQs) will be utilized to summarize COVID-19 events.  
12.4 
Database Sources 
The ATTRibute-CM clinical database will be housed in RAVE EDC (Electronic Data Capture) 
hosted by 
 In addition, 
 will obtain the central laboratory data from 
and 
 
 the central ECG data from ERT Clinical, PK and PD data from 
 
and 
 and the CEC data from central adjudication vendor.  
The central laboratory, Clinical Trial Management System (CTMS), ECG and CEC data will be 
transferred to the
will obtain unblinded 
randomization data collected in the Interactive Web Response System (IWRS), from
 after 
the Month 30 data are locked for analysis.  
Hence, the data used for analysis will include but may not be limited to the below 9 main sources:  
1. the Interactive Web Response System (IWRS),  
2. the eCRF/RAVE EDC, 
3. CTMS,  
4. the central laboratory,  
5.
 
6. central ECG,  
7. PK and   
8. PD data and  
9. the clinical events committee (CEC) database.  
Data from the IWRS will be used to determine treatment assignment. The eCRF will be the source 
for site-level geographic information, all baseline and follow-up data, and will also contain the 
6MWT and KCCQ data entered by the sites. CTMS will be used for site information. The central 
laboratory will provide all laboratory data including prealbumin. The ECG data will be provided 
by a separate laboratory. The CEC will provide adjudicated endpoints for primary analyses. 
13. 
SUBGROUP ANALYSIS 
Descriptive subgroup analyses will be conducted for randomization stratification factors for the 
primary endpoint, the components of the primary endpoint, and for the key secondary endpoints. 


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These factors include ATTRm-CM or ATTRwt-CM type, NT-
2) at screening.   
In addition to the stratification variables, subgroup analyses will be conducted for age (< 78 and 
> 78 years), country of enrollment (United States vs. rest of world) and NYHA class at baseline (I 
or II vs. III). Subgroup analyses for the primary endpoint will be done by using the F-S method 
same as for the primary efficacy analysis. For the key secondary endpoints, the subgroup analyses 
will be performed using the same analyses models as for those endpoints, with the addition of the 
subgroup factor, subgroup x treatment and subgroup x time and subgroup x time x treatment 
interaction terms. 
In addition, summary statistics may be tabulated by subgroups for selected endpoints.  
14. 
SUMMARY OF CHANGES FROM PROTOCOL 
The following changes from Protocol Amendment 6 are reflected in the SAP version 3.0: 
 Assessing circulating prealbumin (transthyretin, TTR) concentration as an in vivo 
biomarker of stabilization has been removed in Other Secondary Objectives. The objective 
has been promoted to Key Secondary Objectives.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15. 
REFERENCES 
Brunner, Edgar, Marc Vandemeulebroecke, and Tobias Mütze. Win odds: An adaptation of the 
win ratio to include ties. Statistics in Medicine (2021).  
Carpenter, James R., James H. Roger, and Michael G. Kenward. Analysis of longitudinal trials 
with protocol deviation: a framework for relevant, accessible assumptions, and inference via 
multiple imputation. Journal of biopharmaceutical statistics 23.6 (2013): 1352-1371. 
Devlin, Nancy J., David Parkin, and John Browne. "Patient
reported outcome measures in the 
NHS: new methods for analysing and reporting EQ
5D data." Health economics 19.8 (2010): 
886-905.  
Finkelstein, Dianne M., and David A. Schoenfeld. Combining mortality and longitudinal measures 
in clinical trials. Statistics in medicine 18.11 (1999): 1341-1354. 
Judge, Daniel P., et al. "Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid 
cardiomyopathy." Journal of the American College of Cardiology 74.3 (2019): 285-295.  
McCullagh, P., and Nelder, J. (1989). Generalized Linear Models, Second Edition, Chapman Hall 
Maurer, Mathew S., et al. Tafamidis treatment for patients with transthyretin amyloid 
cardiomyopathy. New England Journal of Medicine 379.11 (2018): 1007-1016. 
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012 Jan;33(2):176-
82. 
Rubin DB. Multiple imputation for nonresponse in surveys. 1987; John Wiley, New York. 
fallback procedure for evaluating a single family of 
 Journal of biopharmaceutical statistics vol. 15,6 (2005): 929-42. 
 
 
 
 
 
 
 
 
 
 
 




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3. Stratified 
log-rank test 
using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
3. Stratified log-
rank using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
4. Time dependent 
covariate Cox 
model 
5. The primary 
analytic methods 
will also be 
repeated in ITT. 
Other 
Secondary 
 
Combination 
All-Cause 
Mortality, CVH   
and CFB in 
6MWT over 
Month 30 
F-S 
 
1. F-S analysis 
repeated* using 
both Hypothetical 
strategy and 
Principal stratum 
strategy 
Combination 
All-Cause 
Mortality and 
CVH over 
Month 30 
F-S 
 
1. Win odds 
1. F-S analysis 
repeated* using 
both Hypothetical 
strategy and 
Principal stratum 
strategy 
2. Time dependent 
covariate Cox 
model for 
composite of ACM 
or first CVH 


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CV-related 
Mortality by 
Month 30 
1. Cochran-
Mantel-
Haenszel 
2. Cox 
proportional 
hazards 
model 
adjusted for 
stratification 
factors 
3. Stratified 
log-rank test 
  
1. Cochran-Mantel-
Haenszel repeated* 
using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
2. Cox model adj. 
for stratification 
factors repeated* 
using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
3. Stratified log-
rank using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
4. Time dependent 
covariate Cox 
model 
5. The primary 
analytic methods 
will also be 
repeated in ITT. 
CVH Frequency 
1. Negative 
Binomial 
regression 
analysis with 
treatment, 
and an offset 
term (log of 
study 
duration) 
2. CMH row 
mean scores 
3. Zero-
inflated 
Negative 
Binomial 
model 
1. Negative 
Binomial 
regression with an 
offset term (log of 
study duration) 
repeated* using 
both Hypothetical 
strategy and 
Principal stratum 
strategy 
2. CMH row mean 
scores repeated* 
using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 


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TTR 
Stabilization via 
FPE at Month 
30 (PK-PD 
substudy) 
 
Cochran-
Mantel-
Haenszel 
 
 
Cochran-Mantel-
Haenszel repeated* 
using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
TTR 
Stabilization via 
Western Blot at 
Month 30 (PK-
PD substudy) 
Cochran-
Mantel-
Haenszel 
 
 
Cochran-Mantel-
Haenszel repeated* 
using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
 
CFB to Month 
30 in NT-
proBNP 
MMRM with 
an 
unstructured 
covariance 
matrix using 
J2R MI 
approach 
 
 
 
MMRM with an 
unstructured 
Covariance matrix 
using J2R MI 
approach repeated* 
using both 
Hypothetical 
strategy and 
Principal stratum 
strategy 
Note: Exploratory endpoints are not included in this overview. 
* KM plots and CIF plots by treatment and by concomitant tafamidis grouping will be created for 
all components of endpoints and for time to All-Cause Mortality or first CVH. 
**Concomitant tafamidis grouping is defined in Section 3:  
acoramidis only 
placebo only 
acoramidis+tafamidis 
placebo+tafamidis 
 
 
 
 
 




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assessments. For example, Subject A has last visit at Month 12 and Subject B has last visit at 
Month 24, non-missing assessments from Month 12 will be used for comparison.  


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Appendix 1.3 Generic algorithm from Carpenter et al. (2013) 
 
1. Separately for each treatment arm, take all subject
-deviation data and
assuming 
MAR
fit a multivariate normal distribution with unstructured mean (i.e., a separate mean 
for each of the 1+J baseline plus post randomization observation times) and unstructured 
variance covariance matrix (i.e., a (1+J)×(1+J)covariance matrix) using a Bayesian 
approach with an improper prior for the mean and an uninformative Jeffreys prior for the 
variance covariance matrix (Schafer, 1997, p. 155). 
2. Separately for each treatment arm, draw a mean vector and variance covariance matrix 
from the posterior distribution. 
3. For each subject who deviates before the end of the study, use the draws from step 2 to 
build the joint distribution of that subject  pre- and postdeviation outcome data assuming 
J2R (CIR for sensitivity analysis). 
4. For each subject who deviates before the end, use that 
joint distribution in step 3 
to construct the conditional distribution of post deviation given pre deviation outcome data. 
data set. 
5. Repeat steps 2 4 K times, resulting in K imputed data sets. 
6. Fit the model of interest to each imputed data set, and combine the resulting parameter 
 
 
SAS macro code to complete the above imputations can be accessed at www.missingdata.org.uk. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1.4 Sample SAS codes for key secondary and other endpoints. 
Sample SAS code to fit the MMRM specified for the key secondary sensitivity analysis. The 
response variable Y is the change from baseline at the Month 30 visit. 
 
The response variable Y is the change from baseline at the study visits. 
PROC MIXED DATA=xxx  
METHOD=REML; 
CLASS pid trt visit genotype ntbnpgrp gfrgrp; 
MODEL y= ybase trt visit genotype ntbnpgrp gfrgrp trt*visit / S; 
REPEATED visit /SUBJECT= pid r type=UN; 
LSMEANS trt*visit / PDIFF; 
RUN;  
Note: y = change from baseline, ybase = baseline value, trt = treatment, ntbnpgrp = NT-proBNP   
group, gfrgrp = eGFR group 
 
Sample SAS code for the time to event analysis is given below. 
PROC LIFETEST DATA=xxx PLOTS=(s) graphics; 
TIME days*status(0); 
STRATA trt; 
RUN; 
 
 
PROC PHREG DATA=xxx; 
CLASS trt (ref=< >) genotype (ref= < >) renal_function (ref= < >) NT_proBNP (ref= < >); 
MODEL days*status(0)=trt / ties=EXACT; 
STRATA genotype renal_function NT_proBNP; 
RUN 
 
Sample SAS code for the Negative binomial regression: 
PROC DATA=xxx; 
ln_days=log(studydays);* log transformation to normalize duration of participation ; 
RUN; 
 
PROC GENMOD DATA=xxx; 
CLASS TRT(REF
GENOTYPE
1  
; 
  
 
 
  
 
  


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MODEL CVHNUM = TRT GENOTYPE NTBNP RENFUN / DIST=NEGBIN LINK=LOG 
OFFSET=ln_days; 
    
ESTIMATE 'RR' TRT 1 -1/EXP; 
run; 
 
Sample SAS code for the Cochran Mantel-Haenszel test: 
 
PROC FREQ DATA=xx; 
TABLES TRT*STATUS / CMH 
RUN; 
 
 


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Appendix 1.5 Missing Date Handling   
1.  Missing Date Information for Adverse Events 
The following imputation rules apply to cases in which the start date is incomplete (i.e., partly 
missing) for Adverse Events (AEs) stop date and end date are used interchangeably in this 
document. An AE will be considered treatment-emergent if the entered data (e.g., the answer to 
-
eCRF page) and/or the imputed data meet the treatment-emergent criteria. 
A. 
For AEs that occurred prior to the first dose (ie, the answer 
first dose for the AG10-
 
Missing Day and Month 
 If the year is the same as the year of the date of informed consent, the day and month of the 
date of informed consent will be assigned to the missing fields. 
 If the year is prior to the year of the date of informed consent, December 31 will be 
assigned to the missing fields. 
 If the year is after the year of the date of informed consent, January 1 will be assigned to 
the missing fields. 
Missing Month Only 
 The day will be treated as missing, and both month and day will be replaced according to 
the above procedure. 
Missing Day Only  
 If the month and year are the same as the month and year of the date of informed consent, 
the date of informed consent will be assigned to the missing day. 
 If either the year is before the year of the date of informed consent or if both years are the 
same but the month is before the month of the date of informed consent, the last day of the 
month will be assigned to the missing day. 
 If either the year is after the year of the date of informed consent or if both years are the 
same but the month is after the month of the date of informed consent, the first day of the 
month will be assigned to the missing day. 
If the stop date is complete and it is before the date of first dose of IMP and the imputed start date 
as above is after the stop date, the start date will be imputed by the stop date. If the stop date is 
complete and it is on or after the date of first dose of IMP and the imputed start date as above is 
after the stop date, the start date will be imputed by the date immediately before the date of first 
dose of IMP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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If the start date is completely missing, the date of informed consent will be used to impute the start 
date. 
B. 
first dose for the AG10-
 
Missing Day and Month 
 If the year is the same as the year of the date of the first dose of IMP, the day and month of 
the date of the first dose of IMP will be assigned to the missing fields. 
 If the year is prior to the year of the date of the first dose of IMP, December 31 will be 
assigned to the missing fields. 
 If the year is after the year of the date of the first dose of IMP, January 1 will be assigned to 
the missing fields. 
Missing Month Only 
 The day will be treated as missing, and both month and day will be replaced according to 
the above procedure. 
Missing Day Only 
 If the month and year are the same as the month and year of the date of the first dose of 
IMP, the date of the first dose of IMP will be assigned to the missing day. 
 If either the year is before the year of the date of the first dose of IMP or if both years are 
the same but the month is before the month of the date of the first dose of IMP, the last day 
of the month will be assigned to the missing day. 
 If either the year is after the year of the date of the first dose of IMP or if both years are the 
same but the month is after the month of the date of the first dose of IMP, the first day of 
the month will be assigned to the missing day. 
If the stop date is complete and the imputed start date as above is after the stop date, the start date 
will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date: 
 If the stop date is on or after the date of the first dose of IMP, the date of the first dose of 
IMP will be assigned to the missing start date. 
 If the stop date is before the date of the first dose of IMP, the stop date will be assigned to 
the missing start date. 
If the start date is completely missing and the stop date is partial, the following algorithm will be 
used to impute the start date. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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 If there is enough information to determine that the stop date is after the date of the first 
dose of IMP, the date of the first dose of IMP will be assigned to the missing start date.  
 If there is enough information to determine that the stop date is before the date of the first 
dose of IMP, the informed consent date will be assigned to the missing start date.   
If the start date is completely missing and the stop date is either missing or lacks sufficient 
information to determine whether it is before or after date of first dose of IMP, the start date will 
be imputed as date of first dose of IMP. 
2. Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, incomplete (i.e., partly missing) start date will be imputed. 
Medications with missing end date will be treated as ongoing. Partially missing end date will not 
be imputed. The following rules will be applied to impute the missing or incomplete start date. If 
the end date is complete and the imputed start date is after the stop date, the start date will be 
imputed as the end date. 
If all day, month, and year of the start date of medication are missing and end date is after the first 
dose date or ongoing, the medication will be considered as concomitant medication.   
Missing Day and Month 
 If the year of the incomplete start date is the same as the year of the date of the first dose of 
IMP, the day and month of the date of the first dose will be assigned to the missing fields. 
 If the year of the incomplete start date is prior to the year of the date of the first dose of 
IMP, December 31 will be assigned to the missing fields. 
 If the year of the incomplete start date is after the year of the date of the first dose of IMP, 
January 1 will be assigned to the missing fields. 
Missing Month Only 
 The day will be treated as missing, and both month and day will be replaced according to 
the above procedure. 
Missing Day Only 
 If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of IMP, the day of the date of the first dose will be assigned to the 
missing day. 
 If either the year is before the year of the date of the first dose of IMP or if both years are 
the same but the month is before the month of the date of the first dose of IMP, the last day 
of the month will be assigned to the missing day. 
If either the year is after the year of the date of the first dose of IMP or if both years are the 
same but the month is after the month of the date of the first dose of IMP, the first day of 
the month will be assigned to the missing day. 
 
 
 
 
 
 
 
 


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Addendum to Statistical Analysis Plan  
Study AG10-301 (Part B) 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety 
of Acoramidis (AG10) in Subjects with Symptomatic Transthyretin Amyloid 
Cardiomyopathy (ATTRibute-CM Trial) 
SAP Addendum Version: 1.0 Effective:  30 June 2023 
SAP Version: 3.0 Effective: 03 August 2022 
Protocol Date: 16 June 2022   Version: Amendment 6.0 
Sponsor: Eidos Therapeutics, Inc. 
 
 
 
 
 




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1. Section 3 General Analysis Considerations  
 For the purpose of Month 30 efficacy analysis of ACM and CVH, it is defined as up to 907 
days. This is based on operational scheduled Month 30 clinical visit on Day 900 
(Randomization Date +899 Days) plus a 7-day window.  
 Subjects without ACM event will be censored at the Min[Last known alive date, Day 907] 
for the ACM component in the primary analysis and survival analyses. 
 For efficacy analysis of CV-related hospitalizations, the first dose of IMP date was used as 
reference date for calculation of CV-related hospitalization frequency. Modification is 
made to use the randomization date instead to be consistent with study day derivation for 
efficacy analysis. CV-related hospitalization frequency is calculated for the period of (the 
earlier date of (last dose date +30 days) or Day 907 or ACM date for subjects with ACM or 
Last known alive date - randomization date +1).  
 The intent-to-treat population (ITT) is defined as all randomized subjects who have 
received at least one dose of IMP and have at least one post baseline efficacy evaluation 
including 6MWT, KCCQ, EQ-5D-5L, NT-proBNP, Troponin-I, serum TTR, ACM 
(survival status) and CVH.   
 Revised target study days in Section 3.3 Visit Widows for Analysis to be better aligned 
with operational targeted clinical visit dates. No changes to lower bounds and upper bounds 
of corresponding analysis window.  
 
Visit 
Target Study Day 
Baseline 
≤ 1* 
Day 28 
28 
Month 3 
90 
Month 6 
180 
Month 9 
270 
Month 12 
360 
Month 15 
450 
Month 18 
540 
Month 21 
630 
Month 24 
720 
Month 27 
810 
Month 30 
900 
 
*: The day of treatment is used, unless if the first IMP dose is taken on a later date of the protocol scheduled Day 1 
visit, for which both time and date of the first IMP dose will be used as the window threshold. 


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2. Section 11 Efficacy Evaluations 
 For clarifications of footnote 1 and footnote 2 in Figure 2:  
o In pairwise comparison (FS-test, Win Ratio and Win odds) of NT-proBNP at a given 
visit, subject with smaller change from baseline value by a margin of 500 pg/mL wins, 
and if the difference in change from baseline values between the two subjects is less 
than 500 pg/mL, the comparison would be considered as a tie. In pairwise comparison 
of 6MWT at a given visit, subject with larger change from baseline value wins, and if 
the two subjects have the same change from baseline values, the comparison would be 
considered as a tie. 
 In Section 11.1.1, in case Win Ratio equals to 1, the standard error of log (Rw) will be 
derived using asymptotic method (Dong 2018).    
 In Section 11.2.1, missing value will be imputed by sampling with replacement from the 
bottom 5% of observed CFB values in the corresponding arm at a given visit due to 
intercurrent event of death. Bottom refers to the worst change from baseline.   
 In Section 11.1.2.2 Imputation for Missing Data in CFB NT-proBNP and CFB 6MWT, if 
the subject did not discontinue the IMP early and had missing measurements due to CVH, 
then the missing measurements will be imputed by resampling from the bottom 25% in the 
same arm at a given visit. It should be CVH instead of CV-related AE. Bottom refers to the 
worst change from baseline.   
 In Section 11.1.2.3 Multiple Imputation Methods for CV-related hospitalization, for the 
comparison of CVH in FS-Test, calculated rate after imputation between two subjects will 
be compared in this sensitivity analysis. Added Appendix 1.6 for imputation details.  
 In Section 11.1.3, Section 11.2.6 and Section 11.3.7, supplementary analyses were 
proposed for primary endpoint, key secondary endpoints, and other secondary endpoints. 
While Tafamidis use is only allowed after 12 months, there are subjects who initiated 
Tafamidis after randomization and before 12 months. Even though these subjects are 
protocol deviations, these subjects will still be included for the efficacy analysis. Tafamidis 
use from randomization till ACM event date for subjects with ACM events or Min[Last 
known alive date, Day 907] for subjects without ACM events will be included in analysis. 
 In section 11.2.5.4, for imputation of missing values occurring during a CV-related 
hospitalization, missing data is considered during CVH if the targeted visit day +/- 7 days 
window overlaps with the subject’s CVH(s) stay and there’s no other missing reason due to 
death or IMP discontinuation. In case the CVH discharge date is missing, only CVH 
start/admission date will be compared with the targeted visit day +/- 7 days window for 
overlapping.  
 In Section 11.3.3 Cardiovascular mortality by Month 30, it is stated that any all-cause 
mortality adjudicated by the CEC as due to a cardiovascular or undetermined cause up to 
the 30-month duration will be summarized and analyzed as a time to event endpoint. For 
this analysis, receiving a heart transplant (HT) or a cardiac mechanical assist device 
(CMAD) will be treated as cardiovascular mortality. Same rule will also apply to Section 
11.3.7.3 Time Dependent Covariate Cox proportional hazards model for the cardiovascular 
mortality or first CV-related hospitalization and Section 11.3.7.4 Analyses planned for 
cardiovascular mortality on ITT Population. Additionally, a summary of CV Death Type 
Classification per CEC adjudicated results will be provided. 


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 In Section 11.3.6, for analysis of change from baseline in N-terminal pro-Brain-type 
Natriuretic Peptide (NT-proBNP), if the normality assumption is violated, the log-
transformed NT-proBNP will be used in the MMRM model. The estimated geometric 
means for the ratio of NT-proBNP to baseline levels and their 95% confidence intervals 
will also be provided based on the MMRM model. 
 In Section 11 efficacy evaluation, added exploratory analyses of 6MWT, KCCQ, NT-
proBNP, EQ-5D-5L. Results from the MMRM analysis at each individual time point other 
than month 30 will be included. Additional exploratory analyses of 6MWT, KCCQ, NT-
proBNP will include results from the MMRM analysis at each individual time point by 
treatment group, ATTRm-CM or ATTRwt-CM type, NT-proBNP level (≤3000 vs >3000 
pg/mL), renal function defined by eGFR (≥45 vs <45 mL/min/1.73 m2) at screening, age 
(< 78 and > 78 years), country of enrollment (United States vs. rest of world) and NYHA 
class at baseline (I or II vs. III).  
 HT and CMAD will be handled in the same way as death for intercurrent event handling.  
 In Section 11.3.5, it’s stated that FPE percent stabilization will be derived using the mean 
of the triplicates. FPE samples are assayed in triplicates; however, in cases where there is 
insufficient sample volume, data are collected in duplicate. In these cases, FPE data will be 
processed using the mean of the duplicates. 
 
In section 11.4.3,  for some subjects at some visits, the estimate of FPE rate constant may not 
be available. In such cases, the corresponding rate constant estimates will not be included for 
the relevant analyses. 
 
3. Section 12 Safety Evaluations 
 For adverse event related analysis, missing values for severity will be considered as 
“Severe” and missing values for relationship to IMP will be considered as “Related” in the 
summary.   
 
4. Section 13 Subgroup Analysis 
 For subgroup analysis on primary efficacy endpoint, F-S test and Win-Ratio analysis will 
be implemented within each stratum in a similar way as for the primary efficacy analysis. 
In case stratified analysis is not feasible for F-S test and Win-Ratio analysis, unstratified 
analysis will be performed. If the subgroup variable itself is a stratification factor, it will be 
removed from the stratification variable list for the stratified analysis. Within the subgroup 
of ATTRm-CM, unstratified analyses will be implemented.  
 For the key secondary efficacy endpoints of change from baseline to Month 30 in 6MWT, 
KCCQ and TTR, and the secondary endpoint of change from baseline to Month 30 in NT-
proBNP, the subgroup analyses will be performed using the same MMRM models as for 
those endpoints, with the following additional model terms: the subgroup factor, subgroup 
x treatment, subgroup x time and subgroup x time x treatment interaction terms. If the 
subgroup variable is already included in the model as a covariate, the subgroup factor will 
not be repeated. 
 For subgroup analysis on the key secondary efficacy endpoint of ACM by Month 30, the 
time to ACM will be analyzed using the same stratified Cox regression model as for the 
primary analysis, with the following additional model terms: the subgroup factor, subgroup 


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x treatment interaction term. If subgroup variable itself is a stratification factor, then it will 
be removed from the stratification variable list. In addition, stratified log-rank test and 
stratified CMH test will be performed within each subgroup in a similar way as in the 
primary analyses on the ACM endpoints. If the subgroup variable itself is a stratification 
factor, it will be removed from the stratification variable list for the stratified analysis. 
 For subgroup analysis on the secondary efficacy endpoint of CVH frequency by Month 30, 
the same negative binomial regression model as that for the primary analysis will be used. 
The following additional terms will also be included into the model: the subgroup factor 
and subgroup x treatment interaction term. If the subgroup variable is already included in 
the model as a covariate, it will not be repeated. In addition, other planned primary analysis 
on the CVH endpoint will be repeated for each subgroup. 
 
 


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5. Appendix 1.4 Sample SAS codes for key secondary and other endpoints 
 Proc Lifetest  
Before: 
PROC LIFETEST DATA=xxx PLOTS=(s) graphics;  
TIME days*status(0);  
STRATA trt;  
             RUN; 
 
Updated: 
proc lifetest data=xxx; 
time days*status(0); 
strata genotype renal function NT proBNP /group=trtn; 
ods output HomTests=HomTests(where=(test='Log-Rank') keep=test probchisq); 
run; 
 
           /Subgroup Analysis - using renal_function as an example/ 
proc lifetest data=ttacm; 
by renal_function; 
time days*status(0); 
strata genotype NT_proBNP/ group=trtn; 
ods output HomTests=HomTests1(where=(test='Log-Rank') keep=test probchisq 
renal_function); 
run; 
 
Note: "assuming status=0 corresponds to the censoring case". 
 
 Proc Phreg  
Before: 
PROC PHREG DATA=xxx;  
CLASS trt (ref=< >) genotype (ref= < >) renal_function (ref= < >) NT_proBNP (ref= < >);  
MODEL days*status(0)=trt / ties=EXACT;  
STRATA genotype renal_function NT_proBNP;  
RUN 
 
Updated: 
PROC PHREG DATA=xxx;  
CLASS trt (ref=< >) genotype (ref= < >) renal_function (ref= < >) NT_proBNP (ref= < >);  
model days*status(0)=trtn bl6mwt / ties=exact; 
strata genotype renal_function NT_proBNP;  
hazardratio 'H1' trtn / cl=wald; 
LSMEANS trtn / diff cl exp; 
ODS OUTPUT HazardRatios = HazardRatios Diffs=diff; 
RUN; 
 
Note: "assuming status=0 corresponds to the censoring case". 


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 Stratified CMH  
Before: 
PROC FREQ DATA=xx;  
TABLES TRT*STATUS / CMH  
RUN; 
 
After:  
PROC FREQ DATA=xxx; 
TABLES genotype*renal_function*NT_proBNP * trtn * status / cmh; 
ods output CMH=cmh(where=(althypothesis='Row Mean Scores Differ ') 
keep=althypothesis prob); 
RUN; 
 
           /Subgroup Analysis – using renal_function as an example/ 
PROC FREQ DATA=xxx; 
by renal_function; 
TABLES genotype *NT_proBNP * trtn * status / cmh; 
ods output CMH=cmh1(where=(althypothesis=' Row Mean Scores Differ ') 
keep=althypothesis prob renal_function); 
RUN; 
 


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6. Appendix 1.5 Missing Date Handling 
 Use first IMP dose for calculating general concomitant medication (excluding Tafamidis) 
days and partial date imputation.   
 Use randomization date for calculating Tafamidis days and partial date imputation. 
 The partial Prior or Concomitant Medication end date imputation logic  
- 
If only day is missing, then assign it as the last day of the month. 
- 
If both day and month are missing, then assign 31DEC. 
- 
If fully missing, then not imputed. 
- 
The imputed end date should be on or after start date.  
- 
The imputed date cannot be later than subject death date. 
 Rules to impute missing death date 
- 
Missing day part only: Max of [first day of the month from partial death date, last 
known alive date +1] 
- 
Complete missing: Last known alive date +1 
 In case of any incomplete CVH/EOCI start date, imputation rules for missing adverse 
events date outlined in SAP Appendix 1.5 will be followed.  
 Rules to impute partial treatment end date 
 
End of Treatment (EOT) Date 
Completeness 
Imputation Rule for EOT 
Year  
Month 
Date 
Yes 
Yes 
Yes 
NA 
Yes 
Yes 
No 
1. If death Date is available and is in the same or earlier than the 
eCRF EOT Month, impute the death date as the EOT date; 
2. Else, if there are unreturned bottles,  calculate the date the last 
unreturned bottles are expected to be emptied.  
a. If the calculated date is before the month of the partial EOT 
date, then use the first date of the month of the partial EOT date.    
b. If the calculated date is in the same month of the partial EOT 
date, then use the calculated date.  
c. If the calculated date is after the month of partial EOT date, 
then use the last date of the month of the partial EOT date. 
3. Else, if End of Study (EOS) is available, impute the EOT date 
as MIN (EOS, last date of the eCRF EOT Month) 
4. Else, impute the last date of the eCRF EOT Month 
Yes 
No 
No 
1. If death Date is available and is in the same or earlier than the 
eCRF EOT Year, impute the death date as the EOT date; 
2. Else, if there are unreturned bottles,  calculate the date the last 
unreturned bottles are expected to be emptied.  
a. If the calculated date is before the year of the partial EOT date, 
then use the first date of the year of the partial EOT date.    
b. If the calculated date is in the same year of the partial EOT 
date, then use the calculated date.  
c. If the calculated date is after the year of partial EOT date, then 
use the last date of the year of the partial EOT date.3. Else, if EOS 
is available, impute the EOT date as MIN (EOS, last date of the 


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eCRF EOT Year) 
4. Else, impute the last date of the eCRF EOT Year 
No 
No 
No 
1. If death Date is available, impute the death date as the EOT 
date; 
2. Else, if there are unreturned bottles, impute the EOT date as the 
date the last unreturned bottles are expected to be emptied 
3. Else, if EOS is available, impute the EOT date as EOS 
4. Else, impute the EOT date with the last available visit date 
  


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7. Appendix 1.6 Clarification for Section 11.1.2.3 Multiple Imputation Methods 
for CV-related hospitalization 
 A two-stage multiple imputation process will be performed to impute the missing CV-
related hospitalization due to early study discontinuation. The study duration of 30 months 
will be partitioned into 3 intervals of 10 months each. These will be referred to as period 1, 
period 2, and period 3, representing months (0, 10], (10, 20] and >20, respectively. 
Imputation models will be estimated and applied separately for each treatment group. 
Hospitalizations are not imputed for subjects after ACM event. The imputation procedure 
consists of two distinct phases: 1) models for CV-related hospitalization rates are estimated 
for each time interval, and 2) these models are then used to impute the number of 
cardiovascular hospitalizations following censoring (dropout) amongst subjects who 
dropout in an interval. 
 Early study discontinuation is the only source of missing hospitalization data, so there will 
be a monotone missing data pattern. Within each short time interval (10 months), a 
Negative Binomial regression model will be assumed for hospitalization counts. No 
imputation is required for a subject who dies during the interval. Because the model applies 
only to subjects who survive the interval, and subjects who die during the interval are likely 
to have differing hospitalization rates, subjects who die in an interval will be excluded from 
the imputation model estimation. All other subjects still in the study at the beginning of the 
interval are included in the model estimation. The reduced exposure of dropouts during the 
intervals is represented by an exposure multiplier (between 0-10) of the monthly 
hospitalization rate (McCullagh and Nelder, 1989). The monthly hospitalization rate during 
the first period is a function of the stratification factors. The monthly hospitalization rate 
during the second period is a function of the stratification factors and the hospitalization 
counts during the first period. The monthly hospitalization rate during the third period is a 
function of the stratification factors, and the hospitalization counts during the first and 
second periods. 
 PROC GENMOD will be used to compute maximum likelihood estimates (MLE) of the 
parameters of the Negative Binomial regression model. It will also be used to compute the 
variance-covariance matrix for the estimates from each time period. If the number of 
subjects with zero CV-related hospitalization is high, a zero inflated Negative Binomial 
regression will be performed. A total of 1100 imputed data sets will be generated. To 
account for estimation error when forming the imputed data sets, 1100 independent sets of 
the Negative Binomial model parameters will be generated for each time period from a 
multivariate normal distribution with mean equal to the MLE, and with the variance-
covariance matrix equal to the MLE variance-covariance matrix. The ith set of Negative 
Binomial model parameters from each time period are paired together, yielding 1100 sets 
of parameters for generating the 1100 imputed data sets. For each iteration, the individual 
subject Negative Binomial parameters (stopping parameter and success probability) will be 
generated using the Negative Binomial regression coefficient estimates for that iteration. 
The imputation process described here is applied with each set of Negative Binomial model 
parameters. Subjects without complete data are comprised of two types: those with no 
participation during the period, and those with partial participation during the period. For 
those with no participation, the prediction equation will be used to impute a hospitalization 
count for the entire period. For those with partial participation, the prediction model will be 


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applied to impute a hospitalization count appropriate for the remainder of the period after 
the subject dropped out. The imputed value will be added to the actual observed value for 
that subject from the part of the period prior to their dropping out. In case the imputed 
CVH count for a given period is larger than the maximum of the observed CVH counts 
among subjects with full follow-up during that period, the imputed count will be truncated 
as (1 + the maximal CVH count for the given period among subjects with full follow-up). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. Reference  
Dong G, Qiu J, Wang D, Vandemeulebroecke M. The stratified win ratio. J Biopharm Stat. 
2018;28(4):778-796.