Clinical trial NCT03458130
Conditions: Familial ATTR-CM (ATTRm-CM, or FAC) Wild-type ATTR-CM (ATTRwt-CM)
Sponsor: Eidos Therapeutics, a BridgeBio company
Start date: 2018-04-27; Completion date: 2018-10-05
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This prospective, randomized, multicenter, double-blind, parallel group, placebo-controlled, dose-ranging study will evaluate the safety, tolerability, PK (Pharmacokinetic) and PD (Pharmacodynamic) of AG10 compared to placebo administered on a background of stable heart failure therapy. Screening and randomization will be followed by a 28-day blinded, placebo-controlled treatment period.

Detailed description:
A Phase 2, Randomized, Placebo-controlled, Dose-ranging Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AG10 in Patients with Symptomatic Transthyretin Amyloid Cardiomyopathy.

The primary objective of this study is to evaluate the safety and tolerability of AG10 administered to adult patients with symptomatic transthyretin amyloid cardiomyopathy (ATTRCM).

This study will be a Phase 2, randomized, placebo-controlled, dose-ranging study in 45 male and/or female patients with symptomatic ATTR-CM aged 18 through 90 years.

If all doses are well tolerated, the duration of each patient's participation in the study will be 28 days of treatment. In addition, there will be a 28-day screening period before treatment and a 30-day follow-up period before the final Follow-up Visit.

This prospective, randomized, multicenter, double-blind, parallel group, placebo-controlled, dose-ranging study will evaluate the safety, tolerability, PK and PD of AG10 compared to placebo administered on a background of stable heart failure therapy. Screening and randomization will be followed by a 28-day blinded, placebo-controlled treatment period. secondary objectives of this study are: to characterize the pharmacokinetics (PK) of AG10 administered orally twice daily in patients with symptomatic ATTRCM, and to describe the pharmacodynamic (PD) properties of AG10 as assessed by established assays of transthyretin (TTR) stabilization, including Fluorescent Probe Exclusion (FPE) assay and Western blot, and to describe the Pharmacokinetic Pharmacodynamic (PKPD) relationship of AG10 in adult patients with symptomatic ATTRCM.

Eligible patients will be randomized in a 1:1:1 ratio to placebo or one of two different doses of AG10 administered twice daily. A minimum of 30% of patients enrolled will be mutant ATTR-CM.

Arms: arm 1: AG10 400mg tablets twice daily for 28 days arm 2: AG10 800mg tablets twice daily for 28 days arm 3: Placebo tablets twice daily for 28 days
Interventions: intervention 1: AG10 intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: TTR stabilizer intervention 2: Nonactive control

Protocol documents:
SAP_002.pdf: 
Protocol Title: 
A Phase 2, Randomized, Placebo-controlled, Dose-ranging 
Study of the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AG10 in Patients with Symptomatic 
Transthyretin Amyloid Cardiomyopathy 
Protocol Number 
EIDOS AG10-201 
NCT Number: 
NCT03458130 
SAP Version/Date: 
Version 2.0:  05 October 2018































Prot_001.pdf: 
Protocol Title: 
A Phase 2, Randomized, Placebo-controlled, Dose-ranging 
Study of the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AG10 in Patients with Symptomatic 
Transthyretin Amyloid Cardiomyopathy 
Protocol Number 
EIDOS AG10-201 
NCT Number: 
NCT03458130 
Protocol 
Version/Date: 
Original:  10 January 2018 
Amendment 1: 8 February 2018 
Amendment 2: 25 May 2018 






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1.
Acute myocardial infarction, acute coronary syndrome or coronary
revascularization within 90 days prior to Screening.
2.
Experienced stroke within 90 days prior to Screening.
3.
Has hemodynamic instability at Screening or Randomization that, in
the judgment of the PI, would pose too great a risk for participation in
the study.
4.
Has estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 at
Screening.
5.
Is likely to undergo heart transplantation within the next year.
6.
Has confirmed diagnosis of light-chain amyloidosis.
7.
Has abnormal liver function tests at Screening, defined as ALT or AST
>3 × upper limit of normal (ULN) or total bilirubin >2 × ULN.
8.
Has abnormalities in clinical laboratory tests at Screening or
Randomization that, in the judgment of the PI, would pose too great a
risk for participation in the study.
9.
Known hypersensitivity to study drug (AG10 or placebo), its
metabolites, or formulation excipient
10. Current treatment with diflunisal, tafamidis, green tea, doxycycline,
TUDCA/Ursodiol, Patisiran or Inotersen within 14 days or 5 half-lives
of the prior investigational agent (whichever is longer) prior to dosing
with study drug.
11. Females who are pregnant or breastfeeding. Lactating females must
agree to discontinue nursing before the study drug is administered. A
negative serum pregnancy test at Screening and a negative urine
pregnancy test at Randomization visit are required for female patients
of childbearing potential.
12. In the judgment of the investigator, has any clinically significant
ongoing medical condition that might jeopardize the patient’s safety or
interfere with the study, including participation in another
investigational drug or investigational device study within the 30 days
prior to Screening with potential residual effects that might confound
the results of this study.
13. Has any laboratory abnormality or condition that, in the investigator’s
opinion, could adversely affect the safety of the patient or impair the
assessment of study results.
14. Has any condition that, in the opinion of the investigator, would
preclude compliance with the study protocol such as a history of
substance abuse, alcoholism or a psychiatric condition.
15. Has participated in another investigational study within 14 days or
5 half-lives of the prior investigational agent (whichever is longer)
prior to dosing with study drug. Exceptions can be made in the case of
observational and/or registry studies upon consultation with the
Medical Monitor.
Test Product, Dosage, and Mode of 
Administration 
AG10, 
 and 
 mg twice daily, oral administration 
Duration of Study and Treatment 
Study duration: Total of 35 to 42 days, Day 1 through the last treatment 
taken on Day 28, followed by a follow-up visit within 7 to 14 days from  
Day 28 or last dose.  In addition, there will be a 28-day Screening period. 
Treatment duration: 28 days of dosing 
Reference Therapy, Dosage, and 
Mode of Administration 
Placebo tablets matching AG10 twice daily, oral administration 




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 Table 1. 
Schedule of Assessments 
   
Screening 
Period 
(Day -28) 
 
Double Blind Treatment Period (days) 
Follow-up 
(ET)b 
 Day 1a 
Day 7 
(± 3) 
Day 14a 
(± 3) 
Day 21 
(± 3) 
Day 28a 
(± 3) 
7 to 14-day 
follow-up 
visit 
Written Informed 
Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria Review 
X 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
X 
Physical Examc 
X 
X 
 
X 
 
X 
X 
Resting 
transthoracic 
echocardiogram 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
X 
12-lead resting 
ECG 
X 
X 
 
X 
 
X 
X 
PD assaysd 
 
X 
 
X 
 
X 
 
PK sample 
collectiond 
 
X 
 
X 
 
X 
 
Study drug dosing 
during visit 
 
X 
 
X 
 
X 
 
Clinical laboratory 
assessments 
X 
X 
 
X 
 
X 
X 
Pregnancy teste 
X 
X 
 
X 
 
X 
X 
Contact Patientf 
 
 
X 
 
X 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
a. 
Recommended order of assessments (as applicable) at Day 1, Day 14 and Day 28 visits: (1) ECG, (2) 
echocardiogram (3) predose PK/PD sample collection and, all other blood sample collection (4) witnessed study 
drug dosing, and (5) postdose PK/PD sample. All other required visit assessments may occur at any point during 
the study visit.   
b. 
If a patient prematurely discontinues study participation before completing the 28-Day treatment period, the 
patient will be asked to return to the study center for the Follow-up Visit. The Follow-up Visit should be 
performed within 7 to 14 days after last dose.  
c. 
Complete PE including body weight and height measurements, and BMI calculation at Screening, abbreviated PE 
with weight at all other visits. 
d. 
Please refer to updated lab manual on timing of PK and PD collections. 
e. 
Females of Child-Bearing Potential only. Serum pregnancy test at Screening and urine pregnancy test at all other 
visits. 
f. 
Contact patient at Day 7 (±3) and Day 21 (±3) to review adverse events, concomitant medications and study drug 
compliance. 
 
 
 


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2.0 
TABLE OF CONTENTS 
1.0 
SYNOPSIS AND SCHEDULE OF ASSESSMENTS ...................................................................... 2 
2.0 
TABLE OF CONTENTS .................................................................................................................. 6 
3.0 
LIST OF ABBREVIATIONS ........................................................................................................... 8 
4.0 
ETHICAL CONSIDERATIONS .................................................................................................... 10 
4.1 
Institutional Review Board ............................................................................................... 10 
4.2 
Ethical Conduct of the Study ............................................................................................ 10 
4.3 
Patient Information and Consent ...................................................................................... 10 
5.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...................................... 11 
5.1 
Eidos Therapeutics or Designee........................................................................................ 11 
5.2 
Clinical Laboratory Analysis ............................................................................................ 11 
5.3 
Bioanalytical Laboratory .................................................................................................. 11 
5.4 
Data Analysis .................................................................................................................... 11 
6.0 
INTRODUCTION .......................................................................................................................... 12 
6.1 
Known and Potential Risks and Benefits of AG10 to human subjects ............................. 12 
7.0 
STUDY OBJECTIVES ................................................................................................................... 14 
7.1 
Primary Objective ............................................................................................................. 14 
7.2 
Secondary Objectives ....................................................................................................... 14 
8.0 
INVESTIGATIONAL PLAN ......................................................................................................... 15 
8.1 
Overall Study Design and Plan: Description .................................................................... 15 
8.2 
Discussion of Study Design .............................................................................................. 16 
8.3 
Selection of Study Population ........................................................................................... 16 
8.3.1 
Inclusion Criteria ................................................................................................ 16 
8.3.2 
Exclusion Criteria ............................................................................................... 17 
8.3.3 
Removal of Patients from Therapy or Assessment ............................................. 18 
8.3.4 
Replacement Procedures .................................................................................... 19 
8.4 
Treatments ........................................................................................................................ 19 
8.4.1 
Treatments Administered ................................................................................... 19 
8.4.2 
Identity of Investigational Products .................................................................... 19 
8.4.2.1 
Packaging ......................................................................................... 20 
8.4.2.2 
Storage, Dispensing, and Return of Investigational Product ............ 20 
8.4.3 
Method of Assigning Patients to Treatment Groups/Sequences ......................... 20 
8.4.4 
Selection of Dosages in the Study ...................................................................... 21 
8.4.5 
Selection and Timing of Dose for Each Patient .................................................. 22 
8.4.6 
Blinding .............................................................................................................. 22 
8.4.7 
Prior and Concomitant Therapy ......................................................................... 23 
8.4.8 
Treatment Compliance ....................................................................................... 23 
8.5 
Pharmacokinetic, Safety, and Pharmacodynamic Variables ............................................. 23 
8.5.1 
Schedule of Assessments .................................................................................... 23 
8.5.1.1 
Screening (Day –28 to Day -1) ......................................................... 23 
8.5.1.2 
Double-blind Treatment Days .......................................................... 24 
8.5.1.3 
Follow-up Visit (or Early Termination) ............................................ 26 
8.5.2 
Drug Concentration Measurements .................................................................... 27 


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8.5.2.1 
PK Blood Draw Schedule ................................................................. 27 
8.5.2.2 
PD Blood Draw Schedule ................................................................. 27 
8.5.2.3 
PK and PD Blood Sampling Procedures ........................................... 27 
8.5.3 
Safety Assessments ............................................................................................ 27 
8.5.3.1 
Adverse Events ................................................................................. 27 
8.5.3.2 
Serious Adverse Events .................................................................... 29 
8.5.3.3 
Reporting Adverse Events and Serious Adverse Events .................. 30 
8.5.3.4 
Reporting of Pregnancies Occurring During the Study .................... 31 
8.5.3.5 
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest ................................................................................. 31 
8.5.3.6 
Clinical Laboratory Determinations ................................................. 32 
8.5.3.7 
Vital Signs ........................................................................................ 33 
8.5.3.8 
Electrocardiograms ........................................................................... 33 
8.5.3.9 
Other Safety Assessments................................................................. 33 
8.6 
Data Quality Assurance .................................................................................................... 34 
8.6.1 
Data Monitoring ................................................................................................. 34 
8.6.2 
Data Recording and Documentation ................................................................... 34 
8.7 
Statistical Methods and Determination of Sample Size .................................................... 35 
8.7.1 
General Considerations ...................................................................................... 35 
8.7.2 
Timing of Analyses ............................................................................................ 35 
8.7.3 
Analysis Sets and Analysis Conventions ............................................................ 35 
8.7.4 
Demographics and Other Baseline Characteristics ............................................. 35 
8.7.5 
Extent of Exposure and Treatment Compliance ................................................. 35 
8.7.6 
Pharmacokinetic Analyses .................................................................................. 36 
8.7.7 
Safety Analyses .................................................................................................. 36 
8.7.7.1 
Adverse Events ................................................................................. 36 
8.7.7.2 
DMC Safety Reviews ....................................................................... 37 
8.7.8 
Pharmacodynamic Analysis ............................................................................... 37 
8.7.9 
Interim Analysis ................................................................................................. 37 
8.7.10 
Determination of Sample Size ............................................................................ 37 
8.8 
Changes in the Conduct of the Study or Planned Analyses .............................................. 37 
9.0 
STUDY SPONSORSHIP ................................................................................................................ 38 
9.1 
Study Termination ............................................................................................................ 38 
9.2 
Reporting and Publication ................................................................................................ 38 
10.0 
INVESTIGATOR OBLIGATIONS ................................................................................................ 39 
10.1 
Documentation .................................................................................................................. 39 
10.2 
Performance ...................................................................................................................... 39 
10.3 
Use of Investigational Materials ....................................................................................... 40 
10.4 
Case Report Forms, Laboratory Data, and Other Vendor Data ........................................ 40 
10.5 
Retention and Review of Records..................................................................................... 40 
10.6 
Patient Confidentiality ...................................................................................................... 41 
11.0 
INVESTIGATOR’S STATEMENT ............................................................................................... 42 


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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ATTR 
TTR amyloidosis 
ATTR-CM 
TTR cardiomyopathy 
ATTR-PN 
TTR polyneuropathy 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CI 
confidence interval 
ECHO 
echocardiogram 
ECG 
electrocardiogram, electrocardiographic 
EDC 
electronic data capture 
ET 
Early termination 
FDA 
US Food and Drug Administration 
 
 
GCP 
good clinical practice 
β-hCG 
β–human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IB 
Investigator’s Brochure  
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IV 
intravenous 
IRTS 
Interactive Response Technology System 
MABEL 
minimum anticipated biological effect level  
NDA 
New Drug Application 
PCS 
potentially clinically significant 
PD 
pharmacodynamic 
PI 
Principal Investigator 
PK 
pharmacokinetic 


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QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using the Bazett formula 
(QTcB = QT/(RR)½) 
QTcF 
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓) 
QTcNi 
QT interval corrected for heart rate using an individual correction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Le Système International d'Unités (International System of Units) 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


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4.0 
ETHICAL CONSIDERATIONS 
4.1 
INSTITUTIONAL REVIEW BOARD 
It is the responsibility of the Principal Investigator (PI) to obtain the approval of the 
Institutional Review Board (IRB) before the start of the study. The IRB must be 
registered and active with the Office for Human Research Protections of the 
US Department of Health and Human Services. A copy of the approval letter will be 
supplied to the Sponsor, along with a roster of IRB members or the US Department of 
Health and Human Services general assurance number. During the course of the study, 
the PI (or appropriately trained designee) will provide timely and accurate reports to the 
IRB on the progress of the study at appropriate intervals (not to exceed 1 year) and at the 
completion of the study. The PI (or appropriately trained designee) will notify the IRB of 
serious adverse events (SAEs) or other significant safety findings. The study protocol, 
informed consent form (ICF), information sheet advertisements (if any), and amendments 
(if any) will be approved by the IRB at each study center in conformance with CFR, Title 
21, Part 56. 
4.2 
ETHICAL CONDUCT OF THE STUDY 
The study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki. 
This clinical study is designed to comply with ICH Guidance on General Considerations 
for Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997), Nonclinical Safety Studies for 
the Conduct of Human Clinical Trials and Marketing Authority for Pharmaceuticals 
(75 FR 3471, 21 Jan 2010), Good Clinical Practice: Consolidated Guidance (ICH-E6; 
62 FR 25692, 09 May 1997), and Part 312 of the CFR. 
4.3 
PATIENT INFORMATION AND CONSENT 
At screening, competent patients will read the ICF and a HIPAA authorization form (if 
applicable) after being given an explanation of the study. Before signing the ICF and the 
HIPAA form (if applicable), patients will have an opportunity to discuss the contents of 
these forms with study center staff. Patients must assent understanding of and voluntarily 
sign these forms in compliance with 21 CFR, Parts 50 and 312, before participating in 
any study-related procedures. Patients 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; the HIPAA 
authorization, if applicable, contains all the core elements and mandatory statements as 
defined in the CFR. Signed copies of the ICF and the HIPAA authorization form, if 
applicable, will be given to the patient, and both documents will be placed in the PI’s 
study files. The Sponsor will review the ICF before it is submitted to the IRB. 


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5.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
5.1 
EIDOS THERAPEUTICS OR DESIGNEE 
This study will be performed at up to 15 study centers located in the United States (US). 
The PI at each study center will be responsible for ensuring that the investigation is 
conducted according to the signed Investigator’s statement (Section 11.0), the protocol, 
and ICH GCP guidelines. 
The PI at each study center will be responsible for the management of the study, which 
will include but not be limited to maintenance of the study file and patient records, 
correspondence with the IRB, and completion of the electronic case report forms (CRFs). 
5.2 
CLINICAL LABORATORY ANALYSIS 
All clinical laboratory tests will be conducted by a central laboratory in the U.S. Study 
center local laboratories may also be used to conduct some clinical laboratory tests. The 
name and address of the study center local laboratories will be listed on the study center’s 
Form FDA1572. 
5.3 
BIOANALYTICAL LABORATORY 
The AG10 concentrations and its key metabolites in plasma samples will be analyzed at 
. 
5.4 
DATA ANALYSIS 
The Sponsor will be responsible for pharmacokinetic (PK), pharmacodynamic (PD), and 
biostatistical evaluations; report preparation; and auditing of bioanalytic work. Statistical 
programming of safety data may be conducted by a contract research organization. 










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Participation in this Phase 2 study does not preclude participation in other studies of 
AG10, as long as the patient meets eligibility criteria.  
The Schedule of Assessments is provided in Section 1.0. Detailed descriptions of each 
study day can be found in Section 8.5.1. 
8.2 
DISCUSSION OF STUDY DESIGN 
This prospective study is designed to evaluate the safety and tolerability of AG10 in 
patients with ATTR-CM. A randomized, double-blind, placebo-controlled, dose-ranging 
design is considered to be the most appropriate study design for meeting this objective. 
On the basis of information gained from previous clinical experience with AG10, the 
doses used in this study will be selected to determine the dose with the better safety and 
tolerability profile. 
8.3 
SELECTION OF STUDY POPULATION 
Approximately 55 males and females ≥18 and ≤90 years of age with chronic, stable, 
symptomatic ATTR-CM will be randomized in a 1:1:1 ratio (~ 18 patients per arm) in the 
study. Approximately 30% of patients enrolled will have mutant ATTR-CM. 
8.3.1 
Inclusion Criteria 
To be eligible to participate in the study, patients must meet all of 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. Be a male or female ≥18 to ≤90 years of age.
3. Have an established diagnosis of ATTR-CM with either wild-type transthyretin or a
variant transthyretin genotype (assessed by genotyping, with patients with concurrent
monoclonal gammopathy of undetermined significance requiring a confirmatory test
using mass spectrometry) as defined by either positive endomyocardial biopsy or
positive technetium pyrophosphate scan.
4. Have a history of heart failure evidenced by at least one prior hospitalization for heart
failure or clinical evidence of heart failure (without hospitalization) requiring medical
management.
5. Have NYHA Class II-III symptoms.
6. Male patients and female patients of childbearing potential who engage in
heterosexual intercourse must agree to use appropriate method(s) of contraception.


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7. For patients 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.
8.3.2 
Exclusion Criteria 
Patients who meet any of the following criteria 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. Experienced stroke within 90 days prior to Screening.
3. Has hemodynamic instability at Screening or Randomization that, in the judgment of
the PI, would pose too great a risk for participation in the study.
4. Has estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 at Screening.
5. Is likely to undergo heart transplantation within the next year.
6. Has confirmed diagnosis of light-chain amyloidosis.
7. Has abnormal liver function tests at Screening, defined as ALT or AST >3 × upper
limit of normal (ULN) or total bilirubin >2 × ULN.
8. Has abnormalities in clinical laboratory tests at Screening or Randomization that, in
the judgment of the PI, would pose too great a risk for participation in the study.
9. Known hypersensitivity to study drug (AG10 or placebo), its metabolites, or
formulation excipient.
10. Current treatment with diflunisal, tafamidis, green tea, doxycycline,
TUDCA/Ursodiol, Patisiran or Inotersen within 14 days or 5 half-lives of the prior
investigational agent (whichever is longer) prior to dosing with study drug.
11. Females who are pregnant or breastfeeding. Lactating females must agree to
discontinue nursing before the study drug is administered. A negative serum
pregnancy test at Screening and a negative urine pregnancy test at Randomization
visit are required for female patients of childbearing potential.
12. In the judgment of the investigator, has any clinically significant ongoing medical
condition that might jeopardize the patient’s safety or interfere with the study,
including participation in another investigational drug or investigational device study
within the 30 days prior to Screening with potential residual effects that might
confound the results of this study.


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13. Has any laboratory abnormality or condition that, in the investigator’s opinion, could
adversely affect the safety of the patient or impair the assessment of study results.
14. Has any condition that, in the opinion of the investigator, would preclude compliance
with the study protocol such as a history of substance abuse, alcoholism or a
psychiatric condition.
15. Has participated in another investigational study within 14 days or 5 half-lives of the
prior investigational agent (whichever is longer) prior to dosing with study drug.
Exceptions can be made in the case of observational and/or registry studies upon
consultation with the Medical Monitor.
The clinical significance of any abnormal findings found in the physical examination, 
clinical laboratory evaluations, vital sign assessments, and ECGs must be evaluated and 
documented by the PI or a Sub-Investigator. For clinical laboratory tests, the PI or 
Sub-Investigator will assess and document the clinical significance of any values outside 
the reference ranges provided by the clinical laboratory. Abnormal findings that are 
considered not clinically significant by the PI or Sub-Investigator may be reviewed by the 
Sponsor’s Study Physician. 
The Sponsor reserves the right to exclude any patient from the study on the basis of the 
screening medical histories, physical examination findings, clinical laboratory results, 
prior medications, or other entrance criteria. 
8.3.3 
Removal of Patients from Therapy or Assessment 
A premature discontinuation will occur if a patient who signs the ICF and is dosed ceases 
participation in the study, regardless of circumstances, before the completion of the 
protocol-defined study procedures. Patients can be prematurely discontinued from the 
study for any of the following reasons: 
•
Adverse event (AE)
•
Protocol violation
•
Non-compliance with IMP
•
Withdrawal of consent
•
Lost to follow-up (every effort must be made to contact the patient; a registered letter
must be sent)
•
Other reasons, such as administrative reasons or pregnancy
•
Study terminated by Sponsor


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•
Site terminated by Sponsor
If a patient prematurely discontinues from the study because of an AE or for any other 
reason, the study center staff must record the AE as the reason for discontinuation. All 
dosed patients who prematurely discontinue from the study, regardless of cause, will be 
seen for an Early Termination (ET) Visit. Patients refusing to come in to the study center 
for an ET Visit or who cannot be reached must be requested in writing to come in to the 
study center and to return any unused IMP. A copy of the letter will be kept by the study 
center with the source documentation. The reason for premature discontinuation from the 
study will be reflected on the study termination page of the CRF. 
8.3.4 
Replacement Procedures 
Patients may withdraw consent at any time for any reason without prejudice to future 
treatment. In the event of study withdrawal, the ET procedures should occur as a final 
assessment.  
The investigators or Medical Monitor may withdraw a patient from treatment for any 
reason (treatment withdrawal) at any time, and all planned study assessments should then 
be offered for the duration of the trial to ensure appropriate medical care is provided to 
the patient. Patients who develop a new significant medical condition at any point during 
the trial may be withdrawn. 
Patients who prematurely discontinue from the study will be replaced, but their patient 
number will not be reassigned. 
8.4 
TREATMENTS 
8.4.1 
Treatments Administered 
Patients who satisfy the inclusion and exclusion criteria listed in Section 8.3 will be 
randomized to 1 of the following 3 study arms.  
•
-mg dose of AG10 (
 mg tablet + placebo tablets) twice daily
•
-mg dose of AG10 (
 mg tablets) twice daily
•
Matching placebo ( placebo tablets) twice daily
8.4.2 
Identity of Investigational Products 
AG10 
Eidos Therapeutics, Inc. 
 
Matching placebo tablets 


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8.4.2.1 
Packaging 
The investigational medicinal product (IMP) will provided as blinded randomized kits 
assigned to patients using a randomization code.   The kits will be labeled with the 
protocol number, storage information, warning language (“Caution: New Drug—Limited 
by Federal Law to Investigational Use. Keep Out of Reach of Children”), and instructions 
to take as directed.  
Details regarding IMP are provided in the IB and IMP Manual. 
8.4.2.2 
Storage, Dispensing, and Return of Investigational Product 
The Sponsor will provide the study center with drug supplies.  AG10 should be stored at 
.  Full details regarding IMP storage are provided in the IMP 
Manual.  
The site research pharmacy (or appropriately trained designee) 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 disposition record will be kept that specifies the 
amount administered to each patient, the date of administration, and any amount returned 
by the patient. 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. Also 
at the completion of the study, the site research pharmacy (or appropriately trained 
designee) will provide the Sponsor with a complete record of IMP accountability.  
It is the PI’s responsibility to ensure that patients return their unused IMP and empty 
bottles at each visit. 
8.4.3 
Method of Assigning Patients to Treatment Groups/Sequences 
Screening numbers will be assigned through an Interactive Response Technology System 
(IRTS) portal after the patient signs the ICF. Patients who are qualified will be 
randomized into the study and assigned a unique patient number through the IRTS. 




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In summary, at doses of 
 mg twice daily and 
 mg twice daily, AG10 is expected to 
be safe and well-tolerated with measurable pharmacodynamic activity. Therefore, for this 
study, the 
 mg twice daily and 
 mg twice daily doses of AG10 were chosen for 
evaluation versus placebo.   
8.4.5 
Selection and Timing of Dose for Each Patient 
Dosing should occur twice daily, once in the morning and once in the evening. 
8.4.6 
Blinding 
A list of patient randomization numbers and corresponding treatment assignments will be 
generated by an assigned unblinded-statistician using a statistical programming. The 
randomization numbers will be retained in electronic form saved on a secure server. A 
hard copy will be retained by the assigned unblinded-statistician in a secure locked area. 
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if 
a subject’s treatment assignment is disclosed to the investigator, the subject will have 
study treatment discontinued. All subjects will be followed until study completion unless 
consent to do so is specifically withdrawn by the subject. Sponsor may independently 
unblind cases for expedited reporting of suspected unexpected serious adverse reactions 
(SUSARs). 
The investigator is requested to contact the Medical Monitor within 24 hours upon any 
instances of treatment unblinding. 
For a medical emergency in which unblinding of study drug assignment is required to 
enable urgent clinical decision making, the Investigator should first attempt to contact the 
Medical Monitor (or designee). If the Medical Monitor or designee cannot be reached, 
the Investigator may obtain a subject’s study drug assignment by following the 
Emergency Unblinding Procedures outlined in the study procedures manual. Every 
attempt should be made to contact the Sponsor prior to unblinding. In the event of 
emergency unblinding of a subject’s study drug assignment, a full written explanation of 
events requiring study drug unblinding must be provided to the Medical Monitor. Once 
unblinded, the subject will be permanently discontinued from study drug but may 
continue to participate in all other study-related activities including assessments of 
efficacy. 


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8.4.7 
Prior and Concomitant Therapy 
Patients will not be permitted to use any concomitant medications listed in the exclusion 
criteria during the study. Patients will be instructed not to take any of those drugs for at 
least 14 days or 5 half-lives (whichever is longer) before the first day of dosing and 
during the course of the study. 
At Screening, at each visit during the treatment period, and at the Follow-up Visit, study 
center staff will question each patient specifically on the use of all concomitant 
medications and record the medication, dosage, and duration of use in the appropriate 
CRF.  
8.4.8 
Treatment Compliance 
IMP compliance will be closely monitored by counting the number of tablets 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 and empty bottles.  
The study center will keep an accurate drug disposition record that specifies the amount 
of IMP administered to each patient and the date of administration. 
8.5 
PHARMACOKINETIC, SAFETY, AND 
PHARMACODYNAMIC VARIABLES 
8.5.1 
Schedule of Assessments 
The schedule of study procedures and assessments is tabulated by study day in the 
Schedule of Assessments in Section 1.0. The descriptions of the procedures to be 
performed throughout the study are provided below. 
8.5.1.1 
Screening (Day –28 to Day -1) 
Screening will be performed within 28 days before administration of the first dose of 
IMP. At Screening, inclusion and exclusion criteria will be reviewed to determine the 
patient’s eligibility for enrollment. Study procedures will be reviewed with the patient, 
and documentation of informed consent will be obtained. 
The following procedures will also be performed at Screening: 
•
Medical and surgical history assessment
•
Physical examination (Section 8.5.3.10)
•
Vital signs assessment (Section 8.5.3.7)
•
12-lead ECG (Section 8.5.3.8)


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•
Blood sample collection for hematology, serum chemistry, urinalysis (Section
8.5.3.6)
•
Blood sample collection for serum β–human chorionic gonadotropin (β-hCG)
pregnancy test (females of child-bearing potential only)
•
Prior medication use assessment (Section 8.4.7)
•
AE assessment (Section 8.5.3.1)
8.5.1.2 
Double-blind Treatment Days 
Study procedures are listed below by study day, ideally performed in the order listed 
below, for each day.   
Day 1 (Randomization) – Site Visit 
•
Review inclusion/exclusion criteria to confirm patient is eligible
•
Randomize patient to treatment arm and assign randomization number
•
Physical examination
•
Vital signs assessment
•
Conduct 12-lead ECG
•
Conduct resting transthoracic echocardiogram (Section 8.5.3.9)
•
Collect PK blood sample (predose and at 0.5, 1 and 2 hours postdose)
•
Collect PD assay blood sample (predose and at 0.5, 1 and 2 hours postdose)
•
Collect 
(predose)
•
Collect blood and urine samples for clinical laboratory analysis and urine pregnancy
testAdminister IMP with designated witness
•
Assess concomitant medication use
•
AE assessment
Day 7 (±3 days) – Telephone Contact 
•
Assess concomitant medication use


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•
IMP compliance assessment
•
AE assessment
Day 14 (±3 days) – Site Visit 
•
Physical examination
•
Vital signs assessment
•
Conduct 12-lead ECG
•
Collect PK blood sample (predose and at 0.5, 1 and 2 hours postdose)
•
Collect PD assay blood sample (pre-dose and at 0.5, 1 and 2 hours postdose)
•
Collect 
(predose)
•
Collect any unused IMP and check compliance and accountability
Collect blood and urine samples for clinical laboratory analysis and urine pregnancy
test
•
Administer IMP with designated witness
•
Assess concomitant medication
•
IMP compliance assessment
•
AE assessment
Day 21 (±3 days) – Telephone Contact 
•
Assess concomitant medication use
•
IMP compliance assessment
•
AE assessment
Day 28 (±3 days) – Site Visit 
•
Medical history update
•
Physical examination
•
Vital signs assessment


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•
Conduct 12-lead ECG
•
Collect PK blood sample (predose and at 0.5, 1 and 2 hours postdose)
•
Collect PD assay blood sample (pre-dose and at 0.5, 1 and 2 hours postdose)
•
Collect 
 (predose)
•
Collect any unused IMP, check compliance and accountability
•
Collect blood and urine samples for clinical laboratory analysis and urine pregnancy
test
•
Administer IMP with designated witness
•
Assess concomitant medication
•
IMP compliance assessment
•
AE assessment
8.5.1.3 
Follow-up Visit (or Early Termination)   
Patients will have a Follow-up Visit 7 to 14 days after Day 28 or after early withdrawal. 
The following procedures will be performed at the Follow-up Visit: 
•
Medical history update
•
Physical examination
•
Vital signs assessment
•
Conduct 12-lead ECG
•
Collect blood and urine samples for clinical laboratory analysis and urine pregnancy
test
•
Assess concomitant medication
•
AE assessment


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Any clinically significant findings obtained during the final examination at the Follow-up 
or at premature discontinuation (ET visit), including clinically significant laboratory 
abnormalities and the manner in which they are treated, will be followed until the 
condition returns to prestudy status, has resolved or stabilized, or can be explained as 
being unrelated to the IMP. 
8.5.2 
Drug Concentration Measurements 
8.5.2.1 
PK Blood Draw Schedule 
Sampling will be done at the following times to determine AG10 plasma concentrations: 
Days 1, 14 and 28: Predose and at 0.5, 1 and 2 hours Postdose 
8.5.2.2 
PD Blood Draw Schedule 
PD properties of AG10 will be assessed by established assays 
 
. Sampling will be done at the following times to 
perform these PD assays: 
•
Days 1, 14 and 28: Predose and at 0.5, 1 and 2 hours Postdose
Sampling will be done at the following times to measure 
 concentrations: 
•
Day 1, Day 14 and Day 28 Predose
8.5.2.3 
PK and PD Blood Sampling Procedures 
Additional details on PK and PD blood sampling procedures and storage can be found in 
the supplementary Laboratory Manual. 
8.5.3 
Safety Assessments 
Patients must be seen by a physician or an appropriately trained health professional at 
every visit, and the evaluation must be documented. The procedures discussed in this 
section will be performed on the designated study days. 
8.5.3.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product 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). 


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For the purpose of data collection for this study, any untoward event that is reported from 
the time that the patient signs the ICF until the Follow-up visit after the last dose of IMP 
is to be considered an AE. 
Examples of AEs are as follows: 
•
Changes in the general condition of the patient
•
Symptoms offered by or elicited from the patient
•
Objective signs observed by the PI or other study personnel
•
All diseases that occur after the start of the study, including any changes in severity or
frequency of preexisting disease
•
All clinically relevant abnormalities in laboratory values or clinically relevant
physical findings that occur during the study
8.5.3.1.1 
Causality Assessment 
For each AE, the PI or Sub-Investigator must provide an assessment of causal 
relationship to the IMP. The causality assessment must be recorded on the appropriate 
AE reporting page of the patient’s CRF. Causal relationship must be assessed by 
answering the following question: 
Is there a reasonable possibility that the IMP caused the event? 
Yes: 
There is evidence to suggest a causal relationship between the IMP and AE, ie: 
−
There is a reasonable temporal relationship between the IMP and the event,
and/or
−
The event is unlikely to be attributed to underlying/concurrent disease, other
drugs, or other factors, and/or
−
Positive dechallenge and/or rechallenge exist.
No: 
There is no evidence to suggest a causal relationship between the IMP and AE, ie: 
−
There is no reasonable temporal relationship between the IMP and the event,
or
−
The patient did not take the IMP, or
−
The event is likely to be attributed to underlying/concurrent disease, other
drugs, or other factors, or


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−
The event is commonly occurring in the study population independent of drug
exposure.
8.5.3.1.2 
Severity Assessment 
The PI or Sub-Investigator will provide an assessment of the severity of each AE by 
recording a severity rating on the appropriate AE reporting page of the patient’s CRF. 
Severity, which is a description of the intensity of manifestation of the AE, is distinct 
from seriousness, which implies a patient 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 adverse event 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 adverse event 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 participant. 
Severe: 
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
8.5.3.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose 
•
Results in death
•
Is life threatening
•
Requires inpatient 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 patient 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. 


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Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs. 
Preplanned hospitalizations (eg, elective procedures for preexisting conditions that did 
not worsen) are excluded from SAE reporting. 
8.5.3.3 
Reporting Adverse Events and Serious Adverse Events 
Any untoward event that is reported from the time that the patient signs the ICF until the 
Follow-up visit 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, in treatment, or posttreatment period are to be considered AEs (and SAEs if 
appropriate), and consequently recorded and reported as such. 
Patients 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 
(Section 8.5.1). Patients 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 patient’s CRF.  
All AEs and SAEs reported by the patient (or patient representative) or observed or 
otherwise identified by the PI (or other study center personnel) at a defined study visit or 
during any communication with the patient (or patient representative) occurring outside a 
defined study visit (from the time the patient signs the ICF to the Follow-up visit after the 
last dose of IMP) must be documented. 
All AEs must be recorded on the appropriate AE reporting page of the patient’s CRF 
whether or not they are considered causally related to the IMP. 
For every AE, the PI (or appropriately trained designee) must 
•
Provide an assessment of the severity, causal relationship to the IMP, and seriousness
of the event (ie, whether it is an SAE)
•
Document all actions taken with regard to the IMP
•
Detail any other treatment measures taken for the AE
•
Document resolution of the AE
Additional information regarding the expedited reporting required for SAEs is provided 
in Section 8.5.3.5. 


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8.5.3.4 
Reporting of Pregnancies Occurring During the Study 
Study center personnel must report every pregnancy (including the pregnancy of a male 
patient’s partner) from the time the patient 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 and email it to the 
SAE/Pregnancy email address 
, 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 
(eg, if the mother is hospitalized for hemorrhage), a separate SAE Form for Clinical 
Trials must be completed (in addition to the Pregnancy Form) as described in 
Section 8.5.3.5, with the appropriate serious criterion (eg, hospitalization) indicated. 
8.5.3.5 
Immediate Reporting of Serious Adverse Events and Events of 
Special 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 on the SAE Form for Clinical 
Trials. The Sponsor’s Study Physician may also be notified by telephone. 
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
The study center staff must transmit the SAE Form for Clinical Trials to the SAE email 
. Even if an initial report is made by telephone, the study center 
staff must still complete the SAE Form for Clinical Trials with all available details, and 
fax the form within 24 hours of knowledge of the event. 
Supplemental information 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 PI (or appropriately trained designee) is expected to take all therapeutic measures 
necessary for resolution of the SAE. Any medications or procedures necessary for 
treatment of the SAE must be recorded on the appropriate pages of the patient’s CRF. 
The study center staff 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. 


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Email all relevant SAE or pregnancy report forms to the Sponsor at the following email 
address: 
Email for SAEs and pregnancy: 
 
Contact information for the Sponsor’s personnel is as follows: 
 
Sponsor’s Study Physician 
 
Eidos Therapeutics, Inc.,  
101 Montgomery Street 
San Francisco, CA 94104 
8.5.3.6 
Clinical Laboratory Determinations 
Blood and urine samples for clinical laboratory tests will be collected at Screening, 
Day 1, Day 14, Day 28, and at the  Follow-up Visit 7 to 14-days after the last dose. At 
screening, the PI or Sub-Investigator will assess the clinical significance of any values 
outside the reference ranges provided by the laboratory, and patients with abnormalities 
judged to be clinically significant will be excluded from the study. Additional 
information on laboratory tests performed can be found in the supplementary study 
specific Laboratory Manual. 
The following clinical laboratory tests will be performed: 
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, alkaline 
phosphatase, calcium, phosphorus, total and fractionated 
(indirect or direct) bilirubin, uric acid, thyroid-stimulating 
hormone (TSH), troponin I, creatine kinase (CK), CK-
MB, and NT-proBNP  
Urinalysis: 
Complete urinalysis (specific gravity, pH, glucose, 
protein, hemoglobin, leukocyte esterase, and nitrite and 
Urine screen for drugs of abuse) by dipstick. Additionally, 
albumin to creatinine ratio and a microscopic urinalysis 
will be performed on every specimen and will specifically 


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look for casts, bacteria, white blood cells, epithelial cells, 
and red blood cells. 
Others: 
Follicle-stimulating hormone [FSH], estradiol, and 
progesterone (in females of child-bearing potential only) 
will be assessed at Screening only  
PT/PTT/INR: 
Coagulation laboratory tests will be completed at all study 
visits for patients who are receiving warfarin (Coumadin®) 
Pregnancy test: 
Serum β-hCG pregnancy test at Screening; 
urine test on Day 1, Day 14, Day 28, and Follow-up (in 
females of child-bearing potential only) 
Samples will be collected, processed, and stored according to the instructions provided in 
the supplementary Laboratory Manual. 
8.5.3.7 
Vital Signs 
At Screening, Day 1, Day 14, Day 28, and at the Follow-up Visit, study center staff will 
assess vital signs pre- and postdose after a 5-minute rest.  
8.5.3.8 
Electrocardiograms 
At Screening, Day 1, Day 14, Day 28, and at the Follow-up Visit, a standard 12-lead 
ECG will be performed in the supine position after a 30-minute rest. 
8.5.3.9 
Echocardiogram 
At Day 1, a resting transthoracic echocardiogram will be performed in the supine position 
as specified in the study procedures manual. Additional details surrounding transthoracic 
echocardiogram acquisition and transmission can be found in the study procedures 
manual.  
8.5.3.10 
Other Safety Assessments 
8.5.3.10.1 
 Physical Examinations 
At Screening, patients will undergo a complete physical examination (PE) which is to be 
completed by a professionally trained physician or health professional including body 
weight and height measurements, and BMI. An abbreviated PE with weight at all other 
visits, including Day 14, Day 28 and Follow-up Visit. 


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8.6 
DATA QUALITY ASSURANCE 
8.6.1 
Data Monitoring 
Before the first patient is dosed in the study, a representative of the Sponsor will meet 
with the PI and the PI’s staff to review the procedures for conducting the study and to 
train the staff 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 PI and his or her staff. The PI will make available to the Sponsor representative the 
source documents, the signed consent forms, and all other study-related documents. The 
PI (or appropriately trained designee) 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 patient 
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. 
8.6.2 
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 PI’s approval of all changes performed on 
his or her patients’ 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 patient confidentiality in accordance 
with the legal stipulations applying to confidentiality of data. Study records (eg, copies of 
CRFs, regulatory documents) will be retained at the study center, along with adequate 
source documentation, according to FDA and ICH requirements. All study records must 
be available for inspection by the Sponsor, its authorized representatives, and FDA 
officials. 


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8.7 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
8.7.1 
General Considerations 
All statistical summaries may be performed using statistical software specified in the 
Statistical Analysis Plan (SAP). Additional software may be used for the production of 
graphics. PK parameters may be computed using 
. Additional 
information regarding statistical analyses can be found in the SAP. 
8.7.2 
Timing of Analyses 
When final in-clinic visits and post treatment follow-up have been completed for all 
patients, the database will be cleaned and locked, randomized treatment assignments will 
be obtained, and safety analyses will be performed. 
8.7.3 
Analysis Sets and Analysis Conventions 
Applicable analysis sets for the secondary endpoints (eg, PK-PD relationship) will be 
defined in the Statistical Analysis Plan (SAP). 
The analysis set for safety analyses will be the Safety Analysis Set: all patients dosed. 
Baseline values are defined as the last value obtained on or before the date of the first 
dose 
8.7.4 
Demographics and Other Baseline Characteristics 
PK parameters will be calculated by patient and summarized by dose levels. Parameters 
will be reported for the first dose as well as at steady-state, i.e. after the last dose. Only 
patients with sufficient data to calculate each PK parameter will be included in the 
summary of each PK endpoint. 
8.7.5 
Extent of Exposure and Treatment Compliance 
The study investigator must maintain exact records of the number of tablets/ bottles of 
study drug dispensed to each patient by recording the following information: 
•
Patient randomization number
•
Date(s) and visit number when study drug was dispensation
•
Number of bottles of study drug dispensed
•
Number of tablets in each bottle
•
Date of return of each study drug kit.


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•
Number of tablets in each bottle returned
An Investigational Product Dose Log will be provided by the Sponsor and maintained at 
the study site to record information for each patient. 
All used and partially used bottles of study drug will be returned to the site for inspection 
and drug accountability reconciliation.  
In addition, the PK listing will be used if needed to corroborate administration of AG10. 
8.7.6 
Pharmacokinetic Analyses 
PK parameters will be calculated for each patient and summarized by dose levels. 
Parameters will be reported for the first dose and PK profile at steady-state (i.e., after the 
last dose). Only patients with sufficient data to calculate each PK parameter will be 
included in the summary of each PK profile. 
8.7.7 
Safety Analyses 
AEs will be coded using the 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 
patient. Concomitant medications will be coded using the WHO Drug Dictionary with 
generic term and therapeutic use (ATC code) and summarized by ATC code, WHO 
generic name, and treatment. Reasons for early termination will be summarized by 
treatment group assignment. Safety laboratory findings, vital signs, and 12-lead ECG data 
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. 
8.7.7.1 
Adverse Events 
An AE (classified by preferred term) that occurs during the treatment period will be 
considered a treatment-emergent adverse event (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. 
Total number of major clinical events will be summarized by treatment and time to event 
analyses will also be performed. 


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8.7.7.2 
DMC Safety Reviews 
The DMC’s role and responsibilities, timing of meetings and the scope of analysis to be 
provided to the DMC will be provided in a mutually agreed upon charter. 
8.7.8 
Pharmacodynamic Analysis 
 will be measured serially as described in the Schedule of Assessments. 
At each time-point, each of these parameters will be summarized by dose. In addition, 
these parameters will be plotted vs plasma drug concentration and the concentration 
response may be modeled as appropriate. 
8.7.9 
Interim Analysis 
No interim analysis is planned for this study. 
8.7.10 
Determination of Sample Size 
The planned number of patients per dosing cohort is based on feasibility and clinical 
judgment.  
8.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
Any amendment to this protocol will be provided in writing by the Sponsor to the PI. No 
protocol amendment may be implemented (with the exceptions noted below) before it has 
been approved by the IRB and before the signature page, signed by the PI, has been 
received by the Sponsor. If the protocol is amended to eliminate or reduce the risk to 
patients, the amendment may be implemented before IRB review and approval. However, 
the IRB must be informed in writing of such an amendment, and approval must be 
obtained within reasonable time limits. 
Protocol deviations will only be recognized and assessed for ethical, medical, scientific, 
and regulatory implications and for impact on the patient’s participation in the study, and 
will be documented.  


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9.0 
STUDY SPONSORSHIP 
9.1 
STUDY TERMINATION 
The Sponsor reserves the right to terminate the study in its entirety or at a specific study 
center at any time. 
9.2 
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 PI will be patient to mutual agreement between the PI 
and the Sponsor. 


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10.0 
INVESTIGATOR OBLIGATIONS 
10.1 
DOCUMENTATION 
The PI (or appropriately trained designee) must provide the following to the Sponsor 
before the start of the study: 
•
A completed and signed Form FDA 1572. If, during the course of the study, any
changes are made that are not reflected on Form FDA 1572, a new Form FDA 1572
must be completed and forwarded to the Sponsor for submission to the FDA
•
A fully executed contract
•
The curricula vitae and licensure for the PI and all Sub-Investigators listed on Form
FDA 1572, as well as for the Clinical Laboratory Director
•
A copy of the initial IRB 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, as described in Section 4.1
•
A copy of the IRB-approved ICF
•
A copy of the HIPAA authorization form (if applicable)
•
A list of the IRB members or the US Department of Health and Human Services
general assurance number
•
A copy of the clinical laboratory certifications and reference ranges
•
The Investigator’s Statement page in this protocol (Section 11.0) signed and dated by
the PI
•
A financial disclosure statement completed and signed by the PI and all
Sub-Investigators listed on Form FDA 1572. If applicable, the PI and
Sub-Investigators will provide an updated financial disclosure statement to the
Sponsor 1 year after the completion of the study
10.2 
PERFORMANCE 
The PI must demonstrate reasonable efforts to obtain qualified patients for the study. 


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10.3 
USE OF INVESTIGATIONAL MATERIALS 
The PI 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 PI or 
Sub-Investigators listed on Form FDA 1572. 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 PI 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. 
All unused IMP may be returned to the Sponsor after all patients have returned for this 
exit/final visit and a final IMP accountability has been completed for the study site. The 
PI will be responsible for ensuring that patients return their IMP. If unused IMP is not 
returned to the Sponsor, proof of destruction must be provided to the Sponsor. 
10.4 
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 PI will be responsible for verifying that all data entries in the 
CRFs are accurate. The PI 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. 
10.5 
RETENTION AND REVIEW OF RECORDS 
The PI must maintain the documentation relating to this study. If the sponsor, the FDA, 
or another regulatory authority wishes to review any documentation relating to the study, 
the PI must permit access to such records. 
The PI must retain a copy of all records that support CRFs for this study (eg, 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 PI 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.  


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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. 
10.6 
PATIENT CONFIDENTIALITY 
All patient records will only be identified by patient initials and patient number. Patients’ 
names are not to be transmitted to the sponsor. The PI will keep a master patient list on 
which the patient number and the full name, address, and telephone number of each 
patient are listed. 


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11.0 
INVESTIGATOR’S STATEMENT 
I agree to conduct the study (Study AG10-201) in accordance with the protocol and with 
all applicable government regulations and GCP guidance. 
________________________________________ 
_____/_____/_____ 
Principal Investigator’s Signature 
Date 
________________________________________ 
Principal Investigator’s Name