Conditions: Dyslipidemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
A study to evaluate the efficacy of K-877 extended release (ER) once daily (QD) compared to K-877 immediate release (IR) twice daily (BID).

Detailed description:

Arms:
arm 1: K-877-ER dose A administered once daily arm 2: K-877-ER dose B administered once daily arm 3: K-877-IR administered twice daily.

Interventions: intervention 1: K-877-ER (Dose A) intervention 2: K-877-ER (Dose B) intervention 3: K-877-IR
Intervention descriptions: intervention 1: Dose A Oral Administration intervention 2: Dose B Oral Administration intervention 3: K-877-IR Oral Administration

Protocol document:
SAP_002.pdf: 
 
 
 
 
 
 
 
 
 
NCT #: 04447820 
 
SAP Version/Date: Version 1.0, 21 August 2020 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 1 of 30 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A Multicenter, Randomized, Open-Label, 4-Week Study 
to Investigate the Efficacy and 
 Profile of 
K-877-ER 
 Treatment (From 
day to 
 
day) Compared to K-877-IR 
 
 
Treatment (
day) in Adult Patients With Fasting 
Triglyceride Levels ≥200 mg/dL and <500 mg/dL 
 
Protocol Number: 
K-877-ER-201 
Protocol Version/Date: 
Version 1.0, 28 January 2020 
Investigational Product: K-877-ER 
 
 
Sponsor: 
Kowa Research Institute, Inc. 
 
 
 
 
 
SAP Version/Date: 
Version 1.0, 21 August 2020 
 
  
CONFIDENTIAL 
This statistical analysis plan is written for Kowa Research Institute, Inc., and it is a confidential 
communication. This document may not be used or published without the consent of Kowa 
Research Institute, Inc. 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 2 of 30 
 
SIGNATURE PAGE 
Protocol Title: 
A Multicenter, Randomized, Open-Label, 4-Week Study to 
Investigate the Efficacy and 
 Profile of K-
877-ER 
 Treatment (From 
day to 
 
day) Compared to K-877-IR 
 
 
Treatment (
day) in Adult Patients With Fasting 
Triglyceride Levels ≥200 mg/dL and <500 mg/dL 
 
Protocol Number: 
K-877-ER-201 
SAP Version/Date: 
Version 1.0, 21 August 2020 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 3 of 30 
 
VERSION HISTORY 
 
Version 
Version Date 
Description 
1.0 
21AUG2020 
Original signed version 
 
 
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 4 of 30 
 
TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 8 
2 
Study Overview ................................................................................................................... 8 
2.1 
Study Objectives .......................................................................................................... 8 
2.1.1 
Primary Objective ................................................................................................. 8 
2.1.2 
Secondary Objectives ........................................................................................... 8 
2.2 
Study Design ............................................................................................................... 8 
2.2.1 
Overview ............................................................................................................... 8 
2.2.2 
Randomization and Blinding ................................................................................15 
2.2.3 
Study Drug ...........................................................................................................15 
2.2.4 
Sample Size Determination ..................................................................................16 
2.3 
Efficacy and 
 Endpoints ....................................................................16 
2.3.1 
Primary Efficacy Endpoint ....................................................................................16 
2.3.2 
Secondary Efficacy Endpoints .............................................................................16 
 
............................................................................16 
2.4 
Safety Endpoints .........................................................................................................17 
3 
Statistical Methodology ......................................................................................................18 
3.1 
General Considerations ..............................................................................................18 
3.1.1 
Analysis Day ........................................................................................................18 
3.1.2 
Analysis Visits ......................................................................................................18 
3.1.3 
Definition of Baseline ...........................................................................................18 
3.1.4 
Summary Statistics ..............................................................................................18 
3.1.5 
Handling of Dropouts and Missing Data ...............................................................18 
3.2 
Analysis Populations ...................................................................................................18 
3.2.1 
Full Analysis Set (FAS) ........................................................................................18 
3.2.2 
Per-Protocol Set (PPS) ........................................................................................19 
3.2.3 
Safety Analysis Set ..............................................................................................19 
 
..............................................................................19 
3.3 
Subject Data and Study Conduct ................................................................................19 
3.3.1 
Subject Disposition ..............................................................................................19 
3.3.2 
Protocol Deviations ..............................................................................................19 
3.3.3 
Analysis Populations ............................................................................................19 
3.3.4 
Demographic and Baseline Characteristics ..........................................................20 
3.3.5 
Medical History ....................................................................................................20 
3.3.6 
Concomitant Medications .....................................................................................20 
3.3.7 
Study Drug Exposure and Compliance ................................................................21 
3.4 
Efficacy Assessment ...................................................................................................21 
3.4.1 
Primary Efficacy Endpoint ....................................................................................22 
3.4.2 
Secondary Efficacy Endpoints .............................................................................24 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 5 of 30 
 
 
...........................................................................................24 
3.6 
Safety Assessment .....................................................................................................26 
3.6.1 
Adverse Events (AEs) ..........................................................................................26 
3.6.2 
Clinical Laboratory Tests .....................................................................................26 
3.6.3 
Vital Signs ............................................................................................................28 
3.6.4 
Electrocardiograms ..............................................................................................28 
3.6.5 
Physical Examinations .........................................................................................28 
4 
Analysis Timing ..................................................................................................................28 
4.1 
Draft Analysis/Blinded Data Reviews ..........................................................................28 
4.2 
Interim Analysis ..........................................................................................................28 
4.3 
Pre-Final Analysis .......................................................................................................28 
4.4 
Final Analysis ..............................................................................................................28 
5 
Changes from Protocol-Specified Statistical Analyses .......................................................29 
6 
Programming Specifications ..............................................................................................29 
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 6 of 30 
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ALP 
Alanine Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical therapeutic chemical 
 
 
 
 
 
 
 
 
 
 
 
 
 
BLQ 
Below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CK 
Creatinine Kinase 
 
 
 
 
 
 
 
COVID-19 
Coronavirus Disease 2019 
 
 
CRF 
Case report form 
CSR 
Clinical Study Report 
eGFR 
Estimated Glomerular Filtration Rate 
ECG 
12-lead Electrocardiogram 
FAS 
Full Analysis Set 
IRT 
Interactive Response Technology 
 
 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
PPS 
Per-Protocol Set 
 
 
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 7 of 30 
 
Abbreviation 
Definition 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
 
 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TG 
Triglyceride 
 
 
ULN 
Upper limit of normal 
 
 
  
 
 
 
WHO 
World Health Organization 
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 8 of 30 
 
1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number          
K-877-ER-201. The SAP will be finalized prior to database lock. Any deviations from the SAP 
after database lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of this study is to demonstrate the efficacy of K-877-ER 
 
 
(
 compared to K-877-IR 
 
 (
 from baseline to Day 28 in lowering fasting 
triglyceride (TG) levels in patients with fasting TG levels ≥200 mg/dL and <500 mg/dL. 
2.1.2 Secondary Objectives 
The secondary objectives of this study are as follows: 
• 
To demonstrate the efficacy of K-877-ER 
 
 compared to K-877-IR 
 
 
from baseline to Day 28 in lowering fasting TG levels in patients with fasting TG levels 
≥200 mg/dL and <500 mg/dL. 
• 
To evaluate the efficacy of K-877-ER 
 treatments (from 
day to 
day) 
from baseline to Day 28 in altering pharmacodynamic properties, including lipid 
parameters, in patients with fasting TG levels ≥200 mg/dL and <500 mg/dL.  
• 
To evaluate the multiple-dose 
 (
 properties 
of 
K-877-ER 
 
2.2 Study Design 
2.2.1 Overview 
This is a Phase 2, multicenter, randomized, open-label study investigating the efficacy and 
 
profile of K-877-ER 
 treatment (from 
day to 
day) compared to 
K-877-IR 
 
 treatment (
day) in adult patients with fasting TG levels ≥200 mg/dL 
and <500 mg/dL. The study consists of a Screening Period, of up to 10 weeks, and a 4-week 
Treatment Period. During the Treatment Period, patients will receive K-877-ER 
 
 
K-877-ER 
 
 or K-877-IR 
 
 
Approximately 90 patients (from 12 sites in the United States) who meet all the inclusion criteria 
and no exclusion criteria will be enrolled in the study. Of the approximately 90 patients enrolled, 
24 patients will be enrolled as 
 patients, and will have blood samples for 
 assessments 
collected. Non-
 patients will not have blood samples for 
 assessments collected. 
The Screening Period will occur no more than 70 days and no less than 7 days prior to the first 
dose of study drug (Day 1, Visit 4). The up to 10-week Screening Period will allow for a 6-week 
washout period, if needed, followed by up to a 4-week Qualification Period that will be used to 
assess patient eligibility. At the Screening Visit (Visit 1), a patient’s individual TG level must be 
≥180 mg/dL and <550 mg/dL. 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
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Patients on non-permitted background lipid-altering therapy must complete a 6-week washout 
period prior to the first Qualification Period visit (Visit 2). If a patient does not require washout, 
the patient may start the Qualification Period (Visit 2) 24 hours after signing the ICF. Patients 
may continue through the Qualification Period provided there are no prohibitive safety or 
eligibility results from the Screening Visit (Visit 1) laboratory tests. 
 
 
 
 
 
 
 
 
 
Prior to treatment on Day 1, eligible patients will be randomized in a 1:1:1 ratio to one of three 
treatment groups. Randomization will be stratified by sex (male or female), statin use (yes or 
no), and 
 assessment (yes or no). 
Treatment Period will occur from Days 1 through 28. On Days 14 and 28, patients will return to 
the clinical site for efficacy and safety assessments. Patients enrolled as 
 patients will be 
admitted to the clinical site on Day -1 and confined until discharge on Day 2. On Day 27, 
 
patients will be readmitted to the clinical site and confined until discharge on Day 29. 
 
 
Patients will participate in a Follow-Up Telephone Call 7 days (2 days) following the last dose 
of study drug for safety monitoring. 
All procedures to be conducted during the study, including timing of all procedures, are 
described in the Schedule of Procedures.  
Selected study procedures will be performed prior to administration of study drug, as applicable. 
The schedule of procedures for 
 and 
 procedures can be 
found below in Tables 1 and 2 respectively. 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
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Table 1. Schedule of Procedures 
 
a. 
Patients who are screen failures for a modifiable condition, other than failing the TG criteria, can be re-screened once. Before each patient is re-screened, the 
Investigator should discuss the case with the Medical Monitor. 
b. 
At the Screening Visit (Visit 1), patients not needing a washout period may start the Qualification Period (Visit 2) 24 hours after signing the informed consent 
form. Patients may continue through the Qualification Period provided that there are no prohibitive safety or eligibility results from the Screening Visit (Visit 1) 
laboratory tests.  
c. 
All Qualification Period visits will occur 7 days (3 days) apart.  
d. 
The last fasting TG Qualification Period visit (Visit 3 or 3.1) should occur 1 week prior to Day 1 (Visit 4).  
 
Screening Period 
Treatment Period 
Follow-Up 
Telephone 
Callf 
 
Screening 
Visita,b 
Qualification Periodc 
Visit Name 
Visit 1 
Visit 2b 
Visit 3d 
Visit 
3.1d,e 
Visit 4d  
Visit 5 
Visit 6/ET 
Study Day 
-70 to -29 
-28 to -21 
-21 to -14 
-14 to -7 
1 
14 
28 
35 
Visit Window (days) 
 
3  
3  
3  
 
3  
3  
2  
Assessment 
 
 
 
 
 
 
 
 
Informed consentg 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
X 
X 
 
 
 
Fasting TG level 
 
Xh 
Xh 
Xh 
 
 
 
 
Serum FSHi 
X 
 
 
 
 
 
 
 
Pregnancy testj 
X 
 
 
 
Xk 
 
Xk 
 
Height, body weight, and BMI 
X 
 
 
 
 
 
Xk,l 
 
Demographic/medical history 
X 
 
 
 
 
 
 
 
Urine drug screenm 
X 
 
 
 
 
 
 
 
Prior/concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, FT4, and HbA1c 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
Xk 
 
 
 
Physical examinationn 
X 
 
 
 
Xk 
Xk 
Xk 
 
Clinical laboratory testso 
X 
 
 
 
Xk 
Xk 
Xk 
 
Vital signsp 
X 
 
 
 
X 
X 
X 
 
12-lead ECGq 
X 
 
 
 
X 
 
X 
 
PD sampler 
X 
 
 
 
Xk 
Xk 
Xk 
 
Dispense study drugs 
 
 
 
 
X 
 
 
 
Dosingt 
 
 
 
 
X 
 
AEs 
X 
Study drug compliance check 
 
 
 
 
 
X 
X 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
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Page 11 of 30 
 
e. 
Visit 3.1 is only needed if 1 Qualification Period TG level from Visit 2 or 3 is within 10% of the target range (180 mg/dL and <550 mg/dL) and 1 Qualification 
Period TG level from Visit 2 or 3 is within the target range (200 mg/dL and <500 mg/dL).  
f. 
A Follow-Up Telephone Call will be performed 7 days (2 days) following the last dose of study drug. 
g. 
Written consent must be obtained from the patient prior to any study-specific procedure or investigation, including the washout period when applicable. 
 
 
 
 
 
 
 
 
i. 
FSH is to be obtained in women <55 years of age who have not had a menstrual period for 1 year. Female patients will be considered postmenopausal if the 
FSH level is in the central laboratory’s normal range for postmenopausal phase.  
j. 
Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit (Visit 1), a negative urine pregnancy test at Visit 4 
and Visit 6, and must agree to use effective methods of contraception.   
k. 
Assessments will be performed prior to dosing.  
l. 
Only body weight will be measured at Visit 6 prior to dosing. 
m. A urine drug screen will be performed at the discretion of the Investigator. 
n. 
At the Screening Visit, a complete physical examination excludes pelvic, rectal, and breast examinations. All other physical examinations throughout the study 
must include a symptom-directed physical examination, as well as an examination of the heart, lungs, and abdomen and a visual examination of the skin. 
o. 
Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
p. 
Vital signs include systolic and diastolic BP, pulse, respiratory rate, and body temperature and will be measured (sitting) after resting for a minimum of 
5 minutes. Patients should avoid smoking, caffeine, or exercise within 30 minutes prior to BP measurement. On Days 1, 14, and 28, BP and pulse must be 
measured prior to administration of study drug and again approximately 1 hour post-administration.  
q. 
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection. 
r. 
PD assessments will be performed under fasting conditions (8 hours) and include TG, TC, LDL-C, HDL-C, remnant cholesterol (calculated as TC – LDL-C – 
HDL-C), non-HDL-C, FFA.  
s. 
Study drug, for entire treatment period, will be dispensed to eligible patients on Day 1 (Visit 4), after randomization, via the IRT system. 
t. 
Daily oral dose will be administered by the patient and taken according to treatment group starting on Day 1 (Visit 4) and concluding on Day 28 (Visit 6) (28 
dosing days). Patients in the K-877-IR 
 
 treatment group will receive only the morning dose on Day 28. Study drug will be administered in the fed 
state at 0 hour with 240 mL of room temperature tap water. 
AE = adverse event; 
 = 
 BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; ET = Early Termination; FFA = free fatty acid; 
FSH = follicle-stimulating hormone; FT4 = free thyroxine; HbA1c = hemoglobin A1c; HBsAG = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high-
density lipoprotein cholesterol; HIV = human immunodeficiency virus; IRT = interactive response technology; LDL-C = low-density lipoprotein cholesterol; 
PD = pharmacodynamic(s); TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone.  
 
 
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 12 of 30 
 
Table 2. Schedule of Procedures (
 
 
Screening Period 
Check-
In 1 
Treatment Period 
Follow-Up 
Telephone 
Callf 
 
Screening 
Visita,b 
Qualification Periodc 
Visit Name 
Visit 1 
Visit 
2b 
Visit 
3d 
Visit 
3.1d,e 
Visit 
4d 
Discharge 
1 
Visit 
5 
Check-
In 2 
Visit 
6/ET 
Discharge 
2 
Study Day 
-70 to -29 
-28 
to  
-21 
-21 to 
-14 
-14 
to -7 
-1 
1 
2 
14 
27 
28 
29 
35 
Visit Window 
(days) 
 
3  
3  
3  
 
 
 
3  
 
3  
 
2  
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consentg 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Fasting TG level 
 
Xh 
Xh 
Xh 
 
 
 
 
 
 
 
 
Serum FSHi 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Height, body 
weight, and BMI 
X 
 
 
 
 
 
 
 
 
Xk 
 
 
Demographic/ 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screenl 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, FT4, and 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
Xm 
 
 
 
 
 
 
Physical 
examinationn 
X 
 
 
 
 
Xm 
 
Xm 
 
Xm 
 
 
Clinical laboratory 
testso 
X 
 
 
 
 
Xm,p 
 
Xm 
 
Xm,p 
 
 
Vital signsq 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
12-lead ECGr 
X 
 
 
 
 
X 
 
 
 
X 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 13 of 30 
 
Table 2. Schedule of Procedures (
 patients) (Continued) 
 
 
Screening Period 
Check-
In 1 
Treatment Period 
Follow-Up 
Telephone 
Callf 
 
Screening 
Visita,b 
Qualification Periodc 
Visit Name 
Visit 1 
Visit 
2b 
Visit 
3d 
Visit 
3.1d,e 
Visit 
4d 
Discharge 
1 
Visit 
5 
Check-
In 2 
Visit 
6/ET 
Discharge 
2 
Study Day 
-70 to -29 
-28 
to  
21 
-21 to 
-14 
-14 
to -7 
-1 
1 
2 
14 
27 
28 
29 
35 
Visit Window 
(days) 
 
3 
3 
3 
 
 
 
3 
 
3 
 
2 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
PD samples 
X 
 
 
 
 
Xi 
 
Xm 
 
Xm 
 
 
 
Admission to 
clinical site 
 
 
 
 
X 
 
 
 
X 
 
 
 
Discharge from 
clinical site 
 
 
 
 
 
 
X 
 
 
 
X 
 
Dispense study 
drugv 
 
 
 
 
 
X 
 
 
 
 
 
 
Dosingw 
 
 
 
 
 
X 
 
 
AEs 
                                                                                               X 
Study drug 
compliance check 
 
 
 
 
 
 
 
X 
 
X 
 
 
a. 
Patients who are screen failures for a modifiable condition, other than failing the TG criteria, can be re-screened once. Before each patient is re-screened the 
Investigator should discuss the case with the Medical Monitor. 
b. 
At the Screening Visit (Visit 1), patients not needing a washout period may start the Qualification Period 24 hours after signing the informed consent form. 
Patients may continue through the Qualification Period provided that there are no prohibitive safety or eligibility results from the Screening Visit (Visit 1) 
laboratory tests.  
c. 
All Qualification Period visits will occur 7 days (3 days) apart.  
d. 
The last fasting TG Qualification Period visit (Visit 3 or 3.1) should occur 1 week prior to Day 1 (Visit 4). 
e. 
Visit 3.1 is only needed if 1 Qualification Period TG level from Visit 2 or 3 is within 10% of the target range (180 mg/dL and <550 mg/dL) and 1 Qualification 
Period TG level from Visit 2 or 3 is within the target range (200 mg/dL and <500 mg/dL). 
f. 
A Follow-Up Telephone Call will be performed 7 days (2 days) following the last dose of study drug. 
g. 
Written informed consent must be obtained from the patient prior to any study-specific procedure or investigation, including the washout period when 
applicable.  
 
 
 


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i. 
FSH is to be obtained in women <55 years of age who have not had a menstrual period for 1 year. Female patients will be considered postmenopausal if the 
FSH level is in the central laboratory’s normal range for postmenopausal phase.  
j. 
Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit (Visit 1), a negative urine pregnancy test at 
Check-Ins 1 and 2, and must agree to use effective methods of contraception.  
k. 
Only body weight will be measured at Visit 6 prior to dosing. 
l. 
A urine drug screen will be performed at the discretion of the Investigator. 
m. Assessments will be performed prior to dosing. 
n. 
At the Screening Visit, a complete physical examination excludes pelvic, rectal, and breast examinations. All other physical examinations throughout the study 
must include a symptom-directed physical examination, as well as an examination of the heart, lungs, and abdomen and a visual examination of the skin. 
o. 
Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
p. 
Urinalysis is needed on Days 1 (Visit 4) and 28 (Visit 6).  
q. 
Vital signs include systolic and diastolic BP, pulse, respiratory rate, and body temperature and will be measured (sitting) after resting for a minimum of 
5 minutes. Patients should avoid smoking, caffeine, or exercise within 30 minutes prior to BP measurement. On Days 1, 14, and 28, BP and pulse must be 
measured prior to administration of study drug and again approximately 1 hour post-administration. 
r. 
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.  
s. 
PD assessments will be performed under fasting conditions (8 hours) and include TG, TC, LDL-C, HDL-C, remnant cholesterol (calculated as TC – LDL-C – 
HDL-C), non-HDL-C, FFA. 
 
 
 
 
 
 
 
  
v. 
Study drug, for entire treatment period, will be dispensed to eligible patients on Day 1 (Visit 4), after randomization via the IRT system. 
w. Daily oral dose will be administered by the patient and taken according to treatment group starting on Day 1 (Visit 4) and concluding on Day 28 (Visit 6) (28 
dosing days). Patients in the K-877-IR 
 
 treatment group will receive only the morning dose on Day 28. Study drug will be administered in the fed 
state at 0 hour with 240 mL of room temperature tap water. 
AE = adverse event; 
 = 
 BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; ET = Early Termination; FFA = free fatty acid; 
FSH = follicle-stimulating hormone; FT4 = free thyroxine; HbA1c = hemoglobin A1c; HBsAG = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high-
density lipoprotein cholesterol; HIV = human immunodeficiency virus; IRT = interactive response technology; LDL-C = low-density lipoprotein cholesterol; 
 = 
s); PD = pharmacodynamic(s); TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone


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K-877-ER-201                                         
CONFIDENTIAL 
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2.2.2 Randomization and Blinding 
2.2.2.1 Randomization 
On Day 1, prior to dosing, eligible patients will be randomized in a 1:1:1 ratio to 1 of 3 treatment 
groups. Patients will receive K-877-ER 
 
 K-877-ER 
 
 or K-877-IR 
 
 starting on Day 1 through 28. Treatment groups are detailed in Table 3. 
 
Randomization will be stratified by sex (male or female), statin use (yes or no), and 
 
 (yes or no). The Investigator or designee will access interactive response 
technology (IRT) and enter the patient identification number. The IRT system will record the 
randomized treatment assignment for the patient and assign the appropriate study drug kit. 
2.2.2.2 Blinding 
This study is open-label.  
2.2.3 Study Drug 
Study drug, for entire treatment period, will be dispensed to eligible patients beginning on Day 1 
(Visit 4), after randomization, via the IRT system. 
Patients will receive oral doses of K-877-ER 
 
 (one 
 tablet every morning), K-
877-ER 
 
 (two 
 tablets every morning), or K-877-IR 
 
 (one 
 
 the morning and one 
 tablet in the evening) starting on Day 1 and concluding on 
Day 28 in the fed state. Patients in the K-877-IR 
 
 treatment group will receive only 
the morning dose on Day 28. Study drug will be administered in the fed state at 0 hour with 240 
mL of room temperature tap water.  
Table 3. 
 
 
 
 
 
 
K-877-ER 
 
 
K-877-ER 
 
 
 
K-877-ER 
 
 
K-877-ER 
 
 
 
K-877-IR 
 
 
K-877-IR 
 
K-877-IR 
 
 
Within 30 minutes prior to study drug administration on Days 1 and 28, 
 patients confined to 
the clinical site will be administered a meal containing approximately 2300 to 2500 calories, less 
than 60% carbohydrates, and less than 25% fat. On Days 1 and 28, 
 patients will remain 
fasted for at least 4 hours after morning dose. 
 patients will not receive any oral fluids other 
than those used to administer the dose for 1 hour before and 1 hour after dosing on Days 1 and 
28. 
 patients will remain standing or sitting upright for 4 hours after dosing, except as required by 
any study procedure. Patients in the K-877-IR 
 
 treatment group will receive an 
evening dose after a meal.  
Diet and dosing time should remain consistent for all doses throughout the study. Patients will 
be instructed by the site to follow dosing instructions on the drug packaging and to return all 
used, partially used, and unused study drug materials on Day 28. 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
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2.2.4 Sample Size Determination 
Approximately 90 patients will be enrolled. 
Assuming an effect size delta = 0, pooled SD = 21.38, an alpha = 0.05 (1-sided), and a non-
inferiority limit of 15%, a sample size of 26 patients per treatment group provides a power of 
0.80.  
In the case that the actual effect size delta is 10% (effect of tested regimen 10% less than the 
reference regimen), the power is then 0.2. If the real effect is different, the result less likely 
shows non-inferiority.  
To account for potential drop off, a total of 90 patients, 30 patients in each treatment group, is 
planned to be randomized. 
2.3 Efficacy and 
 Endpoints 
2.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in fasting TG from baseline to Day 28. The 
baseline fasting TG level will be defined as the mean of 3 TG levels: 2 Qualification Period TG 
levels within the target range (≥200 mg/dL and <500 mg/dL) and the Day 1 (Visit 4) TG level. 
2.3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the percent change from baseline to Day 28 for the 
following:  
• 
Total cholesterol (TC) 
• 
Low-density lipoprotein cholesterol (LDL-C) 
• 
High-density lipoprotein cholesterol (HDL-C)  
• 
Remnant cholesterol (calculated as TC – LDL-C – HDL-C)  
• 
Non-HDL-C  
• 
Free fatty acids 
2.3.3 
 
 
 
 
 
 
 
 
 
 
• 
                            
  


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2.4 Safety Endpoints  
Safety assessments include analysis of adverse events (AEs), clinical laboratory evaluations 
(serum chemistry, hematology, coagulation, and urinalysis), vital signs (blood pressure, pulse 
rate, respiratory rate, and body temperature), 12-lead electrocardiogram (ECG), and physical 
examinations.    


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3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of randomization. The day of randomization will be 
Day 1, and the day immediately before Day 1 will be Day -1. There will be no Day 0. 
3.1.2 Analysis Visits 
The study consists of a 28-day treatment period where study visits will occur at Day 1, Day 14, 
and Day 28. Scheduled visits will be assigned to analysis visits as recorded on the case report 
form (CRF). Unscheduled and early termination visits will be analyzed at the next available visit 
within the 28-day treatment period. Where multiple measurements for a parameter appear 
within an analysis visit, the scheduled visit will be used. If there is no scheduled visit and 
multiple unscheduled visits and/or early termination visits exist within an analysis visit, the later 
result will be used for the summary measure. 
Analysis visits to be assigned are Baseline, Day 14, and Day 28. 
Any primary or secondary efficacy measurements that have resulted from a non-fasting sample 
will be considered invalid and will not be used in the derivation of the efficacy endpoint. 
3.1.3 Definition of Baseline  
Baseline for TG will be defined as the mean of 3 TG levels: 2 TG levels within the target range 
(≥200 mg/dL and <500 mg/dL) and the Day 1 (Visit 4) TG level. If any of the 3 TG levels are 
missing, the average of non-missing TG levels will be used to calculate baseline. 
Baseline for all other efficacy and safety variables will be defined as the Visit 4 (Day 1) 
measurement. If the measurement at this visit is missing, the last measurement prior to the first 
dose of study drug will be used as baseline. 
3.1.4 Summary Statistics 
All study-collected data will be summarized by treatment group for the appropriate analysis 
population, using descriptive statistics, graphs, and/or raw data listings. Descriptive statistics for 
continuous variables will include n (number of non-missing values), mean, standard deviation, 
first quartile (Q1), median, third quartile (Q3), minimum, and maximum. Analysis of categorical 
variables will include frequency and percentage. 
3.1.5 Handling of Dropouts and Missing Data 
Missing data will be imputed only in the context of sensitivity analysis as described in section 
3.4.1.     
3.2 Analysis Populations 
3.2.1 Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all randomized patients who take at least 1 dose of 
study drug and have a baseline fasting TG measurement. Analyses of primary and secondary 
efficacy endpoints will be performed on the FAS.  


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3.2.2 Per-Protocol Set (PPS) 
The Per-Protocol Set (PPS) will include all FAS patients without any major protocol deviations 
and who have baseline and Day 28 endpoint fasting serum TG measurements. Major protocol 
deviations will be confirmed prior to database lock. Major protocol deviations that may impact 
the primary efficacy assessment may include but are not limited to: 
• 
Failed to meet eligibility criteria 
• 
Discontinued study drug 
• 
Had study drug compliance <80% or >120% 
• 
Took a restricted concomitant medication 
A list of patients with major protocol deviations leading to exclusion from the PPS will be 
finalized prior to database lock. 
The Per-Protocol Set will be the primary analysis population. 
3.2.3 Safety Analysis Set 
The Safety Analysis Set will include all randomized patients who receive at least 1 dose of 
randomized study drug. All safety analyses will be conducted on the Safety Analysis Set. 
3.2.4 
 
 
 
   
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Counts and percentages of patients who were screened (signed informed consent), 
discontinued early during screening (screen failures), and randomized will be summarized in 
total based on all screened patients. Primary reasons for screen failure will also be summarized. 
Patients whose primary reason for screen failure was due to Coronavirus Disease 2019 
(COVID-19) will also be summarized. 
Counts and percentages of patients who were randomized, treated, discontinued early from the 
study, and completed the study will be summarized by treatment and in total based on all 
randomized patients. Primary reasons for early discontinuation will also be summarized. 
Patients whose primary reason for early discontinuation was due to COVID-19 will also be 
summarized. 
3.3.2 Protocol Deviations 
Protocol deviations are defined in the Protocol Deviation Plan and classified as CSR reportable 
or CSR non-reportable. All CSR-reportable protocol deviations will be listed. 
3.3.3 Analysis Populations 
Counts and percentages of patients in each analysis population will be summarized by 
treatment and in total based on all randomized patients.  


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3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years) and age categories (<65 years, ≥65 years) 
• 
Sex (Male or Female) 
• 
Age categories by sex (Age categories include <12 years, 12 - <18 years, 18 - <65 
years, and ≥ 65 years). 
• 
Childbearing potential 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (BMI) (kg/m2)  
• 
Statin Use (Yes, No) 
• 
 
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of patients as appropriate by treatment and in total for all randomized 
patients and each defined analysis population. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 23.0. Dictionary updates will be applied at 
the time of database lock to the latest version available. Counts and percentages of patients 
with medical history by system organ class and preferred term will be summarized by treatment 
and in total based on all randomized patients. 
3.3.6 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the WHODrug Dictionary Global B3, September 2019. Dictionary updates 
will be applied at the time of database lock to the latest version available. For summary 
purposes, medications will be considered prior medications if they were stopped prior to the first 
dose of study drug and concomitant medications if they were taken at any time after the first 
dose of study drug (i.e. started prior to the first dose of study drug and were ongoing or started 
after the first dose of study drug). 
If a medication has incomplete start or stop dates, dates will be imputed to determine whether a 
medication should be considered prior or concomitant. If a medication start date is incomplete, 
the first day of the month will be imputed for missing day and January will be imputed for 
missing month. If a medication stop date is incomplete, the last day of the month will be imputed 
for missing day and December will be imputed for missing month. Incomplete start and stop 
dates will be listed as collected without imputation. 
Counts and percentages of patients taking prior and concomitant medications by ATC class and 
preferred term will be summarized by treatment and in total based on the Safety Analysis Set.   


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3.3.7 Study Drug Exposure and Compliance 
Days of exposure to study drug will be calculated as date of last dose of study drug – date of 
first dose of study drug + 1. Note that the exposure calculation is intended to describe the length 
of time a patient was exposed to study drug and therefore does not take study drug interruptions 
into account. Days of exposure to study drug will be summarized by treatment based on the 
Safety Analysis Set with descriptive statistics.  
Percent compliance to the study drug regimen will be calculated as follows: 
For patients randomized to the K-877-ER 
 
 arm, compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛+ 1
 𝑥 100 
For patients randomized to the K-877-ER 
 
 arm, compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
2 ∗(𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛+ 1)
 𝑥 100 
For patients randomized to the K-877-IR 
 
 arm and completed the 28-day treatment 
period, compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
(2 ∗(𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛+ 1)) −1
 𝑥 100 
For patients randomized to the K-877-IR 
 
 arm and discontinued prior Day 28, 
compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
2 ∗(𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛+ 1)
 𝑥 100 
If study drug is not returned, the number of tablets returned will be considered 0 for the 
compliance calculation.   
Percent compliance to the study drug will be summarized by treatment based on the Safety 
Analysis Set with descriptive statistics and with counts and percentages of patients with 
compliance in the following categories: 
• 
<80% 
• 
80-120% 
• 
>120% 
3.4 Efficacy Assessment 
Efficacy data will be summarized by randomized treatment based on the PPS. The primary and 
secondary efficacy endpoints will also be summarized based on the FAS. Descriptive statistics 
(n, mean, standard deviation [SD], first quartile [Q1], median, third quartile [Q3], minimum, 
maximum, and 90% CI) for the primary endpoint and secondary endpoints will be summarized 
by treatment group at baseline and Days 14 and 28. Descriptive statistics for changes from 
baseline and for percent changes from baseline to each visit will also be summarized. 
All available and derived data for the primary and secondary endpoints will be listed for the 
randomized patients.  


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Spaghetti plots of individual patient data by treatment and box plots of the percent change from 
baseline to each post-baseline visit by treatment will be generated for the primary and 
secondary efficacy endpoints based on the PPS and FAS. Mean ± SD of percent change from 
baseline to each post-baseline visit by treatment will also be generated for the primary and 
secondary efficacy endpoints based on the PPS and FAS. 
 
3.4.1 Primary Efficacy Endpoint 
Primary Analysis 
The primary analysis variable is the percent change in fasting TG from baseline to Day 28. 
The primary efficacy analysis will compare 1 of the 2 K-877-ER treatments (test treatments) to 
the K-877-IR 
 
 treatment (reference treatment) in percent change from baseline to 
Day 28 and will be carried out using mixed model for repeated measures (MMRM) based on the 
PPS. The MMRM model will include percent change from baseline value as the dependent or 
response variable. Variables for Visit (Day 14 or 28), treatment (K-877-ER 
 
 K-877-
ER 
 
 or K-877-IR 
 
 the interaction term between Visit and treatment, 
baseline TG value, sex (male or female), and statin use (yes or no) will be used as fixed effects. 
An unstructured covariance matrix will be used to model the within-subject correlation. The 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. The 
analysis will be performed based on all observed post-baseline scores without any imputation of 
missing data. In the case when the MMRM fails to converge using an unstructured covariance 
matrix in any stage, a less stringent covariance matrix (e.g., autoregressive 1) will be used.  
The sample SAS code for primary efficacy analysis can be found below: 
******************************************************************* 
* PCHG = Percent change in TG 
* VISIT = Visit 
* TRT = Treatment group 
* TRT*VISIT = Treatment group by visit interaction 
* BASE = Baseline value 
* SEX = Gender (Male or Female) 
* STATIN = Statin Use (Yes or No) 
* USUBJID = Unique subject identifier 
********************************************************************; 
PROC MIXED DATA=efficacy METHOD=REML COVTEST; 
 CLASS USUBJID VISIT TRT SEX STATIN; 
 MODEL PCHG = VISIT TRTA TRT*VISIT BASE SEX STATIN/DDFM=KENWARDROGER; 
 REPEATED / TYPE=UN SUBJECT=USUBJID; 
  
 LSMEANS TRT / DIFF CL ALPHA = 0.10;  
  
 LSMESTIMATE TRT 'ER0.4MG - IR0.2MG’ 1 0 -1 / ALPHA = 0.05 CL; 
 LSMESTIMATE TRT 'ER0.8MG - IR0.2MG' 0 1 -1 / ALPHA = 0.05 CL; 
 
 ODS OUTPUT TESTS3= TESTS3 LSMESTIMATES=LSMESTIMATES LSMEANS=LSMEAN DIFFS=D; 
run; 
Point estimates and 2-sided 90% confidence intervals (CIs), as well as 95% CIs of the 
differences of least squares means between either of the test treatments and reference 


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treatment will be calculated. A non-inferiority of tested treatments will be indicated if the upper 
limit of the 2-sided 90% CI is <15% in TG percent change from baseline. 
Secondary Analyses  
As a secondary analysis, the primary analysis described above will be repeated in the FAS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
  
 
     
 
 
     
 
 
 
 
 
 
     
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
      
 
 
      
 
 
 
 
 
      
 
  
 
 
 
 
      
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
     
 
 
     
 
 
     
 
 
 
 


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3.4.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be summarized and analyzed in the same manner as the 
primary analysis (Section 3.4.1). Each secondary endpoint will be evaluated using the MMRM 
model in the PPS where percent change from baseline variable will be used as the dependent 
or response variable. 
The following secondary endpoints will be analyzed: 
• 
TC 
• 
LDL-C 
• 
HDL-C 
• 
Remnant cholesterol (calculated as TC – LDL-C – HDL-C) 
• 
Non-HDL-C 
• 
Free fatty acids 
Analysis of the above secondary efficacy endpoints will also be repeated in the FAS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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3.6 Safety Assessment 
Safety data will be summarized by actual treatment received (and in total for selected analyses) 
based on the Safety Analysis Set. 
3.6.1 Adverse Events (AEs) 
AEs will be captured from the date of informed consent through study completion. All AEs will 
be coded to system organ class and preferred term using MedDRA version 23.0. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that occurred for the first time 
after the first dose of study drug or existed prior to the first dose and worsened during the 
treatment period. AE worsening applies to severity, or relationship to study drug.   
An overview of AEs will be provided including counts and percentages of patients and event 
counts with the following: 
• 
Any TEAEs (overall, by maximum severity, and by relationship to study drug) 
• 
Any study drug related TEAEs (overall and by maximum severity) 
• 
 
• 
Any serious AEs (SAEs) 
• 
Any treatment-emergent serious AEs (TESAEs) 
• 
Any study drug related TESAEs 
• 
Any AEs and TEAEs  leading to death 
• 
Any TEAEs leading to study drug discontinuation 
• 
Any TEAEs leading to study discontinuation 
• 
Any TESAEs leading to study drug discontinuation 
• 
Any study drug related TEAEs leading to study drug discontinuation 
Counts and percentages of patients and event counts will also be presented by system organ 
class and preferred term for each of the categories in the overview. 
Listings will be presented specifically for SAEs and TEAEs leading to discontinuation of study 
drug. 
3.6.2 Clinical Laboratory Tests 
Descriptive statistics for chemistry and hematology parameters will be presented at baseline 
and each post-baseline visit. At each post-baseline visit, change from baseline will also be 
summarized. 
Incidence of lab abnormalities indicated as ‘below the lower limit of normal (LLN) range’ and 
‘above the upper limit of normal (ULN) range’ at each visit will be summarized for chemistry and 
hematology parameters with counts and percentages of patients. 
Post-baseline changes of lab tests abnormalities for alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), creatinine kinase (CK), total bilirubin, alkaline phosphatase (ALP), and 
estimated Glomerular Filtration Rate (eGFR) will be summarized by presenting a shift table with 


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number and percentage of patients in each treatment group with worst post-baseline value 
satisfying each of the criteria in the table below.  
Parameter 
Categories 
ALT 
<Normal 
Normal 
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN 
>5xULN to 
≤10xULN 
>10xULN to 
≤20xULN 
>20x
ULN  
AST 
<Normal 
Normal 
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN 
>5xULN to 
≤10xULN 
>10xULN to 
≤20xULN 
>20x
ULN  
ALP 
<Normal 
Normal 
>1xULN to 
≤ 1.5xULN 
>1.5xULN 
 
 
 
CK 
<Normal 
Normal 
>1xULN to 
≤5xULN 
>5xULN to 
≤10xULN 
>10xULN 
 
 
Total 
Bilirubin 
<Normal 
Normal 
>1xULN to 
≤1.5xULN 
>1.5xULN 
to 
≤2xULN 
>2xULN 
 
 
Total 
Bilirubin 
accompani
ed by ALT 
or AST > 
3xULN 
<Normal 
Normal 
>1xULN to 
≤1.5xULN 
>1.5xULN 
to 
≤2xULN 
>2xULN 
 
 
eGFR 
≥90 
mL/min/
1.73m2 
≥60 to 
<90 
mL/min
/1.73m2 
≥30 to <60 
mL/min/1.7
3m2 
<30   
mL/min/1.7
3m2 
 
 
 
Spaghetti plots of patient data over time and boxplots of the values at baseline and each post-
baseline visit will be presented by treatment for ALP, ALT, AST, CK, and total bilirubin. Normal 
ranges will be displayed on these plots for reference. 
Counts and percentages of patients who meet ALT or AST >3xULN, ALP < 2xULN, and total 
bilirubin ≥2xULN at any time after the first dose of the study drug are identified as potential Hy’s 
Law cases and will be summarized, and data for ALT, AST, ALP and total bilirubin for these 
patients will be listed.  
To assess cases meeting requirements for Hy’s Law, an eDISH (evaluation of drug-induced 
serious hepatotoxicity) figure plotting peak ALT vs. peak total bilirubin (both on a logarithmic 
scale xULN) will be produced as recommended by Watkins et al (2008), so that values within 
the normal reference range (<ULN) for ALT and total bilirubin are found in the lower left 
quadrant, and Hy’s law cases (ALT3×ULN and total bilirubin>2×ULN) can be found in the upper 
right quadrant. Patients with Gilbert’s syndrome or cholestasis are typically found in the upper 
left quadrant, and patients with ALT elevations without significant hepatic impairment (i.e., 
without increased total bilirubin) are found in the lower right quadrant. This plot will also be 
plotted for peak AST by peak total bilirubin. 


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Other clinical laboratory tests categories include Serology, Endocrinology, Coagulation, and 
Urinalysis. Continuous parameters for these categories will be summarized using descriptive 
statistics at baseline and each post-baseline visit along with change from baseline at each visit, 
and categorical parameters will be presented with counts and percentages of patients at each 
scheduled visit. 
All laboratory measurements will be listed. 
A list of laboratory tests to be performed is included in Appendix B of the protocol. 
3.6.3 Vital Signs 
Vital signs to be assessed are height, weight, body mass index, temperature, respiratory rate, 
systolic blood pressure, diastolic blood pressure, and heart rate. Vital signs will be summarized 
at Baseline, Day 14, and Day 28 using descriptive statistics for the Safety Analysis Set.  
At Baseline, Day 14, and Day 28, blood pressure (systolic and diastolic) and heart rate will be 
taken prior to dosing and one hour after dosing. 
Change from baseline at Day 14 and Day 28 will also be summarized. All vital signs 
measurements will also be listed. 
3.6.4 Electrocardiograms 
ECG overall interpretation findings will be summarized for the Safety Analysis Set. Continuous 
parameters will be summarized descriptively at each visit. 
3.6.5 Physical Examinations 
The number and percentage of patients with physical examination findings will be presented for 
the Safety Analysis Set. 
4 ANALYSIS TIMING 
4.1 Draft Analysis/Blinded Data Reviews 
Draft analysis tables, figures, and listings (TFLs) for data reviews will be provided approximately 
1 month prior to the scheduled database lock for final review.     
4.2 Interim Analysis 
No interim analysis is planned.   
4.3 Pre-Final Analysis 
After data entry process is completed, exclusions from analysis populations will be finalized 
prior to database lock and the pre-final analysis will be generated after database lock. Topline 
tables will be provided one week after final database lock. All pre-final TFLs will be provided 
approximately 3 weeks after database lock.   
4.4 Final Analysis 
After all comments on the pre-final analysis have been resolved and the study database is 
declared final, the final analysis will be generated. Final TFLs will be provided approximately 1 
week after the study database is declared final. If there were no changes to the pre-final 


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analysis or the study database, the pre-final TFLs may be considered final. In addition to TFLs, 
Standard Data Tabulation Model (SDTM) data and Analysis Data Model (ADaM) data along with 
associated files will be provided. Associated files may include:  annotated CRFs, SDTM 
specifications, SDTM programs, ADaM specifications, ADaM programs, TFL programs, and 
Clinical Data Interchange Standards Consortium (CDISC) Define packages for both SDTM and 
ADaM data.   
5 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
There are no changes form protocol specified statistical analyses. 
6 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher.  All available data will be 
presented in patient data listings which will be sorted by patient and visit date as applicable.  
Detailed Programming Specifications will be provided in a separate document. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 1.0, 21 August 2020 
Page 30 of 30 
 
APPENDIX A: REFERENCES  
Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to 
learn more about acute drug-induced liver injury. Hepatology. 2008;48(5):1680-1689. 
doi:10.1002/hep.22633 
FDA Guidance for Industry, Drug-induced liver injury: Premarketing Clinical Evaluation. 
Jul2009.  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM174090.pdf 
Little R. (1993) Pattern-Mixture Models for Multivariate Incomplete Data. Journal of the 
American Statistical Association. Vol. 88, No. 421 (Mar, 1993), pp. 125-134 
Ratitch B, O’Kelly M and Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical Statistics 2013; 12 337-347 
 

SAP_003.pdf: 
 
 
 
 
 
 
 
 
 
NCT #: 04447820 
 
SAP Version/Date: Version 2.0, 23 November 2020 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 1 of 30 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A Multicenter, Randomized, Open-Label, 4-Week Study 
to Investigate the Efficacy and 
 Profile of 
K-877-ER 
 Treatment (From 
day to 
 
day) Compared to K-877-IR 
 
 
Treatment (
day) in Adult Patients With Fasting 
Triglyceride Levels ≥150 mg/dL and <500 mg/dL 
 
Protocol Number: 
K-877-ER-201 
Protocol Version/Date: 
Version 2.0, 17 September 2020 
Investigational Product: K-877-ER 
 
 
Sponsor: 
Kowa Research Institute, Inc. 
 
 
 
SAP Version/Date: 
Version 2.0, 23 November 2020 
 
  
CONFIDENTIAL 
This statistical analysis plan is written for Kowa Research Institute, Inc., and it is a confidential 
communication. This document may not be used or published without the consent of Kowa 
Research Institute, Inc. 
 




Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 3 of 30 
 
VERSION HISTORY 
 
Version 
Version Date 
Description 
1.0 
21AUG2020 
Original signed version 
2.0 
23NOV2020 
SAP updated per Protocol Amendment 
v2.0
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 4 of 30 
 
TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................ 8 
2 
Study Overview...................................................................................................................... 8 
2.1 
Study Objectives ............................................................................................................. 8 
2.1.1 
Primary Objective .................................................................................................... 8 
2.1.2 
Secondary Objectives ............................................................................................. 8 
2.2 
Study Design .................................................................................................................. 8 
2.2.1 
Overview ................................................................................................................. 8 
2.2.2 
Randomization and Blinding .................................................................................. 15 
2.2.3 
Study Drug ............................................................................................................ 15 
2.2.4 
Sample Size Determination ................................................................................... 16 
2.3 
Efficacy and 
 Endpoints ..................................................................... 16 
2.3.1 
Primary Efficacy Endpoint ..................................................................................... 16 
2.3.2 
Secondary Efficacy Endpoints ............................................................................... 16 
 
............................................................................. 16 
2.4 
Safety Endpoints .......................................................................................................... 18 
3 
Statistical Methodology ........................................................................................................ 18 
3.1 
General Considerations ................................................................................................ 18 
3.1.1 
Analysis Day .......................................................................................................... 18 
3.1.2 
Analysis Visits ....................................................................................................... 18 
3.1.3 
Definition of Baseline ............................................................................................. 18 
3.1.4 
Summary Statistics ................................................................................................ 19 
3.1.5 
Handling of Dropouts and Missing Data ................................................................ 19 
3.2 
Analysis Populations .................................................................................................... 19 
3.2.1 
Full Analysis Set (FAS) ......................................................................................... 19 
3.2.2 
Per-Protocol Set (PPS) ......................................................................................... 19 
3.2.3 
Safety Analysis Set ............................................................................................... 19 
 
 19 
3.3 
Subject Data and Study Conduct ................................................................................. 19 
3.3.1 
Subject Disposition ................................................................................................ 19 
3.3.2 
Protocol Deviations ............................................................................................... 20 
3.3.3 
Analysis Populations ............................................................................................. 20 
3.3.4 
Demographic and Baseline Characteristics .......................................................... 20 
3.3.5 
Medical History ...................................................................................................... 20 
3.3.6 
Concomitant Medications ...................................................................................... 20 
3.3.7 
Study Drug Exposure and Compliance ................................................................. 21 
3.4 
Efficacy Assessment .................................................................................................... 22 
3.4.1 
Primary Efficacy Endpoint ..................................................................................... 22 
3.4.2 
Secondary Efficacy Endpoints ............................................................................... 24 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 5 of 30 
 
 
 ............................................................................................. 24 
3.6 
Safety Assessment ....................................................................................................... 26 
3.6.1 
Adverse Events (AEs) ........................................................................................... 26 
3.6.2 
Clinical Laboratory Tests ....................................................................................... 27 
3.6.3 
Vital Signs ............................................................................................................. 28 
3.6.4 
Electrocardiograms ............................................................................................... 28 
3.6.5 
Physical Examinations .......................................................................................... 28 
4 
Analysis Timing .................................................................................................................... 28 
4.1 
Draft Analysis/Blinded Data Reviews ........................................................................... 28 
4.2 
Interim Analysis ............................................................................................................ 28 
4.3 
Pre-Final Analysis ......................................................................................................... 29 
4.4 
Final Analysis ............................................................................................................... 29 
5 
Changes from Protocol-Specified Statistical Analyses ........................................................ 29 
6 
Programming Specifications ................................................................................................ 29 
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 6 of 30 
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADaM 
Analysis Data Model
AE 
Adverse event
ALP 
Alanine Phosphatase
ALT 
Alanine Aminotransferase
ANCOVA 
Analysis of Covariance
AST 
Aspartate Aminotransferase
ATC 
Anatomical therapeutic chemical
 
 
 
 
 
 
 
 
 
BLQ 
Below the limit of quantification
CDISC 
Clinical Data Interchange Standards Consortium
CI 
Confidence Interval
CK 
Creatinine Kinase
 
 
 
 
COVID-19 
Coronavirus Disease 2019
 
CRF 
Case report form
CSR 
Clinical Study Report
eGFR 
Estimated Glomerular Filtration Rate
ECG 
12-lead Electrocardiogram
FAS 
Full Analysis Set
IRT 
Interactive Response Technology
 
 
LLN 
Lower limit of normal
LLOQ 
Lower limit of quantification
MedDRA 
Medical Dictionary for Regulatory Activities
 
 
 
 
 
 
 
 
 
PPS 
Per-Protocol Set
 
 
 
 
 


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Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 7 of 30 
 
Abbreviation 
Definition 
SAE 
Serious adverse event
SAP 
Statistical Analysis Plan
SD 
Standard deviation
SDTM 
Study Data Tabulation Model
 
TEAE 
Treatment-emergent adverse event
TESAE 
Treatment-emergent serious adverse event
TG 
Triglyceride 
 
ULN 
Upper limit of normal
 
 
  
 
 
WHO 
World Health Organization
 
 
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 8 of 30 
 
1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number          
K-877-ER-201. The SAP will be finalized prior to database lock. Any deviations from the SAP 
after database lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of this study is to demonstrate the efficacy of K-877-ER 
 
 
(
 compared to K-877-IR 
 
 (
 from baseline to Day 28 in lowering fasting 
triglyceride (TG) levels in patients with fasting TG levels ≥150 mg/dL and <500 mg/dL. 
2.1.2 Secondary Objectives 
The secondary objectives of this study are as follows: 
 
To demonstrate the efficacy of K-877-ER 
 
 compared to K-877-IR 
 
 
from baseline to Day 28 in lowering fasting TG levels in patients with fasting TG levels 
≥150 mg/dL and <500 mg/dL. 
 
To evaluate the efficacy of K-877-ER 
 treatments (from 
day to 
day) 
from baseline to Day 28 in altering pharmacodynamic properties, including lipid 
parameters, in patients with fasting TG levels ≥150 mg/dL and <500 mg/dL.  
 
To evaluate the multiple-dose 
 properties 
 of 
K-877-ER 
 
2.2 Study Design 
2.2.1 Overview 
This is a Phase 2, multicenter, randomized, open-label study investigating the efficacy and 
 
profile of K-877-ER 
 treatment (from 
day to 
day) compared to 
K-877-IR 
 
 treatment (
day) in adult patients with fasting TG levels ≥150 mg/dL 
and <500 mg/dL. The study consists of a Screening Period, of up to 10 weeks, and a 4-week 
Treatment Period. During the Treatment Period, patients will receive K-877-ER 
 
 
K-877-ER 
 
 or K-877-IR 
 
 
Approximately 90 patients (from 12 sites in the United States) who meet all the inclusion criteria 
and no exclusion criteria will be enrolled in the study. Of the approximately 90 patients enrolled, 
24 patients will be enrolled as 
 patients, and will have blood samples for 
 assessments 
collected. 
 patients will not have blood samples for 
 assessments collected. 
The Screening Period will occur no more than 70 days and no less than 7 days prior to the first 
dose of study drug (Day 1, Visit 4). The up to 10-week Screening Period will allow for a 6-week 
washout period, if needed, followed by up to a 4-week Qualification Period that will be used to 
assess patient eligibility. At the Screening Visit (Visit 1), a patient’s individual TG level must be 
≥135 mg/dL and <550 mg/dL. 


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Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
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Patients on non-permitted background lipid-altering therapy must complete a 6-week washout 
period prior to the first Qualification Period visit (Visit 2). If a patient does not require washout, 
the patient may start the Qualification Period 24 hours after signing the ICF. Patients may 
continue through the Qualification Period provided there are no prohibitive safety or eligibility 
results from the Screening Visit (Visit 1) laboratory tests. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Prior to treatment on Day 1, eligible patients will be randomized in a 1:1:1 ratio to one of three 
treatment groups. Randomization will be stratified by sex (male or female), statin use (yes or 
no), and 
 assessment (yes or no). 
Treatment Period will occur from Days 1 through 28. On Days 14 and 28, patients will return to 
the clinical site for efficacy and safety assessments. Patients enrolled as 
 patients will be 
admitted to the clinical site on Day -1 and confined until discharge on Day 2. On Day 27, 
 
patients will be readmitted to the clinical site and confined until discharge on Day 29. 
 
 
Patients will participate in a Follow-Up Telephone Call 7 days (2 days) following the last dose 
of study drug for safety monitoring. 
All procedures to be conducted during the study, including timing of all procedures, are 
described in the Schedule of Procedures.  
Selected study procedures will be performed prior to administration of study drug, as applicable. 
The schedule of procedures for 
 and 
 procedures can be 
found below in Tables 1 and 2 respectively. 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 10 of 30 
 
Table 1. Schedule of Procedures 
 
a. 
Patients who are screen failures for a modifiable condition, other than failing the TG criteria, can be re-screened once. Before each patient is re-screened, the 
Investigator should discuss the case with the Medical Monitor. 
b. 
At the Screening Visit (Visit 1), patients not needing a washout period may start the Qualification Period (Visit 2) 24 hours after signing the informed consent 
form. Patients may continue through the Qualification Period provided that there are no prohibitive safety or eligibility results from the Screening Visit (Visit 1) 
laboratory tests.  
c. 
All Qualification Period visits will occur 7 days (3 days) apart.  
d. 
The last fasting TG Qualification Period visit (Visit 3 or 3.1) should occur 7 days prior to Day 1 (Visit 4).  
 
Screening Period
Treatment Period
Follow-Up 
Telephone 
Callf 
Screening 
Visita,b 
Qualification Periodc 
Visit Name
Visit 1
Visit 2b 
Visit 3d 
Visit 
3.1d,e 
Visit 4d
Visit 5
Visit 6/ET
Study Day
-70 to -29
-28 to -21
-21 to -14
-14 to -7
1
14
28
35
Visit Window (days)
3  
3  
3  
3  
3  
2  
Assessment 
 
 
 
 
 
 
 
 
Informed consentg 
X
 
Inclusion/exclusion criteria 
X
X
X
X 
X
Fasting TG level 
Xh 
Xh 
Xh 
 
Serum FSHi 
X
 
Pregnancy testj 
X
 
Xk 
Xk 
Height, body weight, and BMI 
X
 
Xk,l 
Demographic/medical history 
X
 
Urine drug screenm 
X
 
Prior/concomitant medication 
X
X
X
X 
X
X
X
X
TSH, FT4, and HbA1c 
X
 
Randomization 
 
Xk 
Physical examinationn 
X 
 
Xk 
Xk 
Xk 
Clinical laboratory testso 
X
 
Xk 
Xk 
Xk 
Vital signsp 
X
 
X 
X 
X 
12-lead ECGq 
X
 
X
X
PD sampler 
X
 
Xk 
Xk 
Xk 
Dispense study drugs 
 
X
Dosingt 
 
X
AEs 
X
Study drug compliance check 
 
X
X


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
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e. 
For patients without a qualified medical record, Visit 3.1 is only needed if 1 Qualification Period TG level from Visit 2 or 3 is within 10% of the target range 
(135 mg/dL and <550 mg/dL) and 1 Qualification Period TG level from Visit 2 or 3 is within the target range (150 mg/dL and <500 mg/dL).  
f. 
A Follow-Up Telephone Call will be performed 7 days (2 days) following the last dose of study drug. 
g. 
Written consent must be obtained from the patient prior to any study-specific procedure or investigation, including the washout period when applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
i. 
FSH is to be obtained in women <55 years of age who have not had a menstrual period for 1 year. Female patients will be considered postmenopausal if the 
FSH level is in the central laboratory’s normal range for postmenopausal phase.  
j. 
Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit (Visit 1), a negative urine pregnancy test at Visit 4 
and Visit 6, and must agree to use effective methods of contraception.   
k. 
Assessments will be performed prior to dosing.  
l. 
Only body weight will be measured at Visit 6 prior to dosing. 
m. A urine drug screen will be performed at the discretion of the Investigator. 
n. 
At the Screening Visit, a complete physical examination excludes pelvic, rectal, and breast examinations. All other physical examinations throughout the study 
must include a symptom-directed physical examination, as well as an examination of the heart, lungs, and abdomen and a visual examination of the skin. 
o. 
Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
p. 
Vital signs include systolic and diastolic BP, pulse, respiratory rate, and body temperature and will be measured (sitting) after resting for a minimum of 
5 minutes. Patients should avoid smoking, caffeine, or exercise within 30 minutes prior to BP measurement. On Days 1, 14, and 28, BP and pulse must be 
measured prior to administration of study drug and again approximately 1 hour post-administration.  
q. 
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection. 
r. 
PD assessments will be performed under fasting conditions (8 hours) and include TG, TC, LDL-C, HDL-C, remnant cholesterol (calculated as TC – LDL-C – 
HDL-C), non-HDL-C, FFA.  
s. 
Study drug, for entire treatment period, will be dispensed to eligible patients on Day 1 (Visit 4), after randomization, via the IRT system. 
t. 
Daily oral dose will be administered by the patient and taken according to treatment group starting on Day 1 (Visit 4) and concluding on Day 28 (Visit 6) (28 
dosing days). Patients in the K-877-IR 
 
 treatment group will receive only the morning dose on Day 28. Study drug will be administered in the fed 
state at 0 hour with 240 mL of room temperature tap water. 
AE = adverse event; 
 = 
 BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; ET = Early Termination; FFA = free fatty acid; 
FSH = follicle-stimulating hormone; FT4 = free thyroxine; HbA1c = hemoglobin A1c; HBsAG = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high-
density lipoprotein cholesterol; HIV = human immunodeficiency virus; IRT = interactive response technology; LDL-C = low-density lipoprotein cholesterol; 
PD = pharmacodynamic(s); TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone.  
 


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 12 of 30 
 
Table 2. Schedule of Procedures (
 
 
Screening Period
Check-
In 1
Treatment Period
Follow-Up 
Telephone 
Callf 
 
Screening 
Visita,b 
Qualification Periodc 
Visit Name 
Visit 1 
Visit 
2b 
Visit 
3d 
Visit 
3.1d,e 
Visit 
4d 
Discharge 
1
Visit 
5
Check-
In 2
Visit 
6/ET
Discharge 
2
Study Day 
-70 to -29 
-28 
to  
-21
-21 to 
-14
-14 
to -7
-1
1
2
14
27
28
29
35 
Visit Window 
(days) 
 
3  
3  
3  
3  
3  
2  
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consentg 
X 
Inclusion/exclusion 
criteria 
X 
X
X
X
X
X
Fasting TG level 
 
Xh 
Xh 
Xh 
 
Serum FSHi 
X 
Pregnancy testj 
X 
X
X
Height, body 
weight, and BMI 
X 
Xk 
Demographic/ 
medical history 
X 
Urine drug screenl 
X 
Prior/concomitant 
medication 
X 
X
X
X
X
X
X
X
X
X
X
X
TSH, FT4, and 
HbA1c 
X 
Randomization 
 
Xm 
Physical 
examinationn 
X 
Xm 
Xm 
Xm 
Clinical laboratory 
testso 
X 
Xm,p 
Xm 
Xm,p 
Vital signsp 
X 
X
X
X
12-lead ECGq 
X 
X
X


Kowa Research Institute, Inc. 
 
Statistical Analysis Plan 
K-877-ER-201                                         
CONFIDENTIAL 
Version 2.0, 23 November 2020 
Page 13 of 30 
 
Table 2. Schedule of Procedures (
 (Continued) 
 
 
Screening Period
Check-
In 1
Treatment Period
Follow-Up 
Telephone 
Callf
 
Screening 
Visita,b 
Qualification Periodc
Visit Name 
Visit 1 
Visit 
2b
Visit 
3d
Visit 
3.1d,e
Visit 
4d
Discharge 
1 
Visit 
5
Check-
In 2
Visit 
6/ET
Discharge 
2
Study Day 
-70 to -29 
-28 
to  
21
-21 to 
-14
-14 
to -7
-1
1
2 
14
27
28
29
35
Visit Window 
(days) 
 
3 
3 
3 
 
3 
3 
2 
Assessment 
 
 
PD sampler 
X 
Xi 
 
Xm 
Xm 
 
 
Admission to 
clinical site 
 
X
 
X
Discharge from 
clinical site 
 
X 
X
Dispense study 
drugu 
 
X
 
Dosingv 
 
X
AEs 
                                                                                               X
Study drug 
compliance check 
 
 
X
X
a. 
Patients who are screen failures for a modifiable condition, other than failing the TG criteria, can be re-screened once. Before each patient is re-screened the 
Investigator should discuss the case with the Medical Monitor. 
b. 
At the Screening Visit (Visit 1), patients not needing a washout period may start the Qualification Period 24 hours after signing the informed consent form. 
Patients may continue through the Qualification Period provided that there are no prohibitive safety or eligibility results from the Screening Visit (Visit 1) 
laboratory tests.  
c. 
All Qualification Period visits will occur 7 days (3 days) apart.  
d. 
The last fasting TG Qualification Period visit (Visit 3 or 3.1) should occur 1 week prior to Day 1 (Visit 4). 
e. 
For patients without a qualified medical record, Visit 3.1 is only needed if 1 Qualification Period TG level from Visit 2 or 3 is within 10% of the target range 
(135 mg/dL and <550 mg/dL) and 1 Qualification Period TG level from Visit 2 or 3 is within the target range (150 mg/dL and <500 mg/dL). 
f. 
A Follow-Up Telephone Call will be performed 7 days (2 days) following the last dose of study drug. 
g. 
Written informed consent must be obtained from the patient prior to any study-specific procedure or investigation, including the washout period when 
applicable.  
 
 


Kowa Research Institute, Inc. 
 
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K-877-ER-201                                         
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i. 
FSH is to be obtained in women <55 years of age who have not had a menstrual period for 1 year. Female patients will be considered postmenopausal if the 
FSH level is in the central laboratory’s normal range for postmenopausal phase.  
j. 
Female patients of childbearing potential must have a negative serum pregnancy test at the Screening Visit (Visit 1), a negative urine pregnancy test at 
Check-Ins 1 and 2, and must agree to use effective methods of contraception.  
k. 
Only body weight will be measured at Visit 6 prior to dosing. 
l. 
A urine drug screen will be performed at the discretion of the Investigator. 
m. Assessments will be performed prior to dosing. 
n. 
At the Screening Visit, a complete physical examination excludes pelvic, rectal, and breast examinations. All other physical examinations throughout the study 
must include a symptom-directed physical examination, as well as an examination of the heart, lungs, and abdomen and a visual examination of the skin. 
o. 
Clinical laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
p. 
Vital signs include systolic and diastolic BP, pulse, respiratory rate, and body temperature and will be measured (sitting) after resting for a minimum of 
5 minutes. Patients should avoid smoking, caffeine, or exercise within 30 minutes prior to BP measurement. On Days 1, 14, and 28, BP and pulse must be 
measured prior to administration of study drug and again approximately 1 hour post-administration. 
q. 
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.  
r. 
PD assessments will be performed under fasting conditions (8 hours) and include TG, TC, LDL-C, HDL-C, remnant cholesterol (calculated as TC – LDL-C – 
HDL-C), non-HDL-C, FFA. 
s. 
On Days 1 (Visit 4) and 28 (Visit 6), 
 patients will remain fasted for at least 4 hours after morning dosing. Patients will not receive any oral fluids other than 
those used to administer the dose for 1 hour after dosing on Days 1 (Visit 4) and 28 (Visit 6). Study drug will be administered in the fed state at 0 hour with 
240 mL of room temperature tap water. 
 patients will remain standing or sitting upright for 4 hours after dosing, except as required by any study procedure. 
 
 
 
 
 
  
 
 
v. 
Daily oral dose will be administered by the patient and taken according to treatment group starting on Day 1 (Visit 4) and concluding on Day 28 (Visit 6) (28 
dosing days). Patients in the K-877-IR 
 
 treatment group will receive only the morning dose on Day 28. Study drug will be administered in the fed 
state at 0 hour with 240 mL of room temperature tap water. 
AE = adverse event; 
 = 
 BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; ET = Early Termination; FFA = free fatty acid; 
FSH = follicle-stimulating hormone; FT4 = free thyroxine; HbA1c = hemoglobin A1c; HBsAG = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high-
density lipoprotein cholesterol; HIV = human immunodeficiency virus; IRT = interactive response technology; LDL-C = low-density lipoprotein cholesterol; 
 = 
s); PD = pharmacodynamic(s); TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone


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K-877-ER-201                                         
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2.2.2 Randomization and Blinding 
2.2.2.1 Randomization 
On Day 1, prior to dosing, eligible patients will be randomized in a 1:1:1 ratio to 1 of 3 treatment 
groups. Patients will receive K-877-ER 
 
 K-877-ER 
 
 or K-877-IR 
 
 starting on Day 1 through 28. Treatment groups are detailed in Table 3. 
 
Randomization will be stratified by sex (male or female), statin use (yes or no), and 
 
 (yes or no). The Investigator or designee will access interactive response 
technology (IRT) and enter the patient identification number. The IRT system will record the 
randomized treatment assignment for the patient and assign the appropriate study drug kit. 
2.2.2.2 Blinding 
This study is open-label.  
2.2.3 Study Drug 
Study drug, for entire treatment period, will be dispensed to eligible patients beginning on Day 1 
(Visit 4), after randomization, via the IRT system. 
Patients will receive oral doses of K-877-ER 
 
 (one 
 tablet every morning), K-
877-ER 
 
 (two 
 tablets every morning), or K-877-IR 
 
 (one 
 
tablet in the morning and one 
 tablet in the evening) starting on Day 1 and concluding on 
Day 28 in the fed state. Patients in the K-877-IR 
 
 treatment group will receive only 
the morning dose on Day 28. Study drug will be administered in the fed state at 0 hour with 240 
mL of room temperature tap water.  
Table 3. 
 
 
 
 
 
 
K-877-ER 
 
 
K-877-ER 
 
 
 
 
K-877-ER 
 
 
K-877-ER 
 
 
 
 
K-877-IR 
 
 
K-877-IR 
 
 
K-877-IR 
 
 
 
Within 30 minutes prior to study drug administration on Days 1 and 28, 
 patients confined to 
the clinical site will be administered a meal that is part of a daily diet containing approximately 
2300 to 2500 calories, less than 60% carbohydrates, and less than 25% fat. On Days 1 and 28, 
 patients will remain fasted for at least 4 hours after morning dose. 
 patients will not 
receive any oral fluids other than those used to administer the dose for 1 hour before and 1 hour 
after dosing on Days 1 and 28. 
 patients will remain standing or sitting upright for 4 hours after dosing, except as required by 
any study procedure. Patients in the K-877-IR 
 
 treatment group will receive an 
evening dose after a meal.  
Diet and dosing time should remain consistent for all doses throughout the study. Patients will 
be instructed by the site to follow dosing instructions on the drug packaging and to return all 
used, partially used, and unused study drug materials on Day 28. 


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K-877-ER-201                                         
CONFIDENTIAL 
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2.2.4 Sample Size Determination 
Approximately 90 patients will be enrolled. 
Assuming an effect size delta = 0, pooled SD = 21.38, an alpha = 0.05 (1-sided), and a non-
inferiority limit of 15%, a sample size of 26 patients per treatment group provides a power of 
0.80.  
In the case that the actual effect size delta is 10% (effect of tested regimen 10% less than the 
reference regimen), the power is then 0.2. If the real effect is different, the result less likely 
shows non-inferiority.  
To account for potential drop off, a total of 90 patients, 30 patients in each treatment group, is 
planned to be randomized. 
2.3 Efficacy and 
 Endpoints 
2.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in fasting TG from baseline to Day 28. The 
baseline fasting TG level will be defined based on the protocol version patients consent to. For 
patients who consented to protocol version 1.0, baseline fasting TG level will be defined as the 
mean of 3 TG levels: 2 qualification period TG levels within the target range (൒200 mg/dL and 
<500 mg/dL) and the Day 1 (Visit 4) TG level. For patients who consented to protocol version 
2.0, baseline fasting TG level will be defined as the mean of 3 TG levels: 2 qualification period 
TG levels within the target range (൒150 mg/dL and <500 mg/dL) and the Day 1 (Visit 4) TG level 
for patients who are qualified without a qualified TG medical record. The baseline fasting TG 
level will be defined as the mean of 2 TG levels: 1 qualification period TG level within the target 
range (൒150 mg/dL and <500 mg/dL) and the Day 1 (Visit 4) TG level for patients who are 
qualified via a qualified TG medical record. 
2.3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the percent change from baseline to Day 28 for the 
following:  
 
Total cholesterol (TC) 
 
Low-density lipoprotein cholesterol (LDL-C) 
 
High-density lipoprotein cholesterol (HDL-C)  
 
Remnant cholesterol (calculated as TC – LDL-C – HDL-C)  
 
Non-HDL-C  
 
Free fatty acids 
 
 
 
 
 
 


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C
 
 
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2.4 Safety Endpoints  
Safety assessments include analysis of adverse events (AEs), clinical laboratory evaluations 
(serum chemistry, hematology, coagulation, and urinalysis), vital signs (blood pressure, pulse 
rate, respiratory rate, and body temperature), 12-lead electrocardiogram (ECG), and physical 
examinations.    
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of randomization. The day of randomization will be 
Day 1, and the day immediately before Day 1 will be Day -1. There will be no Day 0. 
3.1.2 Analysis Visits 
The study consists of a 28-day treatment period where study visits will occur at Visit 4 (Day 1), 
Visit 5 (Day 14), and Visit 6 (Day 28). Scheduled visits will be assigned to analysis visits as 
recorded on the case report form (CRF). Unscheduled and early termination visits will be 
analyzed at the next available visit within the 28-day treatment period. Where multiple 
measurements for a parameter appear within an analysis visit, the scheduled visit will be used. 
If there is no scheduled visit and multiple unscheduled visits and/or early termination visits exist 
within an analysis visit, the later result will be used for the summary measure. 
Analysis visits to be assigned are Baseline, Visit 5 (Day 14), and Visit 6 (Day 28). 
Any primary or secondary efficacy measurements that have resulted from a non-fasting sample 
will be considered invalid and will not be used in the derivation of the efficacy endpoint. 
3.1.3 Definition of Baseline  
For patients who consented to protocol version 1.0, baseline fasting TG level will be defined as 
the mean of 3 TG levels: 2 qualification period TG levels within the target range (൒200 mg/dL 
and <500 mg/dL) and the Day 1 (Visit 4) TG level. For patients who consented to protocol 
version 2.0, baseline for fasting TG will be defined as the mean for 3 TG levels: 2 qualification 
period TG levels within the target range (൒150 mg/dL and <500 mg/dL) and the Day 1 (Visit 4) 
TG level for patients who are qualified without a qualified TG medical record. The baseline 
fasting TG level will be defined as the mean of 2 TG levels: 1 qualification period TG level within 
the target range (൒150 mg/dL and <500 mg/dL) and the Day 1 (Visit 4) TG level for patients who 
are qualified via a qualified TG medical record. If any of the TG levels are missing, the average 
of non-missing TG levels will be used to calculate baseline. Baseline for all other efficacy and 
safety variables will be defined as the Visit 4 (Day 1) measurement. If the measurement at this 
visit is missing, the last measurement prior to the first dose of study drug will be used as 
baseline. 


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3.1.4 Summary Statistics 
All study-collected data will be summarized by treatment group for the appropriate analysis 
population, using descriptive statistics, graphs, and/or raw data listings. Descriptive statistics for 
continuous variables will include n (number of non-missing values), mean, standard deviation, 
first quartile (Q1), median, third quartile (Q3), minimum, and maximum. Analysis of categorical 
variables will include frequency and percentage. 
3.1.5 Handling of Dropouts and Missing Data 
Missing data will be imputed only in the context of sensitivity analysis as described in section 
3.4.1.     
3.2 Analysis Populations 
3.2.1 Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all randomized patients who take at least 1 dose of 
study drug and have a baseline fasting TG measurement. Analyses of primary and secondary 
efficacy endpoints will be performed on the FAS.  
3.2.2 Per‐Protocol Set (PPS) 
The Per-Protocol Set (PPS) will include all FAS patients without any major protocol deviations 
and who have baseline and Day 28 endpoint fasting serum TG measurements. Major protocol 
deviations will be confirmed prior to database lock. Major protocol deviations that may impact 
the primary efficacy assessment may include but are not limited to: 
 
Failed to meet eligibility criteria 
 
Discontinued study drug 
 
Had study drug compliance <80% or >120% 
 
Took a restricted concomitant medication 
A list of patients with major protocol deviations leading to exclusion from the PPS will be 
finalized prior to database lock. 
The Per-Protocol Set will be the primary analysis population. 
3.2.3 Safety Analysis Set 
The Safety Analysis Set will include all randomized patients who receive at least 1 dose of 
randomized study drug. All safety analyses will be conducted on the Safety Analysis Set. 
 
 
 
   
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Counts and percentages of patients who were screened (signed informed consent), 
discontinued early during screening (screen failures), and randomized will be summarized in 


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total based on all screened patients. Primary reasons for screen failure will also be summarized. 
Patients whose primary reason for screen failure was due to Coronavirus Disease 2019 
(COVID-19) will also be summarized. 
Counts and percentages of patients who were randomized, treated, discontinued early from the 
study, and completed the study will be summarized by treatment and in total based on all 
randomized patients. Primary reasons for early discontinuation will also be summarized. 
Patients whose primary reason for early discontinuation was due to COVID-19 will also be 
summarized. 
3.3.2 Protocol Deviations 
Protocol deviations are defined in the Protocol Deviation Plan and classified as CSR reportable 
or CSR non-reportable. All CSR-reportable protocol deviations will be listed. 
3.3.3 Analysis Populations 
Counts and percentages of patients in each analysis population will be summarized by 
treatment and in total based on all randomized patients.  
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
 
Age (years) and age categories (<65 years, ≥65 years) 
 
Sex (Male or Female) 
 
Age categories by sex (Age categories include <12 years, 12 - <18 years, 18 - <65 
years, and ≥ 65 years). 
 
Childbearing potential 
 
Race 
 
Ethnicity 
 
Height (cm) 
 
Weight (kg) 
 
Body mass index (BMI) (kg/m2)  
 
Statin Use (Yes, No) 
 
 
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of patients as appropriate by treatment and in total for all randomized 
patients and each defined analysis population. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 23.0, March 2020. Dictionary updates will 
be applied at the time of database lock to the latest version available. Counts and percentages 
of patients with medical history by system organ class and preferred term will be summarized by 
treatment and in total based on all randomized patients. 
3.3.6 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the WHODrug Dictionary Global B3, September 2019. Dictionary updates 


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will be applied at the time of database lock to the latest version available. For summary 
purposes, medications will be considered prior medications if they were stopped prior to the first 
dose of study drug and concomitant medications if they were taken at any time after the first 
dose of study drug (i.e. started prior to the first dose of study drug and were ongoing or started 
after the first dose of study drug). 
If a medication has incomplete start or stop dates, dates will be imputed to determine whether a 
medication should be considered prior or concomitant. If a medication start date is incomplete, 
the first day of the month will be imputed for missing day and January will be imputed for 
missing month. If a medication stop date is incomplete, the last day of the month will be imputed 
for missing day and December will be imputed for missing month. Incomplete start and stop 
dates will be listed as collected without imputation. 
Counts and percentages of patients taking prior and concomitant medications by ATC class and 
preferred term will be summarized by treatment and in total based on the Safety Analysis Set.   
3.3.7 Study Drug Exposure and Compliance 
Days of exposure to study drug will be calculated as date of last dose of study drug – date of 
first dose of study drug + 1. Note that the exposure calculation is intended to describe the length 
of time a patient was exposed to study drug and therefore does not take study drug interruptions 
into account. Days of exposure to study drug will be summarized by treatment based on the 
Safety Analysis Set with descriptive statistics.  
Percent compliance to the study drug regimen will be calculated as follows: 
For patients randomized to the K-877-ER 
 
 arm, compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑െ𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡െ𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛൅1
 𝑥 100 
For patients randomized to the K-877-ER 
 
 arm, compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑െ𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
2 ∗ሺ𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡െ𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛൅1ሻ
 𝑥 100 
For patients randomized to the K-877-IR 
 
 arm and completed the 28-day treatment 
period, compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑െ𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
൫2 ∗ሺ𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡െ𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛൅1ሻ൯െ1
 𝑥 100 
For patients randomized to the K-877-IR 
 
 arm and discontinued prior Day 28, 
compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑െ𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
2 ∗ሺ𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡െ𝐷𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛൅1ሻ
 𝑥 100 
If study drug is not returned, the number of tablets returned will be considered 0 for the 
compliance calculation.   
Percent compliance to the study drug will be summarized by treatment based on the Safety 
Analysis Set with descriptive statistics and with counts and percentages of patients with 
compliance in the following categories: 


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 
<80% 
 
80-120% 
 
>120% 
3.4 Efficacy Assessment 
Efficacy data will be summarized by randomized treatment based on the PPS. The primary and 
secondary efficacy endpoints will also be summarized based on the FAS. Descriptive statistics 
(n, mean, standard deviation [SD], first quartile [Q1], median, third quartile [Q3], minimum, 
maximum, and 90% CI) for the primary endpoint and secondary endpoints will be summarized 
by treatment group at baseline and Days 14 and 28. Descriptive statistics for changes from 
baseline and for percent changes from baseline to each visit will also be summarized. 
All available and derived data for the primary and secondary endpoints will be listed for the 
randomized patients.  
Spaghetti plots of individual patient data by treatment and box plots of the percent change from 
baseline to each post-baseline visit by treatment will be generated for the primary and 
secondary efficacy endpoints based on the PPS and FAS. Mean ± SD of percent change from 
baseline to each post-baseline visit by treatment will also be generated for the primary and 
secondary efficacy endpoints based on the PPS and FAS. 
3.4.1 Primary Efficacy Endpoint 
Primary Analysis 
The primary analysis variable is the percent change in fasting TG from baseline to Day 28. 
The primary efficacy analysis will compare 1 of the 2 K-877-ER treatments (test treatments) to 
the K-877-IR 
 
 treatment (reference treatment) in percent change from baseline to 
Day 28 and will be carried out using mixed model for repeated measures (MMRM) based on the 
PPS. The MMRM model will include percent change from baseline value as the dependent or 
response variable. Variables for Visit (Day 14 or 28), treatment (K-877-ER 
 
 K-877-
ER 
 
 or K-877-IR 
 
 the interaction term between Visit and treatment, 
baseline TG value, sex (male or female), and statin use (yes or no) will be used as fixed effects. 
An unstructured covariance matrix will be used to model the within-subject correlation. The 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. The 
analysis will be performed based on all observed post-baseline scores without any imputation of 
missing data. In the case when the MMRM fails to converge using an unstructured covariance 
matrix in any stage, a less stringent covariance matrix (e.g., autoregressive 1) will be used.  
The sample SAS code for primary efficacy analysis can be found below: 
******************************************************************* 
* PCHG = Percent change in TG 
* VISIT = Visit 
* TRT = Treatment group 
* TRT*VISIT = Treatment group by visit interaction 
* BASE = Baseline value 
* SEX = Gender (Male or Female) 
* STATIN = Statin Use (Yes or No) 
* USUBJID = Unique subject identifier 


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********************************************************************; 
PROC MIXED DATA=efficacy METHOD=REML COVTEST; 
 CLASS USUBJID VISIT TRT SEX STATIN; 
 MODEL PCHG = VISIT TRTA TRT*VISIT BASE SEX STATIN/DDFM=KENWARDROGER; 
 REPEATED / TYPE=UN SUBJECT=USUBJID; 
  
 LSMEANS TRT / DIFF CL ALPHA = 0.10;  
  
 LSMESTIMATE TRT 'ER0.4MG - IR0.2MG’ 1 0 -1 / ALPHA = 0.05 CL; 
 LSMESTIMATE TRT 'ER0.8MG - IR0.2MG' 0 1 -1 / ALPHA = 0.05 CL; 
 
 ODS OUTPUT TESTS3= TESTS3 LSMESTIMATES=LSMESTIMATES LSMEANS=LSMEAN DIFFS=D; 
run; 
Point estimates and 2-sided 90% confidence intervals (CIs), as well as 95% CIs of the 
differences of least squares means between either of the test treatments and reference 
treatment will be calculated. A non-inferiority of tested treatments will be indicated if the upper 
limit of the 2-sided 90% CI is <15% in TG percent change from baseline. 
Secondary Analyses  
As a secondary analysis, the primary analysis described above will be repeated in the FAS. 
 
 
 
 
 
 
 
 
 
 
 
        
 
     
 
     
 
     
 
     
 
 
 
 
 
 
 
 
 
 
 
      
 
      
 
      
 
      
  


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3.4.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be summarized and analyzed in the same manner as the 
primary analysis (Section 3.4.1). Each secondary endpoint will be evaluated using the MMRM 
model in the PPS where percent change from baseline variable will be used as the dependent 
or response variable. 
The following secondary endpoints will be analyzed: 
 
TC 
 
LDL-C 
 
HDL-C 
 
Remnant cholesterol (calculated as TC – LDL-C – HDL-C) 
 
Non-HDL-C 
 
Free fatty acids 
Analysis of the above secondary efficacy endpoints will also be repeated in the FAS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   


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3.6 Safety Assessment 
Safety data will be summarized by actual treatment received (and in total for selected analyses) 
based on the Safety Analysis Set. 
3.6.1 Adverse Events (AEs) 
AEs will be captured from the date of informed consent through study completion. All AEs will 
be coded to system organ class and preferred term using MedDRA version 23.0, March 2020. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that occurred for the first time 
after the first dose of study drug or existed prior to the first dose and worsened during the 
treatment period. AE worsening applies to severity, or relationship to study drug.   
An overview of AEs will be provided including counts and percentages of patients and event 
counts with the following: 
 
Any TEAEs (overall, by maximum severity, and by relationship to study drug) 
 
Any study drug related TEAEs (overall and by maximum severity) 
 
 
 
Any serious AEs (SAEs) 
 
Any treatment-emergent serious AEs (TESAEs) 
 
Any study drug related TESAEs 
 
Any AEs and TEAEs leading to death 
 
Any TEAEs leading to study drug discontinuation 
 
Any TEAEs leading to study discontinuation 
 
Any TESAEs leading to study drug discontinuation 
 
Any study drug related TEAEs leading to study drug discontinuation 
Counts and percentages of patients and event counts will also be presented by system organ 
class and preferred term for each of the categories in the overview. 
Listings will be presented specifically for SAEs and TEAEs leading to discontinuation of study 
drug. 


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3.6.2 Clinical Laboratory Tests 
Descriptive statistics for chemistry and hematology parameters will be presented at baseline 
and each post-baseline visit. At each post-baseline visit, change from baseline will also be 
summarized. 
Incidence of lab abnormalities indicated as ‘below the lower limit of normal (LLN) range’ and 
‘above the upper limit of normal (ULN) range’ at each visit will be summarized for chemistry and 
hematology parameters with counts and percentages of patients. 
Post-baseline changes of lab tests abnormalities for alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), creatinine kinase (CK), total bilirubin, alkaline phosphatase (ALP), and 
estimated Glomerular Filtration Rate (eGFR) will be summarized by presenting a shift table with 
number and percentage of patients in each treatment group with worst post-baseline value 
satisfying each of the criteria in the table below.  
Parameter 
Categories 
ALT 
<Normal 
Normal 
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN 
>5xULN to 
≤10xULN 
>10xULN to
≤20xULN 
>20x
ULN  
AST 
<Normal 
Normal 
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN 
>5xULN to 
≤10xULN 
>10xULN to
≤20xULN 
>20x
ULN  
ALP 
<Normal 
Normal 
>1xULN to 
≤ 1.5xULN 
>1.5xULN 
 
 
 
CK 
<Normal 
Normal 
>1xULN to 
≤5xULN 
>5xULN to 
≤10xULN 
>10xULN 
 
 
Total 
Bilirubin 
<Normal 
Normal 
>1xULN to 
≤1.5xULN 
>1.5xULN 
to 
≤2xULN 
>2xULN 
 
 
Total 
Bilirubin 
accompani
ed by ALT 
or AST > 
3xULN 
<Normal 
Normal 
>1xULN to 
≤1.5xULN 
>1.5xULN 
to 
≤2xULN 
>2xULN 
 
 
eGFR 
≥90 
mL/min/
1.73m2 
≥60 to 
<90 
mL/min
/1.73m2 
≥30 to <60 
mL/min/1.7
3m2 
<30   
mL/min/1.7
3m2 
 
 
 
Spaghetti plots of patient data over time and boxplots of the values at baseline and each post-
baseline visit will be presented by treatment for ALP, ALT, AST, CK, and total bilirubin. Normal 
ranges will be displayed on these plots for reference. 
Counts and percentages of patients who meet ALT or AST >3xULN, ALP < 2xULN, and total 
bilirubin ≥2xULN at any time after the first dose of the study drug are identified as potential Hy’s 


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Law cases and will be summarized, and data for ALT, AST, ALP and total bilirubin for these 
patients will be listed.  
To assess cases meeting requirements for Hy’s Law, an eDISH (evaluation of drug-induced 
serious hepatotoxicity) figure plotting peak ALT vs. peak total bilirubin (both on a logarithmic 
scale xULN) will be produced as recommended by Watkins et al (2008), so that values within 
the normal reference range (<ULN) for ALT and total bilirubin are found in the lower left 
quadrant, and Hy’s law cases (ALT3×ULN and total bilirubin>2×ULN) can be found in the upper 
right quadrant. Patients with Gilbert’s syndrome or cholestasis are typically found in the upper 
left quadrant, and patients with ALT elevations without significant hepatic impairment (i.e., 
without increased total bilirubin) are found in the lower right quadrant. This plot will also be 
plotted for peak AST by peak total bilirubin. 
Other clinical laboratory tests categories include Serology, Endocrinology, Coagulation, and 
Urinalysis. Continuous parameters for these categories will be summarized using descriptive 
statistics at baseline and each post-baseline visit along with change from baseline at each visit, 
and categorical parameters will be presented with counts and percentages of patients at each 
scheduled visit. 
All laboratory measurements will be listed. 
A list of laboratory tests to be performed is included in Appendix B of the protocol. 
3.6.3 Vital Signs 
Vital signs to be assessed are height, weight, body mass index, temperature, respiratory rate, 
systolic blood pressure, diastolic blood pressure, and heart rate. Vital signs will be summarized 
at Baseline, Day 14, and Day 28 using descriptive statistics for the Safety Analysis Set.  
At Baseline, Day 14, and Day 28, blood pressure (systolic and diastolic) and heart rate will be 
taken prior to dosing and one hour after dosing. 
Change from baseline at Day 14 and Day 28 will also be summarized. All vital signs 
measurements will also be listed. 
3.6.4 Electrocardiograms 
ECG overall interpretation findings will be summarized for the Safety Analysis Set. Continuous 
parameters will be summarized descriptively at each visit. 
3.6.5 Physical Examinations 
The number and percentage of patients with physical examination findings will be presented for 
the Safety Analysis Set. 
4 ANALYSIS TIMING 
4.1 Draft Analysis/Blinded Data Reviews 
Draft analysis tables, figures, and listings (TFLs) for data reviews will be provided approximately 
1 month prior to the scheduled database lock for final review.     
4.2 Interim Analysis 
No interim analysis is planned.   


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4.3 Pre‐Final Analysis 
After data entry process is completed, exclusions from analysis populations will be finalized 
prior to database lock and the pre-final analysis will be generated after database lock. Topline 
tables will be provided one week after final database lock. All pre-final TFLs will be provided 
approximately 3 weeks after database lock.   
4.4 Final Analysis 
After all comments on the pre-final analysis have been resolved and the study database is 
declared final, the final analysis will be generated. Final TFLs will be provided approximately 1 
week after the study database is declared final. If there were no changes to the pre-final 
analysis or the study database, the pre-final TFLs may be considered final. In addition to TFLs, 
Standard Data Tabulation Model (SDTM) data and Analysis Data Model (ADaM) data along with 
associated files will be provided. Associated files may include:  annotated CRFs, SDTM 
specifications, SDTM programs, ADaM specifications, ADaM programs, TFL programs, and 
Clinical Data Interchange Standards Consortium (CDISC) Define packages for both SDTM and 
ADaM data.   
5 CHANGES FROM PROTOCOL‐SPECIFIED STATISTICAL ANALYSES 
There are no changes form protocol specified statistical analyses. 
6 PROGRAMMING SPECIFICATIONS 
The creation of analysis datasets and all analyses will be performed using SAS® (version 9.4 or 
higher). 
 parameters will be calculated via SAS® and confirmed with the results of Phoenix 
WinNonlin™ (version 8.1 or higher).  
All available data will be presented in patient data listings which will be sorted by patient and 
visit date as applicable.  Detailed Programming Specifications will be provided in a separate 
document. 
 
  
 
 
 
 
 
 
 
 
 


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APPENDIX A: REFERENCES  
Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to 
learn more about acute drug-induced liver injury. Hepatology. 2008;48(5):1680-1689. 
doi:10.1002/hep.22633 
FDA Guidance for Industry, Drug-induced liver injury: Premarketing Clinical Evaluation. 
Jul2009.  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM174090.pdf 
Little R. (1993) Pattern-Mixture Models for Multivariate Incomplete Data. Journal of the 
American Statistical Association. Vol. 88, No. 421 (Mar, 1993), pp. 125-134 
Ratitch B, O’Kelly M and Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical Statistics 2013; 12 337-347 
 

Prot_001.pdf: 
 
 
 
 
 
 
 
 
 
NCT #: 04447820 
 
Protocol Version Date: 17 September 2020 






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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Kowa Research Institute, Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Kowa Research 
Institute, Inc. and that it may not be further disclosed to third parties. I understand that the study 
may be terminated or enrollment suspended at any time by Kowa Research Institute, Inc., with or 
without cause, or by me if it becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board Regulations and International Council for Harmonisation Guidelines 
for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 






















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TABLE OF CONTENTS 
Protocol Signature Page .................................................................................................................. 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 14 
List of Tables ................................................................................................................................ 18 
List of Figures ............................................................................................................................... 19 
List of Abbreviations and Definition of Terms............................................................................. 20 
1  Introduction and Background Information ............................................................................. 22 
1.1 
Rationale ........................................................................................................................ 22 
1.2 
Risk/Benefit ................................................................................................................... 23 
2  Study Objectives ..................................................................................................................... 24 
2.1 
Primary Objective ......................................................................................................... 24 
2.2 
Secondary Objectives .................................................................................................... 24 
3  Study Description.................................................................................................................... 25 
3.1 
Summary of Study Design ............................................................................................ 25 
4  Selection and Withdrawal of Patients ..................................................................................... 27 
4.1 
Inclusion Criteria ........................................................................................................... 27 
4.2 
Exclusion Criteria .......................................................................................................... 28 
4.3 
Study Drug Discontinuation Criteria ............................................................................. 30 
4.4 
Withdrawal Criteria ....................................................................................................... 30 
4.5 
Re-Screening of Screen Failures ................................................................................... 31 
4.6 
Study Drug Discontinuation for Persistent Abnormal Clinical Laboratory Values ...... 32 
5  Study Treatments .................................................................................................................... 33 
5.1 
Treatment Groups .......................................................................................................... 33 
5.2 
Rationale for Dosing ..................................................................................................... 33 
5.3 
Randomization and Blinding ......................................................................................... 33 
5.4 
Breaking the Blind ........................................................................................................ 33 
5.5 
Drug Supplies ................................................................................................................ 33 
5.5.1  Formulation and Packaging ............................................................................... 33 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 34 


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5.5.3  Study Drug Administration ............................................................................... 34 
5.5.4  Treatment Compliance ...................................................................................... 35 
5.5.5  Storage and Accountability ............................................................................... 35 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 35 
5.6.1  Excluded Medications and/or Procedures ......................................................... 35 
5.6.2  Restricted Medications and/or Procedures ........................................................ 36 
5.6.3  Allowed Medications and/or Procedures .......................................................... 36 
5.6.4  Documentation of Prior and Concomitant Medication Use .............................. 36 
6  Study Procedures .................................................................................................................... 37 
6.1 
Informed Consent .......................................................................................................... 37 
6.2 
Screening Period ........................................................................................................... 37 
6.2.1  Screening Visit .................................................................................................. 37 
6.2.2  Qualification Period .......................................................................................... 37 
6.3 
Randomization .............................................................................................................. 38 
6.4 
Treatment Period ........................................................................................................... 38 
6.5 
Follow-Up Telephone Call ............................................................................................ 38 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................... 38 
7  Efficacy and 
 Assessments ........................................................................... 39 
7.1 
Primary Efficacy Endpoint ............................................................................................ 39 
7.2 
Secondary Efficacy Endpoints ...................................................................................... 39 
 
 ....................................................................................... 39 
8  Safety Assessments ................................................................................................................. 41 
8.1 
Adverse Events .............................................................................................................. 41 
8.1.1  Adverse (Drug) Reaction .................................................................................. 41 
8.1.2  Unexpected Adverse Drug Reaction ................................................................. 42 
8.1.3  Assessment of Adverse Events by the Investigator .......................................... 42 
8.2 
Serious Adverse Events ................................................................................................. 43 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 43 
8.4 
Pregnancy Reporting ..................................................................................................... 44 
8.5 
Expedited Reporting ...................................................................................................... 45 
8.6 
Special Situation Reports .............................................................................................. 45 
8.7 
Clinical Laboratory Evaluations .................................................................................... 46 




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11.6  Retention of Records ..................................................................................................... 53 
11.7  Publication Policy ......................................................................................................... 53 
11.8  Financial Disclosure ...................................................................................................... 54 
12  Study Administrative Information .......................................................................................... 55 
12.1  Protocol Amendments ................................................................................................... 55 
13  References ............................................................................................................................... 56 
Appendix A: Schedule of Procedures ........................................................................................... 57 
Appendix B: Clinical Laboratory Analytes .................................................................................. 62 
 
 
 




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LIST OF FIGURES 
Figure 1.  Illustration of Study Design ........................................................................................ 25 










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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the efficacy of K-877-ER 
 
 
compared to K-877-IR 
 
 from baseline to Day 28 in lowering fasting TG levels in 
patients with fasting TG levels 150 mg/dL and <500 mg/dL. 
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
 To demonstrate the efficacy of K-877-ER 
 
 compared to K-877-IR 
 
 
from baseline to Day 28 in lowering fasting TG levels in patients with fasting TG levels 
150 mg/dL and <500 mg/dL; 
 To evaluate the efficacy of K-877-ER 
 treatments (from 
day to 
day) from 
baseline to Day 28 in altering PD properties, including lipid parameters, in patients with 
fasting TG levels 150 mg/dL and <500 mg/dL; and 
 To evaluate the multiple-dose 
 properties at steady state of K-877-ER 
 
 














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If the patient withdraws from the study, the reason should be captured and could include the 
following:  
1. The patient withdraws consent at any time or requests discontinuation from the study;  
2. The patient fails to comply with protocol requirements or study-related procedures if, in the 
opinion of the Investigator or the Sponsor, the non-compliance will significantly compromise 
data interpretation or safety;  
3. In the Investigator’s judgment, it is in the patient’s best interests;  
4. Violation of the protocol inclusion and exclusion criteria is discovered, if, in the opinion of the 
Investigator or the Sponsor, the violation will significantly compromise data interpretation or 
safety; or  
5. The Sponsor or the regulatory authority terminates the study. 
Patients who choose to withdraw consent will be asked to document withdrawal of consent in 
writing.  
Although a patient is not obligated to give his/her reason for withdrawing prematurely, the 
Investigator will make a reasonable effort to obtain the reason while fully respecting the patient’s 
rights. The reason for withdrawal from the study must be documented in the eCRF. The Clinical 
Study Report will include the reason(s) for withdrawal from the study.  
If a patient withdraws prematurely from the study, study staff will make every effort to complete 
the full panel of assessments scheduled for the Early Termination (ET) visit. 
If a patient withdraws from the study due to an AE, the patient will be asked to return to the site 
for, at a minimum, the evaluations scheduled for the ET Visit. If the AE has still not resolved, 
additional follow-up will be performed, as appropriate, and documented in the patient’s medical 
records. As a minimum requirement, ongoing AEs are to be followed for 30 days after the patient’s 
last dose of study drug. If patients are lost to follow-up, attempts to contact them must be made 
and documented in the study records. Withdrawn patients will not be replaced. 
4.5 
Re-Screening of Screen Failures 
Patients who are screen failures for a modifiable condition (such as elevated HbA1c or 
uncontrolled hypertension), other than failing the TG criteria, can be re-screened once, and 
enrolled in the study at a future date if they are then deemed eligible for study participation based 
on protocol entry criteria after having medications adjusted and stabilized. Before each patient is 
re-screened, the Investigator should discuss the case with the Medical Monitor. 
Patients who are screen failures or run-in failures under Protocol Version 1.0 Inclusion 3 TG 
criteria may rescreen once with the review and approval of the Medical Monitor. 


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4.6 
Study Drug Discontinuation for Persistent Abnormal Clinical Laboratory 
Values 
A patient will discontinue treatment with study drug if persistent elevations in ALT, AST, 
bilirubin, CK, or TG, or a persistent decrease in eGFR, occur according to the following criteria: 
1. ALT or AST >8 × ULN, confirmed on repeat; 
2. ALT or AST >3 × ULN and bilirubin >2 × ULN or international normalized ratio >1.5, 
confirmed on repeat (if patient has Gilbert’s syndrome, bilirubin will require Medical Monitor 
review); 
3. ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) confirmed on repeat; 
4. ALT or AST >5 × ULN which persists for 2 weeks; 
5. Unexplained CK >5 × ULN confirmed on repeat. For patients with CK 10 × ULN, 
Investigators should immediately interrupt study drug while awaiting re-evaluation; 
Note: If the above CK elevation criteria are met with concerns of rhabdomyolysis, evaluations 
should include the patient being questioned about symptoms (e.g., muscle or tendinous pain, 
cramping, or weakness) and potential causes for the CK elevation (e.g., medications, exercise, 
or trauma). The following laboratory measurements should be obtained: CK, CK cardiac 
muscle isoenzyme (CK-MB), CK skeletal muscle isoenzyme (CK-MM), troponin, creatinine, 
myoglobin (serum and urine), transaminases, total bilirubin, and urinalysis including urine 
sediment. A physical examination should be performed, documenting findings such as muscle 
tenderness, weakness, or rash. An ECG should be collected as well. This information should 
be collected on the appropriate eCRF. For abnormalities to be reported as AEs, see Appendix E 
for a list of muscle AE definitions. Abnormalities should be followed until they have returned 
to baseline, or the Investigator considers them clinically stable;  
6. Fasting TG levels >2000 mg/dL (22.60 mmol/L) with signs or symptoms of pancreatitis at any 
time during the study. For repeated or persistent elevations of TG >2000 mg/dL 
(22.60 mmol/L) that are not accompanied by signs or symptoms of pancreatitis, Investigators 
may discontinue study drug at their discretion; or 
7. eGFR <30 mL/min/1.73 m2 occurring on or after Day 14 (Visit 5), confirmed on repeat. 
Note: Repeat testing should occur as soon as possible within 72 hours unless otherwise specified. 
If at any time during the study a patient develops elevations in ALT or AST >3 × ULN, 
CK >5 × ULN, TG >2000 mg/dL (>22.60 mmol/L), or a decrease in eGFR <30 mL/min/1.73 m2 
the study site will receive an alert from the central laboratory.  


















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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. 
All AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of informed consent until the Follow-Up Telephone Call. Patients should be instructed to 
report any AE that they experience to the Investigator, whether or not they think the event is due 
to study treatment. Beginning from the time of informed consent, Investigators should make an 
assessment for AEs at each visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at the Screening Visit should be recorded as medical history 
and not be reported as an AE unless the medical condition or signs or symptoms present at baseline 
changes in severity, frequency, or seriousness at any time during the study. In this case, it should 
be reported as an AE. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at the Screening Visit and significantly worsen during the 
study should be reported as AEs, as described below. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Abnormal test results that are determined to be an error should 
not be reported as an AE. Laboratory abnormalities or other abnormal clinical findings (e.g., ECG 
abnormalities) should be reported as an AE if any of the following are applicable: 
 If an intervention is required as a result of the abnormality; 
 If action taken with the study drug is required as a result of the abnormality; or 
 Based on the clinical judgment of the Investigator. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 


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8.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to study drug using the categories of 
yes or no. 
Assessment of Severity 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment 
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
 The temporal sequence from study drug administration- 
The event must occur after the study drug is given. The length of time from study drug exposure 
to the event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
 Concomitant drug- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
 Known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 




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knowledge of the occurrence. After the 30-day reporting window, any SAE that the Investigator 
considers related to study drug must be reported to the 
 or the 
Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, 
 personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to 
 at 
medpace-safetynotification@medpace.com or call the 
 SAE reporting line (phone 
number listed below), and fax/email the completed paper SAE form to 
 (contact 
information listed in Section 8.6) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered as soon as possible of the system becoming 
available. 
Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (e.g., 
patient discharge summary or autopsy reports) to 
 via fax or email. If it is 
not possible to access the EDC system, refer to the procedures outlined above for initial reporting 
of SAEs.  
8.4 
Pregnancy Reporting 
If a patient becomes pregnant from the time of initiation of study drug through the safety follow-up 
period defined in the protocol, the Investigator is to stop dosing with study drug immediately and 
the patient should be withdrawn from the study. ET procedures should be implemented at that 
time.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to 
 
 within 24 hours of knowledge of the event. 
 will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to 
 
within 24 hours of completion.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety follow-up period defined in the protocol, the Investigator should notify 
 as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
 If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 


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8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the Food and 
Drug Administration (FDA) and in any case no later than 7 days after knowledge by the 
Sponsor/designee of such a case. Relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to investigational medicinal product. 
8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
 Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgement should always be applied. 
In cases of a discrepancy in the drug accountability, overdose will be established only when 
it is clear that the patient has taken additional dose(s) or the Investigator has reason to suspect 
that the patient has taken additional dose(s).  
 Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors, cases of patients missing doses of 
investigational product are not considered reportable as medication errors. 
 Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to 
 (contact information listed below) within 
24 hours of knowledge of the event. All AEs associated with these Special Situation reports should 
be reported as AEs or SAEs as well as recorded on the AE eCRF and/or the SAE report form. 
Details of the symptoms and signs, clinical management, and outcome should be provided, when 
available. 










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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associates 
(CRAs) during monitoring visits. The CRAs will verify data recorded in the EDC system with 
source documents. All corrections or changes made to any study data must be appropriately tracked 
in an audit trail in the EDC system. An eCRF will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities (latest) for medical history and AEs; and 
 World Health Organization Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 


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10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  
10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last patient in the study.  
 


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
11.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of patients. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) GCP Guidelines require 
that approval be obtained from an IRB prior to participation of patients in research studies. Prior 
to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian must be approved by the IRB. 
No drug will be released to the clinical site for dosing until written IRB authorization has been 
received by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all FDA 
regulations/ICH GCP guidelines, local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and must document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. 
A copy of the signed ICF will be given to the patient. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, FDA/ICH GCP, and applicable regulatory requirements, and 
that valid data are entered into the eCRFs. 
To achieve this objective, the CRA’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 


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Investigator and site personnel the following documents: protocol, IB, eCRFs and procedures for 
their completion, informed consent process, and the procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the clinical site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records must be 
retained by the Investigator according to specifications in the FDA regulations/ICH GCP 
guidelines, local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
The Investigator must obtain written permission from the Sponsor before disposing of any records, 
even if retention requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor must 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.  
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


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11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
 


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by 
 or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB and the Sponsor within 5 working days. 


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13 
REFERENCES 
1. 
Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators 
(SPPARMα): the next generation of peroxisome proliferator-activated receptor 
α-agonists. Cardiovasc Diabetol. 2013;12:82. 
2. 
Investigational Brochure for K-877-ER Pemafibrate Extended Release Tablet. 
Version 3.0, 13 August 2020.  
3. 
Brown BG, Stukovsky KH, Zhao XQ. Simultaneous low-density lipoprotein-C lowering 
and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention 
with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid 
trials. Curr Opin Lipidol. 2006;17(6):631-636.  
4. 
Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes 
trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 
2006;48(3):438-445. 
5. 
Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. 
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of 
data from 170,000 participants in 26 randomised trials. Lancet. 
2010;376(9753):1670-1681. 
6. 
Costa J, Borges M, David C, et al. Efficacy of lipid lowering drug treatment for diabetic 
and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ. 
2006;332(7550):1115-1124. 
7. 
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll 
Cardiol. 2004;44(3):720-732. 
8. 
Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in 
serum cholesterol concentration lower risk of ischaemic heart disease? BMJ. 
1994;308(6925):367-372. 
9. 
Robinson JG, Smith B, Maheshwari N, et al. Pleiotropic effects of statins: benefit beyond 
cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol. 
2005;46(10):1855-1862. 
10. 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third 
report of the National Cholesterol Education Program (NCEP) expert panel on detection, 
evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) 
final report. Circulation. 2002;106(25):3143-3421. 
11. 
Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease 
prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European 
Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in 
Clinical Practice (constituted by representatives of nine societies and by invited experts). 
Eur Heart J. 2012;33(13):1635-1701. 
12. 
Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and 
lipoprotein metabolism. Circulation. 1998;98(19):2088-2093. 
13. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009;150(9):604-612.  
 





















Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
NCT #: 04447820 
 
Protocol Version Date: 28 January 2020 






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Kowa Research Institute, Inc. 
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K-877-ER 
 
 
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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Kowa Research Institute, Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Kowa Research 
Institute, Inc. and that it may not be further disclosed to third parties. I understand that the study 
may be terminated or enrollment suspended at any time by Kowa Research Institute, Inc., with or 
without cause, or by me if it becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board Regulations and International Council for Harmonisation Guidelines 
for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 




















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28 January 2020 v1.0 
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TABLE OF CONTENTS 
Protocol Signature Page .................................................................................................................. 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 13 
List of Tables ................................................................................................................................ 17 
List of Figures ............................................................................................................................... 18 
List of Abbreviations and Definition of Terms............................................................................. 19 
1  Introduction and Background Information ............................................................................. 21 
1.1 
Rationale ........................................................................................................................ 21 
1.2 
Risk/Benefit ................................................................................................................... 22 
2  Study Objectives ..................................................................................................................... 23 
2.1 
Primary Objective ......................................................................................................... 23 
2.2 
Secondary Objectives .................................................................................................... 23 
3  Study Description.................................................................................................................... 24 
3.1 
Summary of Study Design ............................................................................................ 24 
4  Selection and Withdrawal of Patients ..................................................................................... 26 
4.1 
Inclusion Criteria ........................................................................................................... 26 
4.2 
Exclusion Criteria .......................................................................................................... 27 
4.3 
Study Drug Discontinuation Criteria ............................................................................. 29 
4.4 
Withdrawal Criteria ....................................................................................................... 29 
4.5 
Re-Screening of Screen Failures ................................................................................... 30 
4.6 
Study Drug Discontinuation for Persistent Abnormal Clinical Laboratory Values ...... 30 
5  Study Treatments .................................................................................................................... 32 
5.1 
Treatment Groups .......................................................................................................... 32 
5.2 
Rationale for Dosing ..................................................................................................... 32 
5.3 
Randomization and Blinding ......................................................................................... 32 
5.4 
Breaking the Blind ........................................................................................................ 32 
5.5 
Drug Supplies ................................................................................................................ 32 
5.5.1  Formulation and Packaging ............................................................................... 32 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 33 






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11.6  Retention of Records ..................................................................................................... 52 
11.7  Publication Policy ......................................................................................................... 52 
11.8  Financial Disclosure ...................................................................................................... 53 
12  Study Administrative Information .......................................................................................... 54 
12.1  Protocol Amendments ................................................................................................... 54 
13  References ............................................................................................................................... 55 
Appendix A: Schedule of Procedures ........................................................................................... 56 
Appendix B: Clinical Laboratory Analytes .................................................................................. 61 
 
 


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K-877-ER 
 
 
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LIST OF TABLES 
Table 1. 
Treatment Groups ....................................................................................................... 32 
Table 2. 
Schedule of Procedures 
 
) .......................................... 56 
Table 3. 
Schedule of Procedures (
 
) ................................................... 58 
 
 
................................. 63 
 
 
................................................................................................. 64 
 
 
 


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LIST OF FIGURES 
Figure 1.  Illustration of Study Design ........................................................................................ 24 










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K-877-ER 
 
 
28 January 2020 v1.0 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to demonstrate the efficacy of K-877-ER 
 
 
compared to K-877-IR 
 
 from baseline to Day 28 in lowering fasting TG levels in 
patients with fasting TG levels 200 mg/dL and <500 mg/dL. 
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
 To demonstrate the efficacy of K-877-ER 
 
 compared to K-877-IR 
 
 
from baseline to Day 28 in lowering fasting TG levels in patients with fasting TG levels 
200 mg/dL and <500 mg/dL; 
 To evaluate the efficacy of K-877-ER 
 treatments (from 
day to 
day) from 
baseline to Day 28 in altering PD properties, including lipid parameters, in patients with 
fasting TG levels 200 mg/dL and <500 mg/dL; and 
 To evaluate the multiple-dose 
 properties at steady state of K-877-ER 
 
 














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K-877-ER 
 
 
28 January 2020 v1.0 
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If the patient withdraws from the study, the reason should be captured and could include the 
following:  
1. The patient withdraws consent at any time or requests discontinuation from the study;  
2. The patient fails to comply with protocol requirements or study-related procedures if, in the 
opinion of the Investigator or the Sponsor, the non-compliance will significantly compromise 
data interpretation or safety;  
3. In the Investigator’s judgment, it is in the patient’s best interests;  
4. Violation of the protocol inclusion and exclusion criteria is discovered, if, in the opinion of the 
Investigator or the Sponsor, the violation will significantly compromise data interpretation or 
safety; or  
5. The Sponsor or the regulatory authority terminates the study. 
Patients who choose to withdraw consent will be asked to document withdrawal of consent in 
writing.  
Although a patient is not obligated to give his/her reason for withdrawing prematurely, the 
Investigator will make a reasonable effort to obtain the reason while fully respecting the patient’s 
rights. The reason for withdrawal from the study must be documented in the eCRF. The Clinical 
Study Report will include the reason(s) for withdrawal from the study.  
If a patient withdraws prematurely from the study, study staff will make every effort to complete 
the full panel of assessments scheduled for the Early Termination (ET) visit. 
If a patient withdraws from the study due to an AE, the patient will be asked to return to the site 
for, at a minimum, the evaluations scheduled for the ET Visit. If the AE has still not resolved, 
additional follow-up will be performed, as appropriate, and documented in the patient’s medical 
records. As a minimum requirement, ongoing AEs are to be followed for 30 days after the patient’s 
last dose of study drug. If patients are lost to follow-up, attempts to contact them must be made 
and documented in the study records. Withdrawn patients will not be replaced. 
4.5 
Re-Screening of Screen Failures 
Patients who are screen failures for a modifiable condition (such as elevated HbA1c or 
uncontrolled hypertension), other than failing the TG criteria, can be re-screened once, and 
enrolled in the study at a future date if they are then deemed eligible for study participation based 
on protocol entry criteria after having medications adjusted and stabilized. Before each patient is 
re-screened, the Investigator should discuss the case with the Medical Monitor. 
4.6 
Study Drug Discontinuation for Persistent Abnormal Clinical Laboratory 
Values 
A patient will discontinue treatment with study drug if persistent elevations in ALT, AST, 
bilirubin, CK, or TG, or a persistent decrease in eGFR, occur according to the following criteria: 
1. ALT or AST >8 × ULN, confirmed on repeat; 
2. ALT or AST >3 × ULN and bilirubin >2 × ULN or international normalized ratio >1.5, 
confirmed on repeat (if patient has Gilbert’s syndrome, bilirubin will require Medical Monitor 
review); 


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3. ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) confirmed on repeat; 
4. ALT or AST >5 × ULN which persists for 2 weeks; 
5. Unexplained CK >5 × ULN confirmed on repeat. For patients with CK 10 × ULN, 
Investigators should immediately interrupt study drug while awaiting re-evaluation; 
6. Fasting TG levels >2000 mg/dL (22.60 mmol/L) with signs or symptoms of pancreatitis at any 
time during the study. For repeated or persistent elevations of TG >2000 mg/dL 
(22.60 mmol/L) that are not accompanied by signs or symptoms of pancreatitis, Investigators 
may discontinue study drug at their discretion; or 
7. eGFR <30 mL/min/1.73 m2 occurring on or after Day 14 (Visit 5), confirmed on repeat. 
Note: Repeat testing should occur as soon as possible within 72 hours unless otherwise specified. 
If at any time during the study a patient develops elevations in ALT or AST >3 × ULN, 
CK >5 × ULN, TG >2000 mg/dL (>22.60 mmol/L), or a decrease in eGFR <30 mL/min/1.73 m2 
the study site will receive an alert from the central laboratory.  












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K-877-ER 
 
 
28 January 2020 v1.0 
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6.4 
Treatment Period  
Following randomization, assigned study drug will be dispensed to patients. Details of initial visit 
along with subsequent visits are detailed in the Schedule of Procedures in Appendix A. The 
Treatment Period begins on Day 1 and concludes on Day 28. 
 patients will be required to 
return to the clinical site on Day 14 (±3 days) and Day 28 (±3 days) for efficacy and safety 
assessments. 
 patients will be admitted to the clinical site on Day -1 and will remain until discharged from 
the clinical site on Day 2. 
 patients will return to the clinical site on Day 14 (±3 days) for 
efficacy and safety assessments. On Day 27, 
 patients will be readmitted to the clinical site and 
will remain until discharged from the clinical site on Day 29. 
6.5 
Follow-Up Telephone Call  
Patients will participate in a Follow-Up Telephone Call 7 days (2 days) following the last dose 
of study drug. 
6.6 
Early Termination Visit and Withdrawal Procedures 
The end of treatment for patients completing the study is Day 28. For patients who are withdrawn 
from the study prior to completion, all Day 28 procedures will be performed at an ET Visit. These 
procedures are outlined in the Schedule of Procedures in Appendix A. 






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Kowa Research Institute, Inc. 
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K-877-ER 
 
 
28 January 2020 v1.0 
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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. 
All AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of informed consent until the Follow-Up Telephone Call. Patients should be instructed to 
report any AE that they experience to the Investigator, whether or not they think the event is due 
to study treatment. Beginning from the time of informed consent, Investigators should make an 
assessment for AEs at each visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at the Screening Visit should be recorded as medical history 
and not be reported as an AE unless the medical condition or signs or symptoms present at baseline 
changes in severity, frequency, or seriousness at any time during the study. In this case, it should 
be reported as an AE. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at the Screening Visit and significantly worsen during the 
study should be reported as AEs, as described below. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Abnormal test results that are determined to be an error should 
not be reported as an AE. Laboratory abnormalities or other abnormal clinical findings (e.g., ECG 
abnormalities) should be reported as an AE if any of the following are applicable: 
 If an intervention is required as a result of the abnormality; 
 If action taken with the study drug is required as a result of the abnormality; or 
 Based on the clinical judgment of the Investigator. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 


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8.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to study drug using the categories of 
yes or no. 
Assessment of Severity 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment 
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
 The temporal sequence from study drug administration- 
The event must occur after the study drug is given. The length of time from study drug exposure 
to the event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
 Concomitant drug- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
 Known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 




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28 January 2020 v1.0 
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knowledge of the occurrence. After the 30-day reporting window, any SAE that the Investigator 
considers related to study drug must be reported to the 
 or the 
Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, 
 personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to 
 at 
 or call the 
 SAE reporting line (phone 
number listed below), and fax/email the completed paper SAE form to 
 (contact 
information listed in Section 8.6) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered as soon as possible of the system becoming 
available. 
Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (e.g., 
patient discharge summary or autopsy reports) to 
 via fax or email. If it is 
not possible to access the EDC system, refer to the procedures outlined above for initial reporting 
of SAEs.  
8.4 
Pregnancy Reporting 
If a patient becomes pregnant from the time of initiation of study drug through the safety follow-up 
period defined in the protocol, the Investigator is to stop dosing with study drug immediately and 
the patient should be withdrawn from the study. ET procedures should be implemented at that 
time.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to 
 
 within 24 hours of knowledge of the event. 
 will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to 
 
within 24 hours of completion.  
If the female partner of a male patient becomes pregnant while the patient is receiving study drug 
or within the safety follow-up period defined in the protocol, the Investigator should notify 
 as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
 If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 


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8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the Food and 
Drug Administration (FDA) and in any case no later than 7 days after knowledge by the 
Sponsor/designee of such a case. Relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to investigational medicinal product. 
8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
 Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgement should always be applied. 
In cases of a discrepancy in the drug accountability, overdose will be established only when 
it is clear that the patient has taken additional dose(s) or the Investigator has reason to suspect 
that the patient has taken additional dose(s).  
 Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
 Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
 Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors, cases of patients missing doses of 
investigational product are not considered reportable as medication errors. 
 Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to 
 (contact information listed below) within 
24 hours of knowledge of the event. All AEs associated with these Special Situation reports should 
be reported as AEs or SAEs as well as recorded on the AE eCRF and/or the SAE report form. 
Details of the symptoms and signs, clinical management, and outcome should be provided, when 
available. 










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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associates 
(CRAs) during monitoring visits. The CRAs will verify data recorded in the EDC system with 
source documents. All corrections or changes made to any study data must be appropriately tracked 
in an audit trail in the EDC system. An eCRF will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities (latest) for medical history and AEs; and 
 World Health Organization Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 


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10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  
10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last patient in the study.  
 


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
11.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of patients. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) GCP Guidelines require 
that approval be obtained from an IRB prior to participation of patients in research studies. Prior 
to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient or 
patient’s legal guardian must be approved by the IRB. 
No drug will be released to the clinical site for dosing until written IRB authorization has been 
received by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all FDA 
regulations/ICH GCP guidelines, local regulatory requirements, and legal requirements.  
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and must document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. 
A copy of the signed ICF will be given to the patient. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, FDA/ICH GCP, and applicable regulatory requirements, and 
that valid data are entered into the eCRFs. 
To achieve this objective, the CRA’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 


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Investigator and site personnel the following documents: protocol, IB, eCRFs and procedures for 
their completion, informed consent process, and the procedure for reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the clinical site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records must be 
retained by the Investigator according to specifications in the FDA regulations/ICH GCP 
guidelines, local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
The Investigator must obtain written permission from the Sponsor before disposing of any records, 
even if retention requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor must 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.  
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


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11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
 


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by 
 or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB and the Sponsor within 5 working days. 


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13 
REFERENCES 
1. 
Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators 
(SPPARMα): the next generation of peroxisome proliferator-activated receptor 
α-agonists. Cardiovasc Diabetol. 2013;12:82. 
2. 
Investigational Brochure for K-877-ER Pemafibrate Extended Release Tablet. 
Version 2.0, 07 November 2019.  
3. 
Brown BG, Stukovsky KH, Zhao XQ. Simultaneous low-density lipoprotein-C lowering 
and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention 
with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid 
trials. Curr Opin Lipidol. 2006;17(6):631-636.  
4. 
Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes 
trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 
2006;48(3):438-445. 
5. 
Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. 
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of 
data from 170,000 participants in 26 randomised trials. Lancet. 
2010;376(9753):1670-1681. 
6. 
Costa J, Borges M, David C, et al. Efficacy of lipid lowering drug treatment for diabetic 
and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ. 
2006;332(7550):1115-1124. 
7. 
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll 
Cardiol. 2004;44(3):720-732. 
8. 
Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in 
serum cholesterol concentration lower risk of ischaemic heart disease? BMJ. 
1994;308(6925):367-372. 
9. 
Robinson JG, Smith B, Maheshwari N, et al. Pleiotropic effects of statins: benefit beyond 
cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol. 
2005;46(10):1855-1862. 
10. 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third 
report of the National Cholesterol Education Program (NCEP) expert panel on detection, 
evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) 
final report. Circulation. 2002;106(25):3143-3421. 
11. 
Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease 
prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European 
Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in 
Clinical Practice (constituted by representatives of nine societies and by invited experts). 
Eur Heart J. 2012;33(13):1635-1701. 
12. 
Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and 
lipoprotein metabolism. Circulation. 1998;98(19):2088-2093. 
13. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009;150(9):604-612.  
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
Table 2. 
Schedule of Procedures 
 Patients) 
a. 
Patients who are screen failures for a modifiable condition, other than failing the TG criteria, can be re-screened once. Before each patient is re-screened, the Investigator 
should discuss the case with the Medical Monitor. 
b. 
At the Screening Visit (Visit 1), patients not needing a washout period may start the Qualification Period (Visit 2) 24 hours after signing the informed consent form. Patients 
may continue through the Qualification Period provided that there are no prohibitive safety or eligibility results from the Screening Visit (Visit 1) laboratory tests.  
c. 
All Qualification Period visits will occur 7 days (3 days) apart.  
 
Screening Period 
Treatment Period 
Follow-Up 
Telephone 
Callf 
Screening 
Visita,b 
Qualification Periodc 
Visit Name
Visit 1 
Visit 2b
Visit 3d
Visit 3.1d,e
Visit 4d  
Visit 5 
Visit 6/ET 
Study Day
-70 to -29 
-28 to -21 
-21 to -14 
-14 to -7 
1 
14 
28 
35
Visit Window (days)
 
3  
3  
3  
 
3  
3  
2  
Assessment 
 
 
 
 
 
 
 
 
Informed consentg 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
X 
X 
 
 
 
Fasting TG level 
 
Xh
Xh
Xh 
 
 
 
Serum FSHi 
X 
 
 
 
 
 
 
 
Pregnancy testj 
X 
 
 
 
Xk
 
Xk
 
Height, body weight, and BMI 
X 
 
 
 
 
 
Xk,l
 
Demographic/medical history 
X 
 
 
 
 
 
 
 
Urine drug screenm 
X 
 
 
 
 
 
 
 
Prior/concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, FT4, and HbA1c 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
Xk
 
 
 
Physical examinationn 
X
 
 
 
Xk
Xk
Xk
 
Clinical laboratory testso 
X 
 
 
 
Xk
Xk
Xk
 
Vital signsp 
X 
 
 
 
X
X
X
 
12-lead ECGq 
X 
 
 
 
X 
 
X 
 
PD sampler 
X 
 
 
 
Xk
Xk
Xk
 
Dispense study drugs 
 
 
 
 
X 
 
 
 
Dosingt 
 
 
 
 
X 
 
AEs 
X 
Study drug compliance check 
 
 
 
 
 
X 
X