Conditions: Severe Hypertriglyceridemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 551
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of K-877 in adult patients with fasting high triglyceride levels ≥500 mg/dL and \<2000 mg/dL and normal renal function.

Detailed description:

Arms:
arm 1: K-877 or placebo comparator twice daily for 12 weeks arm 2: K-877 with placebo matching fenofibrate or fenofibrate with placebo matching K-877 for 40 weeks

Interventions: intervention 1: K-877 intervention 2: Fenofibrate intervention 3: Placebo (for K-877) intervention 4: Placebo (for Fenofibrate)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
SAP_002.pdf: 
 
CONFIDENTIAL 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 3, Multi-Center, Placebo-Controlled, Randomized, 
Double-Blind, 12-Week Study With a 40-Week, Active-Controlled, 
Double-Blind Extension to Evaluate the Efficacy and Safety of K-877 in 
Adult Patients With Fasting Triglyceride Levels ≥500 mg/dL and 
<2000 mg/dL and Normal Renal Function 
 
 
 
Drug Name:  
K-877 
Study Number: 
K-877-301 
EudraCT Number: 
2015-003511-37 
US IND Number 
109388 
Sponsor: 
Kowa Research Institute, Inc. 
Address: 
430 Davis Drive, Suite 200 
Morrisville, NC 27560 
United States of America 
 
 
Protocol Version/Date: 
V1.0, 13 September 2016 
 
 
SAP Version: 
V1.0 
SAP Date: 
19 October 2016 




Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 3 of 27 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................... 5 
1. 
INTRODUCTION .......................................................................................... 6 
2. 
STUDY OBJECTIVES AND STUDY DESIGN ........................................... 6 
2.1 
Study Objectives ............................................................................................. 6 
2.1.1 
Primary Objective .................................................................................... 6 
2.1.2 
Secondary Objectives ............................................................................... 6 
2.1.3 
Exploratory Objective .............................................................................. 6 
2.2 
Study Design ................................................................................................... 6 
2.3 
Study Endpoints ............................................................................................ 11 
2.3.1 
Primary Efficacy Endpoint .................................................................... 11 
2.3.2 
Secondary Efficacy Endpoints ............................................................... 11 
2.3.3 
Exploratory Efficacy Endpoints ............................................................. 12 
2.3.4 
Safety Endpoints .................................................................................... 12 
2.3.5 
Pharmacokinetic/Pharmacodynamic Endpoints ..................................... 12 
3. 
STATISTICAL METHODOLOGY ............................................................. 12 
3.1 
Baseline, Endpoint, and Other Statistical Considerations ............................ 12 
3.2 
Analysis Sets ................................................................................................. 13 
3.2.1 
Full Analysis Set .................................................................................... 13 
3.2.2 
Per-Protocol Set ..................................................................................... 13 
3.2.3 
Safety Analysis Set ................................................................................ 13 
3.2.4 
Pharmacokinetic Analysis Set ................................................................ 13 
3.3 
Patient Disposition ........................................................................................ 13 
3.4 
Demographics and Baseline Characteristics ................................................. 14 
3.5 
Prior/Concomitant Medications .................................................................... 14 
3.6 
Study medication Exposure and Compliance ............................................... 14 
3.7 
Analysis of Efficacy ..................................................................................... 15 
3.7.1 
Descriptive Statistics .............................................................................. 15 
3.7.2 
Hypothesis Testing Procedure ............................................................... 15 
3.7.3 
Primary Endpoint Analyses ................................................................... 16 
3.7.4 
Secondary Endpoint Analyses ............................................................... 18 
3.8 
Analysis of Safety ......................................................................................... 18 
3.8.1 
Adverse Events ...................................................................................... 19 
3.8.2 
Clinical Laboratory Assessments ........................................................... 20 
3.8.3 
12-Lead Electrocardiogram ................................................................... 21 
3.8.4 
Physical Examination ............................................................................. 21 
3.8.5 
Vital Signs, Weight, Height, BMI ......................................................... 21 
3.8.6 
Other Safety Parameters ........................................................................ 21 
3.9 
Analysis of Pharmacokinetic/Pharmacodynamic Data ................................. 21 
3.10 
Interim Analysis............................................................................................ 21 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 4 of 27 
 
4. 
SAMPLE SIZE DETERMINATION ........................................................... 22 
5. 
PROGRAMMING SPECIFICATIONS ....................................................... 22 
6. 
REFERENCES ............................................................................................. 23 
7. 
APPENDIX .................................................................................................. 24 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 5 of 27 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Apo  
Apolipoprotein 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Class 
CK 
Creatine kinase 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
FFA 
Free fatty acid 
FGF21 
Fibroblast growth factor 21 
 
 
γ-GTP 
Gamma-glutamyl transpeptidase 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HOMA-β 
Homeostatic model assessment for beta-cell function  
HOMA-IR 
Homeostatic model assessment for insulin resistance 
hsCRP 
High-sensitivity C-reactive protein 
IND 
Investigational New Drug 
IQR 
Inter-quartile range 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
MMRM 
Mixed-effect model repeat measurement 
NMR 
Nuclear magnetic resonance 
QUICKI 
Quantitative insulin sensitivity check index 
Q1 
25th percentile 
Q3 
75th percentile 
SAE 
Serious adverse event 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
 
 
ULN 
Upper limit of normal 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 6 of 27 
 
1. 
INTRODUCTION 
This document provides a description of the statistical methods and procedures to be 
implemented for the analyses of data from the study with protocol number K-877-301, 
version V1.0, 13 September 2016.  Any deviations from this Statistical Analysis Plan (SAP) 
will be documented in the final clinical study report. 
2. 
STUDY OBJECTIVES AND STUDY DESIGN  
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of the study is to demonstrate the efficacy of K-877 0.2 mg twice 
daily compared to placebo from baseline to Week 12 in lowering fasting TG levels in 
patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 
mmol/L). 
2.1.2 
Secondary Objectives 
The secondary objectives of the study are the following: 
 To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 52 in 
lowering fasting TG levels in patients with fasting TG levels ≥500 mg/dL 
(5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L);  
 To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 12 and 
Week 52 in altering lipid parameters in patients with fasting TG levels ≥500 mg/dL 
(5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L);  
 To evaluate the safety and tolerability of K-877 0.2 mg twice daily in patients with 
fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L); 
and 
 To determine the plasma concentrations of K-877 for the purpose of use in 
population pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) analysis. 
 
 
 
  
2.2 
Study Design 
This is a Phase 3, multi-center, randomized, double-blind study to confirm the efficacy and 
safety of K-877 0.2 mg twice daily compared to matching placebo (in the 12-week 
Efficacy Period) and an active comparator, fenofibrate (in the 40-week Extension Period), 
in patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L) and normal renal function. 
Eligible patients will enter a 4- to 6-week lifestyle stabilization period (4-week stabilization 
for patients not requiring washout and 6-week washout and stabilization for patients on 
lipid-altering therapy other than statins, ezetimibe, or proprotein convertase subtilisin/kexin 
type 9 [PCSK9] inhibitors). The stabilization period will be followed by a 2-week TG 
qualifying period (Visits 2 [Week -2] and 3 [Week -1]), and patient eligibility will be 
assessed based on the mean TG value from these 2 visits. If the patient’s mean TG level 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 7 of 27 
 
during the TG qualifying period is 450 mg/dL (5.09 mmol/L) and <500 mg/dL 
(5.65 mmol/L), an additional TG measurement can be taken 1 week later at Visit 3.1. The 
mean of all 3 TG measurements will be used to determine eligibility for the study. After 
confirmation of qualifying fasting TG values, eligible patients will enter a 12-week, 
randomized, double-blind Efficacy Period. At Visit 4 (Day 1), patients will be randomly 
assigned in a 2:1 ratio to K-877 0.2 mg twice daily or identical matching placebo tablets 
twice daily. During the 12-week Efficacy Period, patients will return to the site at Visit 5 
(Week 4), Visit 6 (Week 8), and Visit 7 (Week 12) for efficacy and safety evaluations. 
Patients who successfully complete the 12-week Efficacy Period are eligible to continue in 
a 40-week, double-blind, active-controlled Extension Period after completing the Visit 7 
(Week 12) procedures. Patients randomized to receive K-877 0.2 mg twice daily in the 
12-week Efficacy Period will continue to receive K-877 0.2 mg twice daily, as well as 
placebo matching fenofibrate 145 mg once daily, in the 40-week Extension Period. Patients 
randomized to receive placebo matching K-877 0.2 mg twice daily in the 12-week 
Efficacy Period will receive fenofibrate 145 mg once daily and placebo matching K-877 
0.2 mg twice daily in the 40-week Extension Period.  
From Visit 7 (Week 12), patients not on statins, ezetimibe, or PCSK9 inhibitors may initiate 
therapy, and patients receiving statins,  ezetimibe, or PCSK9 inhibitors may alter their dose, 
as indicated by guidelines or local standard of care. 
After Visit 8 (Week 16), patients are to return to the site every 12 weeks until the last visit 
(Visit 11 [Week 52]). 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 8 of 27 
 
Table 1: 
Clinical Evaluation Schedule 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 
Lifestyle 
Stabilization/
Washout 
Period 
Triglyceride Qualifying 
Period [1] 
12-Week Efficacy Period 
40-Week Extension Period 
Time 
Week -8 or -6 
Week -2 
±3 days 
Week -1 
±3 days 
Day 1 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Week 28 
±7 days 
Week 40 
±7 days 
Week 52 
±7 days or ET 
Visit Number 
1 [2] 
2 
3 [1] 
4 
5 
6 
7 
8 
9 
10 
11 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, and family history, and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
Vital signs (heart rate, respiratory rate, and 
blood pressure) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height [3], weight, and waist 
circumference 
X 
 
 
X 
 
 
X 
 
 
 
X 
Register screening number with IRT 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug and blood alcohol screen [4] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase and lipase 
X 
 
 
X 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Insulin, glycated albumin, HOMA-IR, 
HOMA-β, and QUICKI 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Serum pregnancy test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for WOCBP 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry, hematology, coagulation, and 
urinalysis 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Plasma Population PK sampling [7] 
PK/PD sampling [8] 
TG, TC, HDL-C, non-HDL-C, LDL-C, 
and remnant cholesterol [9] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*footnotes on following page 
Error! Reference source not found.(Continued) 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 9 of 27 
 
Lifestyle 
Stabilization/
Washout 
Period 
Triglyceride Qualifying 
Period [1] 
12-Week Efficacy Period 
40-Week Extension Period 
Time 
Week -8 or -6 
Week -2 
±3 days 
Week -1 
±3 days 
Day 1 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Week 28 
±7 days 
Week 40 
±7 days 
Week 52 
±7 days or ET 
Visit Number 
1 [2] 
2 
3 [1] 
4 
5 
6 
7 
8 
9 
10 
11 
Apo A1, Apo A2, Apo B, Apo B48, 
Apo B100, Apo C2, Apo C3, and Apo E 
 
 
 
X 
X 
 
X 
 
X 
 
X 
FFAs 
 
 
 
X 
 
 
X 
 
X 
 
X 
Ion mobility analysis and lipoprotein 
fraction (NMR) 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Withdraw lipid-altering medication(s) 
other than statins, ezetimibe, or PCSK9 
inhibitors, if applicable 
X 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
X 
 
 
X 
 
 
 
X 
Physical examination 
X 
 
 
X 
 
 
X 
 
 
 
X 
Assess and record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLC counseling [12] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Dispense study drug (efficacy period) 
 
 
 
X 
X 
X 
 
 
 
 
 
Dispense study drug (extension period) 
 
 
 
 
 
 
X 
X 
X 
X 
 
Collect study drug and record 
accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
1. 
Triglyceride levels are based on the mean of the Visit 2 (Week -2) and Visit 3 (Week -1) values. In cases in which a patient’s mean TG level from Visit 2 (Week -2) and Visit 3 (Week -1) falls outside the required range for entry into the 
study but is 450 mg/dL (5.09 mmol/L) and <500 mg/dL (5.65 mmol/L), an additional TG measurement can be collected 1 week (±3 days) later (Visit 3.1). If Visit 3.1 is required, the TG qualifying period will be extended, and Visit 4 will 
occur 1 week (±3 days) after Visit 3.1. If a third sample is collected, entry into the 12-week Efficacy Period is based on the mean of the values from Visit 2 (Week -2), Visit 3 (Week -1), and Visit 3.1. 
2. 
Visit 1 for patients who require a washout is at Week -8. Visit 1 for patients who do not require a washout is at Week -6. 
3. 
Height is measured at Visit 1 (Week -8 or Week -6) only. 
 
 
 
 
 
 
*footnotes continued on following page 
 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 10 of 27 
 
Error! Reference source not found. (Continued) 
 
 
 
 
 
 
   
 
  
9. All lipid laboratory blood specimens must be obtained under fasting conditions (i.e., after the patient has fasted for at least 10 hours). 
 
 
12. TLC counseling can be provided by the Investigator or designee (see Section Error! Reference source not found.). 
AE = adverse event; Apo = apolipoprotein; ET = Early Termination; FFA = free fatty acid; 
 HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; HOMA-β = homeostasis model 
assessment for beta-cell function; HOMA-IR = homeostasis model assessment for insulin resistance; IRT = Interactive Response Technology; LDL-C = low-density lipoprotein cholesterol; NMR = nuclear magnetic resonance; PCSK9 = 
proprotein convertase subtilisin/kexin type 9; PD = pharmacodynamic; PK = pharmacokinetic; QUICKI = quantitative insulin sensitivity check index; 
 TC = total cholesterol; TG = triglycerides; TLC = therapeutic lifestyle 
changes; Tmax = time to maximum plasma concentration; 
 WOCBP = women of childbearing potential. 
 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 11 of 27 
 
2.3 
Study Endpoints 
2.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in fasting TG from baseline to 
Week 12. Baseline for TG will be defined as the mean of Visit 4 (Day 1) and the preceding 
TG qualifying visit (either Visit 3 [Week -1] or Visit 3.1, if required) measurements. 
2.3.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the 12-week Efficacy Period include the following: 
 
Percent change from baseline to Week 12 in remnant cholesterol (calculated as total 
cholesterol [TC] − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 
 
Percent change from baseline to Week 12 in TC, LDL-C, free fatty acids (FFAs), 
Apo A2, Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; 
 
Change from baseline to Week 12 in FGF21 and high-sensitivity C-reactive protein 
(hsCRP), and percent change from baseline to Week 12 in ion mobility analysis and 
lipoprotein fraction (nuclear magnetic resonance [NMR]); and  
 
Percent change from baseline to Week 12 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and 
Apo C3:Apo C2. 
The secondary efficacy endpoints for the 40-week Extension Period include the 
following: 
 
Percent change from baseline to Week 52 in fasting TG; 
 
Percent change from baseline to Week 52 in remnant cholesterol (calculated as 
TC − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 
 
Percent change from baseline to Week 52 in TC, LDL-C, FFAs, Apo A2, Apo B, 
Apo B48, Apo B100, Apo C2, Apo C3, and Apo E;  
 
Change from baseline to Week 52 in FGF21 and hsCRP, and percent change from 
baseline to Week 52 in ion mobility analysis and lipoprotein fraction (NMR); and  
 
Percent change from baseline to Week 52 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and 
Apo C3:Apo C2. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either 
Visit 3 [Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy 
and safety variables will be defined as Visit 4 (Day 1). If the measurement at this visit is 
missing, the last measurement prior to the first dose of randomized study drug will be 
used. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 12 of 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.4 
Safety Endpoints 
Safety assessments include adverse events (AEs), clinical laboratory measurements 
(chemistry, hematology, coagulation profile, 
 and urinalysis), 12-lead 
electrocardiograms (ECGs), vital signs (heart rate, respiratory rate, and blood pressure), 
and physical examinations. 
2.3.5 
Pharmacokinetic/Pharmacodynamic Endpoints 
Pharmacokinetic concentrations collected during the 12-week Efficacy Period will be 
used for population PK analysis and PK/PD analysis. 
3. 
STATISTICAL METHODOLOGY 
3.1 
Baseline, Endpoint, and Other Statistical Considerations 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding lipid qualifying visit (either Visit 
3 [Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy and 
safety variables will be defined as Visit 4 (Day 1). If the measurement at this visit is missing, 
the last measurement prior to the first dose of randomized study drug will be used. 
 
 
  
Post-baseline lipid assessments will be assigned a visit number based on the date of 
assessment relative to the first dose of the double-blind study drug. Visit windows will be 
defined as the scheduled time from dosing date with a 7-day window (±7 days). Within a 
visit window, if a scheduled visit occurs, then the measurement from this scheduled visit 
will be used as the measurement for this visit window. If no scheduled visit occurs within 
a visit window, the last unscheduled measurement within the window will be used. If no 
visits occur within a visit window, the measurement of this visit will be treated as missing.  
Any lipid measurements that have resulted from a non-fasting sample will be considered 
invalid and will not be used in the derivation of an efficacy endpoint. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 13 of 27 
 
Descriptive statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum, 25th (Q1) percentile and 75th (Q3) percentile) will be used to summarize the 
continuous data. Discrete measures will be summarized using counts and percentages.  
3.2 
Analysis Sets 
3.2.1 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized patients who take at least 1 dose 
of double-blind study drug, and have a baseline TG measurement. The FAS is the primary 
analysis population. All efficacy analyses will be performed on the FAS.  
3.2.2 
Per-Protocol Set 
The Per-Protocol Set will include all FAS patients for the 12-week Efficacy Period who 
complete the 12-week placebo-controlled Efficacy Period without any major protocol 
deviations and have baseline and Week 12 endpoint fasting serum TG measurements. 
Major protocol deviations will be pre-specified prior to unblinding the study. The following 
criterion will be evaluated for major deviations prior to unblinding of the treatment 
allocation: 
 No eligibility criterion violations, 
 Did not discontinue study drug, 
 Study medication compliance within 80-120%, 
 Not taken any prohibited concomitant medication, 
 Not unblinded during the 12-week double-blind treatment period, and 
 No other substantial protocol violations. 
The Per-Protocol Set will be used to assess robustness of the primary analysis results during 
the 12-week Efficacy Period. 
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 
Pharmacokinetic Analysis Set 
The PK Analysis Set includes all patients from the Safety Analysis Set who have at least 
1 PK sample.  
3.3 
Patient Disposition 
The reason given for each screen failure will be summarized and listed. Patient disposition 
will be provided for all randomized patients. The number and percentage of patients in each 
of the following disposition categories will be presented: 
 Patients who are randomized, 
 Patients who start study drug, 
 Patients who complete the 12-week Efficacy Period  on study drug, 
 Patients who complete the 12-week Efficacy Period but stopped study drug during 
the 12-week Efficacy Period, 
 Patients who withdraw from the study during the 12-week Efficacy Period, 
 Patients who enter the 40-week Extension Period, 
 Patients who complete the 40-week Extension Period,  


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 14 of 27 
 
 Patients who withdraw from the study during the 40-week Extension Period. 
For randomized patients who withdraw from the study, the primary reason for the 
withdrawal will be listed and summarized. 
The number of patients included in each analysis set will be summarized. 
3.4 
Demographics and Baseline Characteristics 
Demographics (age, sex, race, and ethnicity), body weight, height, and BMI will be 
summarized by randomized treatment using descriptive statistics for the randomized 
patients and the Full Analysis Set. Age group (<65 years versus ≥65 years and 18-64 years, 
65-84 years, and ≥85 years) and current statin therapy use (not on statin therapy versus 
currently receiving statin therapy), ezetimibe use (yes/no), PCSK9 inhibitor use (yes/no), 
any lipid-altering medications use including statins, ezetimibe and/or PCSK9 inhibitor 
(yes/no) will also be summarized. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding lipid qualifying visit (either Visit 3 
[Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy and safety 
variables will be defined as Visit 4 (Day 1). If the measurement at this visit is missing, the 
last measurement prior to the first dose of randomized study drug will be used.  
 
 
 
Patient medical history will be summarized by randomized treatment using descriptive 
statistics for the randomized patients and the Full Analysis Sets   
3.5 
Prior/Concomitant Medications 
The use of any prior medication and concomitant or post-treatment medication will be listed 
for the Safety Analysis Set with an indication of whether the medication was prior or 
concomitant during the 12-week Efficacy Period, or concomitant during the 40-week 
Extension Period.   
The number and percentage of patients taking each concomitant medication will be 
summarized by preferred term within Anatomical Therapeutic Chemical (ATC) 
classification and by treatment group for the Safety Analysis Set. 
Statins, ezetimibe and PCSK9 inhibitors will be summarized by preferred term and dose at 
baseline for each treatment group for the Safety Analysis Set during the 12-week Efficacy 
Period and 40-week Extension Period. 
Lipid medications including statin that are added or changed during the 12-week Efficacy 
Period and 40-week Extension Period will be summarized for the Safety Analysis Set. 
3.6 
Study medication Exposure and Compliance 
Days of exposure to study medication will be summarized by treatment group for the Safety 
Analysis Set using descriptive statistics. Exposure in days is defined as the date of last dose 
of study drug minus the date of first dose of study drug plus 1. In addition, a contingency 
table will be provided to display the number and percentage of patients with exposure in 
the following categories: 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 15 of 27 
 
For K-877 
 1 to ≤4 weeks (1-28 days) 
 >4 to ≤8 weeks (29-56 days) 
 >8 to ≤12 weeks (57-84 days) 
 >12 to ≤16 weeks (85-112 days) 
 >16 to ≤28 weeks (113-196 days) 
 >28 to ≤40 weeks (197-280 days) 
 >40 to ≤52 weeks (281-364 days) 
 >52 weeks (≥365 days) 
For placebo 
 1 to ≤4 weeks (1-28 days) 
 >4 to ≤8 weeks (29-56 days) 
 >8 to ≤12 weeks (57-84 days) 
 >12 weeks (≥85 days) 
For fenofibrate 
 1 to ≤4 weeks (1-28 days) 
 >4 to ≤16 weeks (29-112 days) 
 >16 to ≤28 weeks (113-196 days) 
 >28 to ≤40 weeks (196-280 days) 
 >40 weeks (≥281 days) 
Percent compliance with the study medication at the 12-week Efficacy Period and during 
the 40-week Extension Period will be summarized by treatment group for the Safety 
Analysis Set using descriptive statistics.  Additionally the number and percentage of 
patients within each treatment group with overall compliance in the following categories: 
<80%, 80% to 120%, and >120%, will be provided. 
3.7 
Analysis of Efficacy 
3.7.1 
Descriptive Statistics 
All available original and derived lipid data will be listed for the randomized patients. 
Descriptive statistics of the baseline, change from baseline and percent change from 
baseline to each post-baseline value will be presented by treatment group for each measured 
lipid level and derived ratio for the Full Analysis Set and the Per-Protocol Set. 
Spaghetti plots of the individual patient data over time by treatment for lipid parameters 
will be provided for the Full Analysis Set. Boxplots of the percent change in lipid 
parameters from baseline to each post-baseline visit by treatment will also be produced.   
3.7.2 
Hypothesis Testing Procedure 
In order to control the family-wise Type I error at a 0.05 level, a fixed sequential testing 
procedure will be implemented. In a hierarchical step-down manner, the primary endpoint 
will be tested first, followed by secondary endpoints, tested in the following hierarchical 
manner: percent change from baseline to Week 12 (1) remnant cholesterol, (2) HDL-C, (3) 
Apo A1, and (4) non-HDL-C. Each test is planned to be performed at a 0.05 level. 
Inferential conclusions about these efficacy endpoints will require statistical significance 
of the previous one. 
For other efficacy endpoints, nominal p-values and 95% confidence intervals will be 
presented, but should not be considered as confirmatory. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 16 of 27 
 
3.7.3 
Primary Endpoint Analyses 
Several analyses (the primary analysis, and sensitivity analyses) will be carried out on the 
primary endpoint (the percent change in fasting TG from baseline to Week 12).  
3.7.3.1 Statistical Analyses of Primary Efficacy Endpoint 
Hodges-Lehmann Estimator with A Pattern Mixture Model Imputation  
Due to the known distribution of TG and percent change from TG, normality assumption 
is usually difficult to satisfy. Also from historical data, the variances of percent change 
from baseline in TG are significantly unequal between K-877 0.2 mg and placebo. A 
nonparametric approach will be used as the primary analysis for the primary efficacy 
endpoint. As an extension to the Wilcoxon rank-sum test, the Hodges-Lehmann method 
will be used to estimate the median difference and its corresponding 95% CI for percent 
changes between K-877 0.2 mg and placebo.  
The SAS code for Hodges-Lehmann estimates is listed below: 
 proc npar1way hl alpha=.05; 
      class TRT01PN; 
      var PCHG; 
   run; 
For this study, during the 12-week Efficacy Period, patients who discontinue study drug 
prematurely will remain in the study until Visit 7 (Week 12). If a patient who has 
discontinued study drug fails to attend any follow-up appointments, reasonable efforts 
(telephone calls to family members or friends, e-mail contacts, etc.) will be made in order 
to encourage the patient to complete the study visits. 
A pattern-mixture model will be used as the primary imputation method as part of the 
primary analysis for the Week 12 percent change from baseline in fasting TGs. This 
imputation model will include factors such as patient demographics, disease status, and 
baseline TGs, as well as adherence to therapy. The imputation model will impute missing 
Week 12 TG values as follows: 
 For patients who do not adhere to therapy and who do not have Week 12 
measurements, the missing data imputation method will use patients in the same 
treatment arm who do not adhere to therapy and have Week 12 measurements; and 
 If there are no patients in the same treatment arm who do not adhere to therapy and 
have Week 12 measurements, missing Week 12 TG values will be imputed as 
follows: 
o For the K-877 arm, the treatment effect is considered washed out and 
baseline TG values will be used to impute the Week 12 TG values; and 
o For the placebo arm, missing Week 12 TG values will be imputed assuming 
missing at random, including patient demographics, disease status, and 
baseline and post-baseline efficacy data from the placebo arm.  
After the multiple imputation step, each imputed dataset will be analyzed by nonparametric 
Hodges-Lehmann method. Hodges-Lehmann estimator and standard error will be 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 17 of 27 
 
combined to produce treatment difference estimate and 95% confidence interval and 
p-value. 
Details of the primary imputation method is described in Appendix 1. 
The multiple imputation procedure in the pattern mixture model will be conducted by two 
parts: PROC MI and PROC MIANALYZE. The first procedure will generate 100 multiple 
samples and then perform the Hodges-Lehmann analysis for each sample. The SAS 
procedure (PROC NPAR1WAY) specified above will generate two statistics in the output: 
• 
Hodges-Lehmann Estimation 
• 
Asymptotic Standard Error 
These two statistics can be read into PROC MIANALYZE to get the overall estimate of 
location difference (treatment difference), as well as the confidence interval and p-value.  
The primary efficacy analysis will be performed on the FAS population. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 18 of 27 
 
 
 
 
 
 
 
 
 
 
 
  
3.7.4 
Secondary Endpoint Analyses 
Secondary efficacy endpoints included in the hierarchical step-down testing procedure 
include percent change from baseline to Week 12 in a fixed sequence of (1) remnant 
cholesterol, (2) HDL-C, (3) Apo A1, and (4) non-HDL-C. 
The secondary and exploratory efficacy endpoints during the 12-week Efficacy Period will 
be analyzed using an ANCOVA model with the same imputation method used for the 
primary analysis. The ANCOVA model will include country, current statin therapy use (not 
on statin therapy versus currently receiving statin therapy), and treatment as factors; 
baseline value as a covariate. Estimates for treatment difference, p-values and 95% 
confidence intervals will be provided. If normality assumption is not met, 
Hodges-Lehmann estimator with the same imputation method used for the primary analysis 
will be used. 
The secondary efficacy endpoint of percent change from baseline to Week 52 in fasting TG 
will be summarized descriptively by treatment on the FAS. 
 
 
 Other efficacy endpoints during the Extension Period will be summarized 
descriptively in the same manner. No hypothesis testing will be performed for the percent 
change or change from baseline to Week 52 endpoints. 95% confidence interval will be 
presented for percent change or change from baseline within each treatment group. 
 
 
 
 
 
 
 
 
 
 
3.8 
Analysis of Safety 
The safety data will be presented for the Safety Analysis Set for the 12-week Efficacy 
Period, 40-week Extension Period, and overall period. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 19 of 27 
 
3.8.1 
Adverse Events 
A Treatment-Emergent Adverse Event (TEAE) is defined as any AE that occurred for the 
first time after the first dose of double-blind study drug or existed prior to the first dose and 
worsened during the post dosing period. AE worsening applies to severity, or relationship 
to study drug.  
A summary overview of TEAEs will be provided, which presents the number and 
percentage of patients in each treatment group from the Safety Analysis Set for the 12-week 
Efficacy Period and the 40-week Extension Period and overall period satisfying each of the 
following categories: 
 Any TEAEs, 
 Maximum severity of TEAEs, 
 Study drug-related TEAEs, 
 Maximum severity of study drug-related TEAEs, 
 All TE-SAEs, 
 All study drug-related TE-SAEs, 
 TEAEs leading to death, 
 TEAEs leading to interruption/study drug discontinuation, and 
 Study drug-related TEAEs leading to interruption/study drug discontinuation. 
The number and percentage of patients with TEAEs will be summarized by their MedDRA 
preferred term within system organ class and by treatment.  AEs will be counted by number 
of events as well as the number of patients. For event count summaries, multiple AE events 
with the same MedDRA coded terms (preferred term and system organ class) and onset 
date and time from the same patient will only be counted once. For patient count 
summaries, multiple AE events with the same MedDRA coded terms (preferred term and 
system organ class) from the same patient will only be counted once. Whether the AE 
belongs to the 12-week Efficacy Period and the 40-week Extension Period will be 
determined by the AE onset date. 
The number and percentage of patients with TEAEs will be summarized by reported 
maximum severity within each MedDRA preferred term within system organ class and by 
treatment.   
The number and percentage of patients with any drug-related TEAEs, drug-related TE-
SAEs, and TEAEs and TE-SAEs that lead to study drug discontinuation will be 
summarized by preferred term within system organ class and by treatment. In these 
summaries, any patients reporting multiple episodes of the same TEAE (i.e., same preferred 
term and system organ class), will be counted once. 
All SAEs will be listed with an indication of whether the SAE was treatment emergent or 
started prior to treatment. 
All TEAEs that are reported as having led to a withdrawal of study drug will be listed. 
The number of events and number of patients with TEAEs by each 12 weeks of treatment 
(0-12, 12-24, 24-36, 36-48, 48-52 and >52 weeks) will also be summarized for each 
MedDRA preferred term, system organ class, and treatment. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 20 of 27 
 
3.8.2 
Clinical Laboratory Assessments 
3.8.2.1 Chemistry and Hematology 
Descriptive statistics of each chemistry and hematology parameter will be presented for 
baseline, ‘Time point’, and Change from Baseline to each ‘Time point’; where ‘Time point’ 
is each post-baseline assessment. These will be presented by treatment group for each 
parameter using the Safety Analysis Set.   
Counts and percentages of patients with any post-baseline observation that is below the 
lower limit of normal (<LLN) or above the upper limit of normal (>ULN) will be 
summarized for each chemistry and hematology parameter by treatment group and overall. 
Post-baseline changes of specified lab tests (ALT, AST, CK, serum creatinine, total 
bilirubin, alkaline phosphatase) abnormalities will be summarized by presenting the 
number and percentage of patients in each treatment group whose worst post-baseline value 
satisfies each of the following criteria in the table below and shift tables will be produced 
during the 12-week Efficacy Period and during the 40-week Extension Period and overall 
period. 
Parameter  
Categories 
ALT  
Normal  
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN  
>5xULN to 
≤10x ULN 
>10xULN to 
≤20x ULN 
> 20x ULN 
AST 
Normal  
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN  
>5xULN to 
≤10x ULN 
>10xULN to 
≤20x ULN 
> 20x ULN 
CK 
 
Normal  
>1xULN to 
≤5xULN 
 
>5xULN to 
≤10xULN  
>10xULN 
 
 
Serum 
Creatinine 
Normal 
>1xULN to 
≤1.5xULN 
 
>1.5xULN 
to ≤2xULN  
>2xULN 
 
 
Serum 
Creatinine 
≥2xbaseline 
 
 
 
 
 
ALP 
Normal 
>1xULN to 
≤1.5xULN 
>1.5xULN 
 
 
 
Total 
Bilirubin  
Normal  
>1xULN to 
≤1.5xULN  
>1.5xULN 
to ≤2xULN 
>2xULN 
 
 
Total 
Bilirubin 
accompany 
by ALT or 
AST>3xUL
N 
Normal  
>1xULN to 
≤1.5xULN  
>1.5xULN 
to ≤2xULN 
>2xULN 
 
 
eGFR 
 ≥90 
mL/min/1.73
m2 
≥60 to <90 
mL/min/1.73
m2 
≥30 to <60 
mL/min/1.73
m2 
<30 
mL/min/1.73
m2 
 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 21 of 27 
 
Spaghetti plots of the individual patient data over time and boxplots of the values at baseline 
and each post-baseline visit will be presented by treatment for ALT, AST, CK, serum 
creatinine, total bilirubin, and alkaline phosphatase. Normal reference ranges will be 
plotted on these plots.   
The number and percentage of patients who meet ALT or AST >3xULN 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 these patients’ ALT, AST, ALP and total bilirubin 
data 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 left lower quadrant and Hy’s Law case candidates are in the upper 
right quadrant (ALT>3×ULN and total bilirubin>2×ULN). Subjects with Gilbert’s 
syndrome or cholestasis are typically found in the upper left quadrant, and subjects 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. 
3.8.3 
12-Lead Electrocardiogram 
ECG overall interpretation findings will be summarized by randomized treatment using 
descriptive statistics for the Safety Analysis Set. 
3.8.4 
Physical Examination 
The number and percentage of patients with physical examination findings will be 
presented for the Safety Analysis Set. 
3.8.5 
Vital Signs, Weight, Height, BMI 
Vital signs parameters will be summarized using descriptive statistics for the Safety 
Analysis Set. The change from baseline will also be presented. 
3.8.6 
Other Safety Parameters 
Other safety data will be listed. 
3.9 
Analysis of Pharmacokinetic/Pharmacodynamic Data 
Population PK and PK/PD data will be analyzed and reported separately. 
 
 
 
 
 
 
 
 
3.10 
Interim Analysis 
No interim analysis was planned for this study. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 22 of 27 
 
4. 
SAMPLE SIZE DETERMINATION 
Approximately 630 patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L) will be randomized in a 2:1 ratio into one of the following 
treatment groups: K-877 0.2 mg twice daily or identical matching placebo twice daily. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
PROGRAMMING SPECIFICATIONS 
Statistical analyses will be performed using SAS® (Cary, NC) version 9.3 or above. All 
available data will be presented in subject data listings, which will be sorted by site number, 
unique subject identifier and where appropriate, visit number and visit/assessment date. 
The programming specification, including the mock-up validity listings, analysis tables, 
figures, and data listings, as well as the derived database specification, will be prepared in 
stand-alone documents. The programming specification document will be finalized prior to 
the database lock and unblinding the treatment code. 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 23 of 27 
 
6. 
REFERENCES 
Glynn R., Laird N., Rubin DB (1986). Selection Modeling Versus Mixture Modeling with 
Nonignorable Nonresponse. Drawing Inferences from Self-Selected Samples. pp 115-142. 
 
Hogan J. W., Roy J., and Korkontzelou C.. Handling Drop-out in Longitudinal Studies. 
Statistical Medicine, 23:1455–1497. 2004;  
 
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 
 
Little, R., Yau, L. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. 
Biometrics, 1996, vol. 52, 1324-1333. 
 
Ratitch B.; and O’Kelly M.; Implementation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedures. PharmaSUG2011 - Paper SP04, 2011 
 
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 
 
Rubin, D.B. Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & 
Sons, Inc. 1987 
 
Tangen, C.M. and Koch, G.G.. Nonparametric Analysis of Covariance for Hypothesis 
Testing with Logrank and Wilcoxon scores and Survival-rate estimation in a Randomized 
Clinical Trial. Journal of Biopharmaceutical. Statistics, 9:2, 307-338, 1999. 
 
Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using Controlled Clinical 
Trials to Learn More About Drug-Induced Liver Injury. Hepatology. 2008, 48:1680-1689.  
 
Woolson, R.F., and Lachenbruch, P.A.. Rank Analysis of Covariance with Right-censored 
Data. Biometrics, 39:727-733, 1983 
 
Yang, Y.. Sensitivity Analysis in Multiple Imputation for Missing Data. SAS Global Forum 
2014-SAS270, 2014.  
.


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 24 of 27 
 
7. 
APPENDIX  
Appendix 1 Primary Analysis Imputation Method for Missing Week 12 Efficacy Data 
– A Pattern Mixture Model 
Pattern mixture model was first introduced by Glynn et al (1986) and Little (1993). Later 
Little and Yau (1993) suggested control based pattern mixture models, which assume that 
after discontinuation, subjects on the experimental treatment who withdraw will tend to 
have efficacy close to subjects on the control treatment. The imputation model for this study 
will impute missing Week 12 fasting TG measurements as follows: 
I. 
For patients who do not adhere to therapy and who do not have Week 12 fasting TG 
measurements, the missing data imputation method will use patients in the same 
treatment arm who do not adhere to therapy and have Week 12 fasting TG 
measurements. 
Patients without Week 12 fasting TG measurements and patients with Week 12 
fasting TG measurements but discontinue treatment prior to Week 12 will be 
selected.  
DATA DATAIN1; 
SET ALLTG;  
IF TRTCOMPL=’N’ THEN OUTPUT DATAIN1; /*output patients who did not complete 12-week 
treatment and have Week-12 TG and those missing Week 12*/ 
RUN;  
 
Missing Week 12 TG data will be imputed PROC MI procedure with a multivariate 
imputation by fully conditional specification methods to create 100 datasets. In the 
imputation model, patient demographics (age, sex, ethnicity, country, and baseline 
BMI), current statin therapy use (not on statin therapy versus currently receiving 
statin therapy), disease status (baseline systolic and diastolic blood pressures, 
baseline eGFR), and baseline TG. The FCS statement will be used. This statements 
calls a multivariate imputation by fully conditional specification methods. 
 
PROC MI DATA=DATAIN1 OUT=IMOUT1 MINIMUM=0 SEED=98547 NIMPUTE=100; 
BY TRT; 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN; 
FCS; /* fully conditional specification method*/ 
TRANSFORM LOG(BASE) LOG(WEEK12); 
RUN; 
 
 
II. 
If there are no patients in the same treatment arm who do not adhere to therapy and 
have Week 12 TG measurements, missing Week 12 TG measurements will be 
imputed as follows: 
 
DATA DATA21 DATA22; 
SET DATAIN1; 
IF TRT=’K-877’ THEN OUTPUT DATA21;  
ELSE IF TRT=’PLACEBO’ THEN OUTPUT DATA22; 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 25 of 27 
 
RUN; 
a. For the K-877 arm, the treatment effect is considered washed out and 
baseline TG measurements will be used to impute the Week 12 TG 
measurements. Missing Week 12 TG values will be imputed by using the 
method which was proposed by Ratitch et al (2013). 
DATA DATA21a; 
LENGTH SUBJID2 $8 ; 
SET DATA21(RENAME=(WEEK12=WEEK12A)); 
SUBJID2 ="ORI"; 
WEEK12 = BASE; 
OUTPUT; 
IF WEEK12A =. THEN DO  ;  
SUBJID2 ="IMP"; 
WEEK12 = .; 
OUTPUT; 
END; 
RUN; 
 
PROC MI DATA= DATA21a OUT=IMOUT1a MINIMUM=0 SEED=68756 NIMPUTE=100; 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN; 
FCS; /* fully conditional specification method*/ 
TRANSFORM LOG(WEEK12); 
RUN; 
 
DATA IMOUT1a; 
SET IMOUT1a; 
IF WEEK12A^=. THEN WEEK12=WEEK12A; /*set Week12 back to use the observed Week 12 
values for those not missing Week 12*/ 
RUN; 
 
b. For the placebo arm, missing Week 12 TG values will be imputed assuming 
missing at random, including patient demographics, disease status, and 
baseline and post-baseline efficacy data from the placebo arm. 
PROC MI DATA=DATA22 OUT=IMOUT22 MINIMUM=0 SEED=63546 NIMPUTE=100; 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK 4 WEEK8 
WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN; 
FCS;/* fully conditional specification method*/ 
TRANSFORM LOG(BASE) LOG(WEEK4) LOG(WEEK8) LOG(WEEK12); 
RUN; 
 
III. 
For patients who adhere to therapy (complete the 12 week efficacy treatment) and 
who do not have Week 12 fasting TG measurements, the missing data imputation 
method will use patients in the same treatment arm who adhere to therapy and have 
Week 12 fasting TG measurements. i.e. Missing at random assumption will be used. 
DATA DATA21c; 
SET ALLTG; 
IF (WEEK12=. & TRTCOMPL=’Y’)  |  (WEEK12^=. & TRTCOMPL=’Y’); 
RUN; 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 26 of 27 
 
 
PROC MI DATA= DATA21c OUT=IMOUT1c MINIMUM=0 SEED=745369 NIMPUTE=100; 
BY TRT; 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK4 WEEK8 
WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN; 
FCS; /* fully conditional specification method*/ 
TRANSFORM LOG(BASE) LOG(WEEK4) LOG(WEEK8) LOG(WEEK12); 
RUN; 
 
If there are no patients who adhere to therapy and miss Week 12 fasting TG 
measurement in DATA21c, 100 datasets will be created from DATA21c in order to 
merge with the 100 imputed datasets from the others. 
After imputation step, percentage change in TG will be calculated and each of the 100 
multiply imputed datasets for FAS patients will be analyzed by either PROC NPAR1WAY 
procedure or PROC MIXED procedure. The estimate and standard error for treatment effect 
from the analysis will be analyzed by PROC MIANALYZE to obtain the overall estimate 
of treatment difference, as well as the confidence interval and p-value. 
For example, the primary analysis method will output the Hodges-Lehmann estimation and 
asymptotic standard error from PROC NPAR1WAY procedure. 
PROC MIANALYZE DATA=DIFF;  
MODELEFFECTS ESTIMATE;  
STDERR STDERR;  
 RUN;  
 
The SAP could be updated as a result of a blind review of the data and will be finalized 
before breaking the blind. Final imputed values will be saved in analysis database when the 
SAP is finalized as well as when the blind is subsequently broken. 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V1.0 
19 October 2016 
 
Page 27 of 27 
 
Appendix 2 Sensitivity Imputation Method: Probabilities of Missing Estimated by 
Logistic Regressions 
Below is a summary of steps/description of the imputation with probabilities of missing 
estimated by logistic regressions with the imputation forward for an early withdrew 
subject i: 
Step 1: To calculate the probabilities for missing data for Visit 5, a logit model is 
performed with treatment, baseline TG value, country, and baseline current statin 
therapy use (not on statin therapy versus currently receiving statin therapy) in the 
model. Percent change in TG at Visit 5 is calculated based on the formula below. 
PCHG5i = (1 – P5i) x (the median PCHG from the control group at Visit 5). 
TG5i = BTGi + (PCHG5i /100) x BTGi 
Step 2: Imputed Percent change in TG at Visit 5 is put into the data for those with missing 
Visit 5 to calculate the probabilities for missing data for Visit 6 using the same 
logit model with treatment, baseline value, country, and baseline current statin 
therapy use and Visit 5 TG as covariates. 
PCHG6i = (1 – P6i) x PCHG5i. 
TG6i = BTGi + (PCHG6i /100) x BTGi; 
Step 3: Imputed Percent change in TG at Visit 6 is put into the data for those with missing 
Visit 7 to calculate the probabilities for missing data for Visit 7 using the same 
logit model with treatment, baseline value, country, and baseline current statin 
therapy use and Visit 6 TG as covariates. 
PCHG7i = (1 – P7i) x PCHG6i. 
TG7i = BTGi + (PCHG7i /100) x BTGi; 
Where for subject i, 
PCHG5i PCHG6i PCHG7i = percent change in TG at Visit 5(Week 4), Visit 
6(Week 8), Visit 7(Week 12) respectively, 
TG5i TG6i TG7i = TG at Visit 5(Week 4), Visit 6(Week 8), Visit 7(Week 12) 
respectively, 
BTGi =baseline TG 
P5i P6i P7i = probability of missing estimated from the logistic regression 
respectively, 
 
Firth’s penalized likelihood approach will be used to address any issues of separability. 
 

SAP_004.pdf: 
Statistical Analysis Plan Addendum 
Drug Substance 
K-877 
Protocol Number K-877-301 
Edition Number 
1.0 
Date 
21 October 2019 
A Phase 3, Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 
12-Week Study With a 40-Week, Active-Controlled, Double-Blind 
Extension to Evaluate the Efficacy and Safety of K-877 in Adult Patients 
With Fasting Triglyceride Levels >=500 mg/dL and <2000 mg/dL and 
Normal Renal Function 
Investigational Product: K-877 
Protocol Number: K-877-301 
Original Protocol Version 1.0: 13 September 2016 
Protocol Version 2.0:  18 August 2017 
 
                                                       SAP Version: 1.0 
SAP Date: 19 October 2016 
 
SAP Version: 2.0 
SAP Date: 21 June 2019 
 
SAP Addendum Version: 1.0 
SAP Addendum Date: 21 October 2019 
 
 




Statistical Analysis Plan Addendum 
Protocol Number: K-877-301 
Edition Number: 1.0  
Date: 21 October 2019 
 
3 
 
TABLE OF CONTENTS 
TITLE PAGE ......................................................................................................................... 1 
SIGNATURE PAGE ............................................................................................................. 2 
1. 
INTRODUCTION ..................................................................................................... 4 
2. 
DATA ANALYSIS CHANGES ............................................................................... 4 
2.1 
Imputation error due to lab parameters with value of 0............................................. 4 
2.2 
Secondary efficacy endpoints for lab parameters with a baseline value of 0 ............ 5 
 
 
3. 
DATA ANLAYSIS CLARIFICATION .................................................................... 6 
4. 
PRIMARY IMPUTATION METHOD ..................................................................... 6 
5. 
REFERENCES .......................................................................................................... 7 
 
 
 


Statistical Analysis Plan Addendum 
Protocol Number: K-877-301 
Edition Number: 1.0  
Date: 21 October 2019 
 
4 
 
1. 
INTRODUCTION 
The statistical analysis plan, version 2.0, for study with protocol number K-877-301 was finalized 
on June 21, 2019.  The study was finished with the database locked on August 23, 2019. The 
treatment code was unblinded on August 26, 2019. Due to issue in coding process for prior and 
concomitant medications coding and medical history coding in electronic data capture system, the 
database was corrected and locked again on September 11, 2019. 
The study results were reviewed. After the systemic review, the decision was made to perform the 
post-lock data analysis change or clarification as described in this document. 
Summary of changes: 
 The primary imputation method in the SAP did not take into account the scenario of 
imputing missing data when observed data had a value of 0. We have specified all 
scenarios for the primary imputation method.  
 The secondary efficacy endpoint, where data value of 0 is observed at baseline, will 
additionally include analysis for ‘change from baseline to week 12’ given percent change 
not being calculable for such lab parameters. However, for these lab parameters, analysis 
of percent change from baseline to week 12 will be performed using data where percent 
change from baseline is available. 
  
 
 
 
 
2. 
DATA ANALYSIS CHANGES 
2.1 
Imputation error due to lab parameters with value of 0 
After database lock and unblinding, it was observed that some lab parameters had a value of 0 at 
baseline or at week 12 or both. With such values, the primary imputation, which includes log-
transformation of lab values at baseline and week 12, returned an error. The following parameters 
from the K-877-301 study had a data value of 0 for lab parameters that resulted in an error for log 
transformation: 
Lab Category Parameter (Unit) 
Number of subjects with value 0 
 
 
Baseline 
Week 12 
Lipoprotein 
Fraction 
HDL Particles-Large (umol/L) 
43 
23 
Lipoprotein 
Fraction 
HDL Particles-Medium (umol/L) 
42 
54 


Statistical Analysis Plan Addendum 
Protocol Number: K-877-301 
Edition Number: 1.0  
Date: 21 October 2019 
 
5 
 
Lipoprotein 
Fraction 
HDL Particles-Small (umol/L) 
0 
1 
Lipoprotein 
Fraction 
IDL Particles (nmol/L) 
18 
18 
Lipoprotein 
Fraction 
LDL Particles (total) (nmol/L) 
1 
1 
Lipoprotein 
Fraction 
LDL Particles-Large (nmol/L) 
339 
202 
Lipoprotein 
Fraction 
LDL Particles-Small (nmol/L) 
3 
3 
Lipoprotein 
Fraction 
VLDL & Chylomicron Particles-Medium 
(nmol/L) 
20 
13 
Lipoprotein 
Fraction 
VLDL & Chylomicron Particles-Small 
(nmol/L) 
86 
65 
 
It was decided post database lock that an extension to the existing pattern mixture model multiple 
imputation method with fully conditional specification methods will be applied to the above 
parameters to account for the observed data values of 0. This method is called the predictive mean 
matching method which uses a simulated regression model to impute values randomly from a set 
of observed values whose predicted values are close to the predicted value of the missing value. 
2.2 
Secondary efficacy endpoints for lab parameters with a baseline value of 0 
The protocol defined one of the secondary endpoints as percent change from baseline to week 12 
in lipoprotein fraction (nuclear magnetic resonance). Since a few lipoprotein parameters have one 
or multiple records with a baseline value of 0, the percent change cannot be determined for such 
records. In such cases, the secondary endpoints for the lipoprotein parameters will be evaluated 
additionally for change from baseline to week 12. Analysis for percent change from baseline will 
be performed for patients who do not have a value of 0 at baseline. 
 
 
 
 
 
 


Statistical Analysis Plan Addendum 
Protocol Number: K-877-301 
Edition Number: 1.0  
Date: 21 October 2019 
 
6 
 
3. 
DATA ANLAYSIS CLARIFICATION 
The changes in analysis described in sections 2.1 and 2.2 of this document were applied only to 
the lab parameters where lab value of 0 was observed at baseline or post-baseline. This change as 
well as the change in section 2.3 of this document will not impact the results for the primary 
endpoint as well as secondary endpoints that were tested in a hierarchical step-down manner. 
4. 
PRIMARY IMPUTATION METHOD 
For the main analysis of the primary efficacy variable, missing Week 12 endpoint will be imputed 
using the pattern mixture model using the fully conditional specification method.  This imputation 
method will include factors such as patient demographics, disease status, and baseline values. The 
imputation method was specified in the SAP Appendix 1, pages 25, 26 and 27. 
It was found after database lock that there was an error imputing data with a value of 0 as the 
pattern mixture model using the fully conditional specification method utilized log transformation 
of the observed values. The parameters mentioned in section 2.1 of this document resulted in 
imputation error because of log transformation of 0 values. After reviewing the methodology in 
SAP, it was decided that this scenario would be handled using the predictive mean matching 
method as an extension to the pattern mixture model of imputation. 
Below is a summary of description of the imputation using the predictive mean matching method: 
In addition to following the same description of steps in Appendix 1 (in Pages 25-27) of the SAP 
version 2.0, any lab parameter with a 0 value at baseline or week 12 will utilize the following SAS 
code to include the predictive mean matching method to impute missing data. 
Step II a. 
PROC MI DATA= DATA21a OUT=IMOUT1a  
           MINIMUM=0 SEED=68756 NIMPUTE=100 ROUND=1E-10;  
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN WEEK12; CLASS 
SEX ETHNICITY COUNTRY STATIN;  
FCS REGPMM; /* fully conditional specification method with predictive mean matching 
method.*/  
RUN; 
Step II b. 
PROC MI DATA=DATA22 OUT=IMOUT22  
                 MINIMUM=0 SEED=63546 NIMPUTE=100 ROUND=1E-10;   
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK 4   
                WEEK8 WEEK12;  
CLASS SEX ETHNICITY COUNTRY STATIN;  
FCS REGPMM; /*fully conditional specification method with predictive mean matching 
method/* 
RUN; 


Statistical Analysis Plan Addendum 
Protocol Number: K-877-301 
Edition Number: 1.0  
Date: 21 October 2019 
 
7 
 
Step III. 
PROC MI DATA= DATA21c OUT=IMOUT1c  
                  MINIMUM=0 SEED=745369 NIMPUTE=100 ROUND=1E-10;    
BY TRT;  
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK4  
                   WEEK8 WEEK12;  
CLASS SEX ETHNICITY COUNTRY STATIN;  
FCS REGPMM; /*fully conditional specification method with predictive mean matching 
method*/  
RUN; 
5. 
REFERENCES 
O'Kelly M, and Ratitch B (2014), Clinical Trials with Missing Data: A Guide for Practitioners, 
Willey, U.K. 
Dmitrienko A, and Koch G.G. (2017), Analysis of Clinical Trials Using SAS: A Practical Guide, Second 
Edition, SAS Institute 

SAP_003.pdf: 
 
CONFIDENTIAL 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 3, Multi-Center, Placebo-Controlled, Randomized, 
Double-Blind, 12-Week Study With a 40-Week, Active-Controlled, 
Double-Blind Extension to Evaluate the Efficacy and Safety of K-877 in 
Adult Patients With Fasting Triglyceride Levels ≥500 mg/dL and 
<2000 mg/dL and Normal Renal Function 
 
 
 
Drug Name:  
K-877 
Study Number: 
K-877-301 
EudraCT Number: 
2015-003511-37 
US IND Number 
109388 
Sponsor: 
Kowa Research Institute, Inc. 
Address: 
430 Davis Drive, Suite 200 
Morrisville, NC 27560 
United States of America 
 
 
Protocol Version/Date: 
V1.0, 13 September 2016 
 
 
SAP Version: 
V1.0 
SAP Date: 
19 October 2016 
 
SAP Amendment Version: V2.0 
SAP Date: 
21 June 2019 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019  
 
Page 2 of 29 
 
VERSION 
DATE 
DESCRIPTION OF CHANGES 
1.0 
19 OCTOBER 2016 
Final document 
2.0 
21 JUNE 2019 
Updates made to existing primary analysis 
imputation method when sufficient data is 
not available for imputation in Section 
(3.7.3 and Section 7: Appendix A1, Part II 
a and b, and additional method added after 
Part III) of the SAP. Updates made to 
section 3.7.4 of SAP to include additional 
method for secondary endpoint analysis. 
One column added in table under section 
3.8.2, subsection 3.8.2.1. 
  
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 3 of 29 
 
 
  
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 4 of 29 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................... 6 
1. 
INTRODUCTION .......................................................................................... 7 
2. 
STUDY OBJECTIVES AND STUDY DESIGN ........................................... 7 
2.1 
Study Objectives ............................................................................................. 7 
2.1.1 
Primary Objective .................................................................................... 7 
2.1.2 
Secondary Objectives ............................................................................... 7 
2.1.3 
Exploratory Objective .............................................................................. 7 
2.2 
Study Design ................................................................................................... 7 
2.3 
Study Endpoints ............................................................................................ 12 
2.3.1 
Primary Efficacy Endpoint .................................................................... 12 
2.3.2 
Secondary Efficacy Endpoints ............................................................... 12 
2.3.3 
Exploratory Efficacy Endpoints ............................................................. 13 
2.3.4 
Safety Endpoints .................................................................................... 13 
2.3.5 
Pharmacokinetic/Pharmacodynamic Endpoints ..................................... 13 
3. 
STATISTICAL METHODOLOGY ............................................................. 13 
3.1 
Baseline, Endpoint, and Other Statistical Considerations ............................ 13 
3.2 
Analysis Sets ................................................................................................. 14 
3.2.1 
Full Analysis Set .................................................................................... 14 
3.2.2 
Per-Protocol Set ..................................................................................... 14 
3.2.3 
Safety Analysis Set ................................................................................ 14 
3.2.4 
Pharmacokinetic Analysis Set ................................................................ 14 
3.3 
Patient Disposition ........................................................................................ 14 
3.4 
Demographics and Baseline Characteristics ................................................. 15 
3.5 
Prior/Concomitant Medications .................................................................... 15 
3.6 
Study medication Exposure and Compliance ............................................... 15 
3.7 
Analysis of Efficacy ..................................................................................... 16 
3.7.1 
Descriptive Statistics .............................................................................. 16 
3.7.2 
Hypothesis Testing Procedure ............................................................... 16 
3.7.3 
Primary Endpoint Analyses ................................................................... 17 
3.7.4 
Secondary Endpoint Analyses ............................................................... 19 
3.8 
Analysis of Safety ......................................................................................... 20 
3.8.1 
Adverse Events ...................................................................................... 20 
3.8.2 
Clinical Laboratory Assessments ........................................................... 21 
3.8.3 
12-Lead Electrocardiogram ................................................................... 22 
3.8.4 
Physical Examination ............................................................................. 22 
3.8.5 
Vital Signs, Weight, Height, BMI ......................................................... 22 
3.8.6 
Other Safety Parameters ........................................................................ 22 
3.9 
Analysis of Pharmacokinetic/Pharmacodynamic Data ................................. 22 
3.10 
Interim Analysis ........................................................................................... 22 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 5 of 29 
 
4. 
SAMPLE SIZE DETERMINATION ........................................................... 23 
5. 
PROGRAMMING SPECIFICATIONS ....................................................... 23 
6. 
REFERENCES ............................................................................................. 24 
7. 
APPENDIX .................................................................................................. 25 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 6 of 29 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Apo  
Apolipoprotein 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Class 
CK 
Creatine kinase 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
FFA 
Free fatty acid 
FGF21 
Fibroblast growth factor 21 
 
 
γ-GTP 
Gamma-glutamyl transpeptidase 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HOMA-β 
Homeostatic model assessment for beta-cell function  
HOMA-IR 
Homeostatic model assessment for insulin resistance 
hsCRP 
High-sensitivity C-reactive protein 
IND 
Investigational New Drug 
IQR 
Inter-quartile range 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
MMRM 
Mixed-effect model repeat measurement 
NMR 
Nuclear magnetic resonance 
QUICKI 
Quantitative insulin sensitivity check index 
Q1 
25th percentile 
Q3 
75th percentile 
SAE 
Serious adverse event 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
 
 
ULN 
Upper limit of normal 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 7 of 29 
 
1. 
INTRODUCTION 
This document provides a description of the statistical methods and procedures to be 
implemented for the analyses of data from the study with protocol number K-877-301, 
version V1.0, 13 September 2016.  Any deviations from this Statistical Analysis Plan (SAP) 
will be documented in the final clinical study report. 
2. 
STUDY OBJECTIVES AND STUDY DESIGN  
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of the study is to demonstrate the efficacy of K-877 0.2 mg twice 
daily compared to placebo from baseline to Week 12 in lowering fasting TG levels in 
patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 
mmol/L). 
2.1.2 
Secondary Objectives 
The secondary objectives of the study are the following: 
 To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 52 in 
lowering fasting TG levels in patients with fasting TG levels ≥500 mg/dL 
(5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L);  
 To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 12 and 
Week 52 in altering lipid parameters in patients with fasting TG levels ≥500 mg/dL 
(5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L);  
 To evaluate the safety and tolerability of K-877 0.2 mg twice daily in patients with 
fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L); 
and 
 To determine the plasma concentrations of K-877 for the purpose of use in 
population pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) analysis. 
2.1.3 
Exploratory Objective 
 
 
  
2.2 
Study Design 
This is a Phase 3, multi-center, randomized, double-blind study to confirm the efficacy and 
safety of K-877 0.2 mg twice daily compared to matching placebo (in the 12-week 
Efficacy Period) and an active comparator, fenofibrate (in the 40-week Extension Period), 
in patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L) and normal renal function. 
Eligible patients will enter a 4- to 6-week lifestyle stabilization period (4-week stabilization 
for patients not requiring washout and 6-week washout and stabilization for patients on 
lipid-altering therapy other than statins, ezetimibe, or proprotein convertase subtilisin/kexin 
type 9 [PCSK9] inhibitors). The stabilization period will be followed by a 2-week TG 
qualifying period (Visits 2 [Week -2] and 3 [Week -1]), and patient eligibility will be 
assessed based on the mean TG value from these 2 visits. If the patient’s mean TG level 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 8 of 29 
 
during the TG qualifying period is 450 mg/dL (5.09 mmol/L) and <500 mg/dL 
(5.65 mmol/L), an additional TG measurement can be taken 1 week later at Visit 3.1. The 
mean of all 3 TG measurements will be used to determine eligibility for the study. After 
confirmation of qualifying fasting TG values, eligible patients will enter a 12-week, 
randomized, double-blind Efficacy Period. At Visit 4 (Day 1), patients will be randomly 
assigned in a 2:1 ratio to K-877 0.2 mg twice daily or identical matching placebo tablets 
twice daily. During the 12-week Efficacy Period, patients will return to the site at Visit 5 
(Week 4), Visit 6 (Week 8), and Visit 7 (Week 12) for efficacy and safety evaluations. 
Patients who successfully complete the 12-week Efficacy Period are eligible to continue in 
a 40-week, double-blind, active-controlled Extension Period after completing the Visit 7 
(Week 12) procedures. Patients randomized to receive K-877 0.2 mg twice daily in the 
12-week Efficacy Period will continue to receive K-877 0.2 mg twice daily, as well as 
placebo matching fenofibrate 145 mg once daily, in the 40-week Extension Period. Patients 
randomized to receive placebo matching K-877 0.2 mg twice daily in the 12-week 
Efficacy Period will receive fenofibrate 145 mg once daily and placebo matching K-877 
0.2 mg twice daily in the 40-week Extension Period.  
From Visit 7 (Week 12), patients not on statins, ezetimibe, or PCSK9 inhibitors may initiate 
therapy, and patients receiving statins,  ezetimibe, or PCSK9 inhibitors may alter their dose, 
as indicated by guidelines or local standard of care. 
After Visit 8 (Week 16), patients are to return to the site every 12 weeks until the last visit 
(Visit 11 [Week 52]). 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 9 of 29 
 
Table 1: 
Clinical Evaluation Schedule 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 
Lifestyle 
Stabilization/
Washout 
Period 
Triglyceride Qualifying 
Period [1] 
12-Week Efficacy Period 
40-Week Extension Period 
Time 
Week -8 or -6 
Week -2 
±3 days 
Week -1 
±3 days 
Day 1 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Week 28 
±7 days 
Week 40 
±7 days 
Week 52 
±7 days or ET 
Visit Number 
1 [2] 
2 
3 [1] 
4 
5 
6 
7 
8 
9 
10 
11 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, and family history, and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
Vital signs (heart rate, respiratory rate, and 
blood pressure) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height [3], weight, and waist 
circumference 
X 
 
 
X 
 
 
X 
 
 
 
X 
Register screening number with IRT 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug and blood alcohol screen [4] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase and lipase 
X 
 
 
X 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Insulin, glycated albumin, HOMA-IR, 
HOMA-β, and QUICKI 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Serum pregnancy test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for WOCBP 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry, hematology, coagulation, and 
urinalysis 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Plasma Population PK sampling [7] 
PK/PD sampling [8] 
TG, TC, HDL-C, non-HDL-C, LDL-C, 
and remnant cholesterol [9] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*footnotes on following page 
Error! Reference source not found.(Continued) 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 10 of 29 
 
Lifestyle 
Stabilization/
Washout 
Period 
Triglyceride Qualifying 
Period [1] 
12-Week Efficacy Period 
40-Week Extension Period 
Time 
Week -8 or -6 
Week -2 
±3 days 
Week -1 
±3 days 
Day 1 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Week 28 
±7 days 
Week 40 
±7 days 
Week 52 
±7 days or ET 
Visit Number 
1 [2] 
2 
3 [1] 
4 
5 
6 
7 
8 
9 
10 
11 
Apo A1, Apo A2, Apo B, Apo B48, 
Apo B100, Apo C2, Apo C3, and Apo E 
 
 
 
X 
X 
 
X 
 
X 
 
X 
FFAs 
 
 
 
X 
 
 
X 
 
X 
 
X 
Ion mobility analysis and lipoprotein 
fraction (NMR) 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Withdraw lipid-altering medication(s) 
other than statins, ezetimibe, or PCSK9 
inhibitors, if applicable 
X 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
X 
 
 
X 
 
 
 
X 
Physical examination 
X 
 
 
X 
 
 
X 
 
 
 
X 
Assess and record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLC counseling [12] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Dispense study drug (efficacy period) 
 
 
 
X 
X 
X 
 
 
 
 
 
Dispense study drug (extension period) 
 
 
 
 
 
 
X 
X 
X 
X 
 
Collect study drug and record 
accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
1. 
Triglyceride levels are based on the mean of the Visit 2 (Week -2) and Visit 3 (Week -1) values. In cases in which a patient’s mean TG level from Visit 2 (Week -2) and Visit 3 (Week -1) falls outside the required range for entry into the 
study but is 450 mg/dL (5.09 mmol/L) and <500 mg/dL (5.65 mmol/L), an additional TG measurement can be collected 1 week (±3 days) later (Visit 3.1). If Visit 3.1 is required, the TG qualifying period will be extended, and Visit 4 will 
occur 1 week (±3 days) after Visit 3.1. If a third sample is collected, entry into the 12-week Efficacy Period is based on the mean of the values from Visit 2 (Week -2), Visit 3 (Week -1), and Visit 3.1. 
2. 
Visit 1 for patients who require a washout is at Week -8. Visit 1 for patients who do not require a washout is at Week -6. 
3. 
Height is measured at Visit 1 (Week -8 or Week -6) only. 
 
 
 
 
 
 
*footnotes continued on following page 
 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 11 of 29 
 
Error! Reference source not found. (Continued) 
 
 
 
 
 
 
   
 
  
9. All lipid laboratory blood specimens must be obtained under fasting conditions (i.e., after the patient has fasted for at least 10 hours). 
 
 
12. TLC counseling can be provided by the Investigator or designee (see Section Error! Reference source not found.). 
AE = adverse event; Apo = apolipoprotein; ET = Early Termination; FFA = free fatty acid; 
 HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; HOMA-β = homeostasis model 
assessment for beta-cell function; HOMA-IR = homeostasis model assessment for insulin resistance; IRT = Interactive Response Technology; LDL-C = low-density lipoprotein cholesterol; NMR = nuclear magnetic resonance; PCSK9 = 
proprotein convertase subtilisin/kexin type 9; PD = pharmacodynamic; PK = pharmacokinetic; QUICKI = quantitative insulin sensitivity check index; 
 TC = total cholesterol; TG = triglycerides; TLC = therapeutic lifestyle 
changes; Tmax = time to maximum plasma concentration; 
 WOCBP = women of childbearing potential. 
 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 12 of 29 
 
2.3 
Study Endpoints 
2.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in fasting TG from baseline to 
Week 12. Baseline for TG will be defined as the mean of Visit 4 (Day 1) and the preceding 
TG qualifying visit (either Visit 3 [Week -1] or Visit 3.1, if required) measurements. 
2.3.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the 12-week Efficacy Period include the following: 
 
Percent change from baseline to Week 12 in remnant cholesterol (calculated as total 
cholesterol [TC] − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 
 
Percent change from baseline to Week 12 in TC, LDL-C, free fatty acids (FFAs), 
Apo A2, Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; 
 
Change from baseline to Week 12 in FGF21 and high-sensitivity C-reactive protein 
(hsCRP), and percent change from baseline to Week 12 in ion mobility analysis and 
lipoprotein fraction (nuclear magnetic resonance [NMR]); and  
 
Percent change from baseline to Week 12 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and 
Apo C3:Apo C2. 
The secondary efficacy endpoints for the 40-week Extension Period include the 
following: 
 
Percent change from baseline to Week 52 in fasting TG; 
 
Percent change from baseline to Week 52 in remnant cholesterol (calculated as 
TC − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 
 
Percent change from baseline to Week 52 in TC, LDL-C, FFAs, Apo A2, Apo B, 
Apo B48, Apo B100, Apo C2, Apo C3, and Apo E;  
 
Change from baseline to Week 52 in FGF21 and hsCRP, and percent change from 
baseline to Week 52 in ion mobility analysis and lipoprotein fraction (NMR); and  
 
Percent change from baseline to Week 52 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and 
Apo C3:Apo C2. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either 
Visit 3 [Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy 
and safety variables will be defined as Visit 4 (Day 1). If the measurement at this visit is 
missing, the last measurement prior to the first dose of randomized study drug will be 
used. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 13 of 29 
 
 
 
 
2.3.3 
Exploratory Efficacy Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.4 
Safety Endpoints 
Safety assessments include adverse events (AEs), clinical laboratory measurements 
(chemistry, hematology, coagulation profile, 
 and urinalysis), 12-lead 
electrocardiograms (ECGs), vital signs (heart rate, respiratory rate, and blood pressure), 
and physical examinations. 
2.3.5 
Pharmacokinetic/Pharmacodynamic Endpoints 
Pharmacokinetic concentrations collected during the 12-week Efficacy Period will be 
used for population PK analysis and PK/PD analysis. 
3. 
STATISTICAL METHODOLOGY 
3.1 
Baseline, Endpoint, and Other Statistical Considerations 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding lipid qualifying visit (either Visit 
3 [Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy and 
safety variables will be defined as Visit 4 (Day 1). If the measurement at this visit is missing, 
the last measurement prior to the first dose of randomized study drug will be used. 
 
 
  
Post-baseline lipid assessments will be assigned a visit number based on the date of 
assessment relative to the first dose of the double-blind study drug. Visit windows will be 
defined as the scheduled time from dosing date with a 7-day window (±7 days). Within a 
visit window, if a scheduled visit occurs, then the measurement from this scheduled visit 
will be used as the measurement for this visit window. If no scheduled visit occurs within 
a visit window, the last unscheduled measurement within the window will be used. If no 
visits occur within a visit window, the measurement of this visit will be treated as missing.  
Any lipid measurements that have resulted from a non-fasting sample will be considered 
invalid and will not be used in the derivation of an efficacy endpoint. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 14 of 29 
 
Descriptive statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum, 25th (Q1) percentile and 75th (Q3) percentile) will be used to summarize the 
continuous data. Discrete measures will be summarized using counts and percentages.  
3.2 
Analysis Sets 
3.2.1 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized patients who take at least 1 dose 
of double-blind study drug, and have a baseline TG measurement. The FAS is the primary 
analysis population. All efficacy analyses will be performed on the FAS.  
3.2.2 
Per-Protocol Set 
The Per-Protocol Set will include all FAS patients for the 12-week Efficacy Period who 
complete the 12-week placebo-controlled Efficacy Period without any major protocol 
deviations and have baseline and Week 12 endpoint fasting serum TG measurements. 
Major protocol deviations will be pre-specified prior to unblinding the study. The following 
criterion will be evaluated for major deviations prior to unblinding of the treatment 
allocation: 
 No eligibility criterion violations, 
 Did not discontinue study drug, 
 Study medication compliance within 80-120%, 
 Not taken any prohibited concomitant medication, 
 Not unblinded during the 12-week double-blind treatment period, and 
 No other substantial protocol violations. 
The Per-Protocol Set will be used to assess robustness of the primary analysis results during 
the 12-week Efficacy Period. 
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 
Pharmacokinetic Analysis Set 
The PK Analysis Set includes all patients from the Safety Analysis Set who have at least 
1 PK sample.  
3.3 
Patient Disposition 
The reason given for each screen failure will be summarized and listed. Patient disposition 
will be provided for all randomized patients. The number and percentage of patients in each 
of the following disposition categories will be presented: 
 Patients who are randomized, 
 Patients who start study drug, 
 Patients who complete the 12-week Efficacy Period  on study drug, 
 Patients who complete the 12-week Efficacy Period but stopped study drug during 
the 12-week Efficacy Period, 
 Patients who withdraw from the study during the 12-week Efficacy Period, 
 Patients who enter the 40-week Extension Period, 
 Patients who complete the 40-week Extension Period,  


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 15 of 29 
 
 Patients who withdraw from the study during the 40-week Extension Period. 
For randomized patients who withdraw from the study, the primary reason for the 
withdrawal will be listed and summarized. 
The number of patients included in each analysis set will be summarized. 
3.4 
Demographics and Baseline Characteristics 
Demographics (age, sex, race, and ethnicity), body weight, height, and BMI will be 
summarized by randomized treatment using descriptive statistics for the randomized 
patients and the Full Analysis Set. Age group (<65 years versus ≥65 years and 18-64 years, 
65-84 years, and ≥85 years) and current statin therapy use (not on statin therapy versus 
currently receiving statin therapy), ezetimibe use (yes/no), PCSK9 inhibitor use (yes/no), 
any lipid-altering medications use including statins, ezetimibe and/or PCSK9 inhibitor 
(yes/no) will also be summarized. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding lipid qualifying visit (either Visit 3 
[Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy and safety 
variables will be defined as Visit 4 (Day 1). If the measurement at this visit is missing, the 
last measurement prior to the first dose of randomized study drug will be used.  
 
 
 
Patient medical history will be summarized by randomized treatment using descriptive 
statistics for the randomized patients and the Full Analysis Sets   
3.5 
Prior/Concomitant Medications 
The use of any prior medication and concomitant or post-treatment medication will be listed 
for the Safety Analysis Set with an indication of whether the medication was prior or 
concomitant during the 12-week Efficacy Period, or concomitant during the 40-week 
Extension Period.   
The number and percentage of patients taking each concomitant medication will be 
summarized by preferred term within Anatomical Therapeutic Chemical (ATC) 
classification and by treatment group for the Safety Analysis Set. 
Statins, ezetimibe and PCSK9 inhibitors will be summarized by preferred term and dose at 
baseline for each treatment group for the Safety Analysis Set during the 12-week Efficacy 
Period and 40-week Extension Period. 
Lipid medications including statin that are added or changed during the 12-week Efficacy 
Period and 40-week Extension Period will be summarized for the Safety Analysis Set. 
3.6 
Study medication Exposure and Compliance 
Days of exposure to study medication will be summarized by treatment group for the Safety 
Analysis Set using descriptive statistics. Exposure in days is defined as the date of last dose 
of study drug minus the date of first dose of study drug plus 1. In addition, a contingency 
table will be provided to display the number and percentage of patients with exposure in 
the following categories: 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 16 of 29 
 
For K-877 
 1 to ≤4 weeks (1-28 days) 
 >4 to ≤8 weeks (29-56 days) 
 >8 to ≤12 weeks (57-84 days) 
 >12 to ≤16 weeks (85-112 days) 
 >16 to ≤28 weeks (113-196 days) 
 >28 to ≤40 weeks (197-280 days) 
 >40 to ≤52 weeks (281-364 days) 
 >52 weeks (≥365 days) 
For placebo 
 1 to ≤4 weeks (1-28 days) 
 >4 to ≤8 weeks (29-56 days) 
 >8 to ≤12 weeks (57-84 days) 
 >12 weeks (≥85 days) 
For fenofibrate 
 1 to ≤4 weeks (1-28 days) 
 >4 to ≤16 weeks (29-112 days) 
 >16 to ≤28 weeks (113-196 days) 
 >28 to ≤40 weeks (196-280 days) 
 >40 weeks (≥281 days) 
Percent compliance with the study medication at the 12-week Efficacy Period and during 
the 40-week Extension Period will be summarized by treatment group for the Safety 
Analysis Set using descriptive statistics.  Additionally the number and percentage of 
patients within each treatment group with overall compliance in the following categories: 
<80%, 80% to 120%, and >120%, will be provided. 
3.7 
Analysis of Efficacy 
3.7.1 
Descriptive Statistics 
All available original and derived lipid data will be listed for the randomized patients. 
Descriptive statistics of the baseline, change from baseline and percent change from 
baseline to each post-baseline value will be presented by treatment group for each measured 
lipid level and derived ratio for the Full Analysis Set and the Per-Protocol Set. 
Spaghetti plots of the individual patient data over time by treatment for lipid parameters 
will be provided for the Full Analysis Set. Boxplots of the percent change in lipid 
parameters from baseline to each post-baseline visit by treatment will also be produced.   
3.7.2 
Hypothesis Testing Procedure 
In order to control the family-wise Type I error at a 0.05 level, a fixed sequential testing 
procedure will be implemented. In a hierarchical step-down manner, the primary endpoint 
will be tested first, followed by secondary endpoints, tested in the following hierarchical 
manner: percent change from baseline to Week 12 (1) remnant cholesterol, (2) HDL-C, (3) 
Apo A1, and (4) non-HDL-C. Each test is planned to be performed at a 0.05 level. 
Inferential conclusions about these efficacy endpoints will require statistical significance 
of the previous one. 
For other efficacy endpoints, nominal p-values and 95% confidence intervals will be 
presented, but should not be considered as confirmatory. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 17 of 29 
 
3.7.3 
Primary Endpoint Analyses 
Several analyses (the primary analysis, and sensitivity analyses) will be carried out on the 
primary endpoint (the percent change in fasting TG from baseline to Week 12).  
3.7.3.1 Statistical Analyses of Primary Efficacy Endpoint 
Hodges-Lehmann Estimator with A Pattern Mixture Model Imputation  
Due to the known distribution of TG and percent change from TG, normality assumption 
is usually difficult to satisfy. Also from historical data, the variances of percent change 
from baseline in TG are significantly unequal between K-877 0.2 mg and placebo. A 
nonparametric approach will be used as the primary analysis for the primary efficacy 
endpoint. As an extension to the Wilcoxon rank-sum test, the Hodges-Lehmann method 
will be used to estimate the median difference and its corresponding 95% CI for percent 
changes between K-877 0.2 mg and placebo.  
The SAS code for Hodges-Lehmann estimates is listed below: 
 proc npar1way hl alpha=.05; 
      class TRT01PN; 
      var PCHG; 
   run; 
For this study, during the 12-week Efficacy Period, patients who discontinue study drug 
prematurely will remain in the study until Visit 7 (Week 12). If a patient who has 
discontinued study drug fails to attend any follow-up appointments, reasonable efforts 
(telephone calls to family members or friends, e-mail contacts, etc.) will be made in order 
to encourage the patient to complete the study visits. 
A pattern-mixture model will be used as the primary imputation method as part of the 
primary analysis for the Week 12 percent change from baseline in fasting TGs. This 
imputation model will include factors such as patient demographics, disease status, and 
baseline TGs, as well as adherence to therapy. The imputation model will impute missing 
Week 12 TG values as follows: 
 For patients who do not adhere to therapy and who do not have Week 12 
measurements, the missing data imputation method will use patients in the same 
treatment arm who do not adhere to therapy and have Week 12 measurements; and 
 If there are no or very few patients in the same treatment arm who do not adhere to 
therapy and have Week 12 measurements, missing Week 12 TG values will be 
imputed as follows: 
o For the K-877 arm, the treatment effect is considered washed out and 
baseline TG values of all K-877 patients will be used to impute the Week 
12 TG values; and 
o For the placebo arm, missing Week 12 TG values will be imputed assuming 
missing at random, including patient demographics, disease status, and 
baseline and post-baseline efficacy data from the placebo arm including 
patients who completed the efficacy period and have a valid Week 12 TG 
value.  


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 18 of 29 
 
After the multiple imputation step, each imputed dataset will be analyzed by nonparametric 
Hodges-Lehmann method. Hodges-Lehmann estimator and standard error will be 
combined to produce treatment difference estimate and 95% confidence interval and 
p-value. 
Details of the primary imputation method is described in Appendix 1. 
The multiple imputation procedure in the pattern mixture model will be conducted by two 
parts: PROC MI and PROC MIANALYZE. The first procedure will generate 100 multiple 
samples and then perform the Hodges-Lehmann analysis for each sample. The SAS 
procedure (PROC NPAR1WAY) specified above will generate two statistics in the output: 
• 
Hodges-Lehmann Estimation 
• 
Asymptotic Standard Error 
These two statistics can be read into PROC MIANALYZE to get the overall estimate of 
location difference (treatment difference), as well as the confidence interval and p-value.  
The primary efficacy analysis will be performed on the FAS population. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 19 of 29 
 
 
 
 
 
 
 
 
 
 
 
  
3.7.4 
Secondary Endpoint Analyses 
Secondary efficacy endpoints included in the hierarchical step-down testing procedure 
include percent change from baseline to Week 12 in a fixed sequence of (1) remnant 
cholesterol, (2) HDL-C, (3) Apo A1, and (4) non-HDL-C. These secondary efficacy 
endpoints will be analyzed using the same statistical method used for the primary analysis 
which is Hodges-Lehmann Estimation including the same multiple imputation procedure 
for the FAS population. The endpoints will be tested at a level of 0.05 in order if the 
previous one is statistically significant. Additionally, the endpoints will be analyzed using 
the ANCOVA model stated in the next paragraph as supplementary analyses. 
The other secondary and exploratory efficacy endpoints during the 12-week Efficacy 
Period will be analyzed using an ANCOVA model with the same imputation method used 
for the primary analysis. The ANCOVA model will include country, current statin therapy 
use (not on statin therapy versus currently receiving statin therapy), and treatment as 
factors; baseline value as a covariate. Estimates for treatment difference, p-values and 95% 
confidence intervals will be provided. If normality assumption is not met, 
Hodges-Lehmann estimator with the same imputation method used for the primary analysis 
will be used.  
The secondary efficacy endpoint of percent change from baseline to Week 52 in fasting TG 
will be summarized descriptively by treatment on the FAS. 
 
 
 Other efficacy endpoints during the Extension Period will be summarized 
descriptively in the same manner. No hypothesis testing will be performed for the percent 
change or change from baseline to Week 52 endpoints. 95% confidence interval will be 
presented for percent change or change from baseline within each treatment group. 
 
 
 
 
 
 
 
 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 20 of 29 
 
3.8 
Analysis of Safety 
The safety data will be presented for the Safety Analysis Set for the 12-week Efficacy 
Period, 40-week Extension Period, and overall period. 
3.8.1 
Adverse Events 
A Treatment-Emergent Adverse Event (TEAE) is defined as any AE that occurred for the 
first time after the first dose of double-blind study drug or existed prior to the first dose and 
worsened during the post dosing period. AE worsening applies to severity, or relationship 
to study drug.  
A summary overview of TEAEs will be provided, which presents the number and 
percentage of patients in each treatment group from the Safety Analysis Set for the 12-week 
Efficacy Period and the 40-week Extension Period and overall period satisfying each of the 
following categories: 
 Any TEAEs, 
 Maximum severity of TEAEs, 
 Study drug-related TEAEs, 
 Maximum severity of study drug-related TEAEs, 
 All TE-SAEs, 
 All study drug-related TE-SAEs, 
 TEAEs leading to death, 
 TEAEs leading to interruption/study drug discontinuation, and 
 Study drug-related TEAEs leading to interruption/study drug discontinuation. 
The number and percentage of patients with TEAEs will be summarized by their MedDRA 
preferred term within system organ class and by treatment.  AEs will be counted by number 
of events as well as the number of patients. For event count summaries, multiple AE events 
with the same MedDRA coded terms (preferred term and system organ class) and onset 
date and time from the same patient will only be counted once. For patient count 
summaries, multiple AE events with the same MedDRA coded terms (preferred term and 
system organ class) from the same patient will only be counted once. Whether the AE 
belongs to the 12-week Efficacy Period and the 40-week Extension Period will be 
determined by the AE onset date. 
The number and percentage of patients with TEAEs will be summarized by reported 
maximum severity within each MedDRA preferred term within system organ class and by 
treatment.   
The number and percentage of patients with any drug-related TEAEs, drug-related TE-
SAEs, and TEAEs and TE-SAEs that lead to study drug discontinuation will be 
summarized by preferred term within system organ class and by treatment. In these 
summaries, any patients reporting multiple episodes of the same TEAE (i.e., same preferred 
term and system organ class), will be counted once. 
All SAEs will be listed with an indication of whether the SAE was treatment emergent or 
started prior to treatment. 
All TEAEs that are reported as having led to a withdrawal of study drug will be listed. 
The number of events and number of patients with TEAEs by each 12 weeks of treatment 
(0-12, 12-24, 24-36, 36-48, 48-52 and >52 weeks) will also be summarized for each 
MedDRA preferred term, system organ class, and treatment. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 21 of 29 
 
3.8.2 
Clinical Laboratory Assessments 
3.8.2.1 Chemistry and Hematology 
Descriptive statistics of each chemistry and hematology parameter will be presented for 
baseline, ‘Time point’, and Change from Baseline to each ‘Time point’; where ‘Time point’ 
is each post-baseline assessment. These will be presented by treatment group for each 
parameter using the Safety Analysis Set.   
Counts and percentages of patients with any post-baseline observation that is below the 
lower limit of normal (<LLN) or above the upper limit of normal (>ULN) will be 
summarized for each chemistry and hematology parameter by treatment group and overall. 
Post-baseline changes of specified lab tests (ALT, AST, CK, serum creatinine, total 
bilirubin, alkaline phosphatase) abnormalities will be summarized by presenting the 
number and percentage of patients in each treatment group whose worst post-baseline value 
satisfies each of the following criteria in the table below and shift tables will be produced 
during the 12-week Efficacy Period and during the 40-week Extension Period and overall 
period. 
Parameter 
Categories 
ALT  
<Normal 
Normal  
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN  
>5xULN to 
≤10x ULN 
>10xULN 
to 
≤20x 
ULN 
> 20x ULN 
AST 
<Normal 
Normal  
>1xULN to 
≤3xULN 
>3xULN to 
≤5xULN  
>5xULN to 
≤10x ULN 
>10xULN 
to 
≤20x 
ULN 
> 20x ULN 
CK 
 
<Normal 
Normal  
>1xULN to 
≤5xULN 
 
>5xULN to 
≤10xULN  
>10xULN 
 
 
Serum 
Creatinine 
<Normal 
Normal 
>1xULN to 
≤1.5xULN 
 
>1.5xULN 
to ≤2xULN  
>2xULN 
 
 
Serum 
Creatinine 
≥2xbaseline 
 
 
 
 
 
 
ALP 
<Normal 
Normal 
>1xULN to 
≤1.5xULN 
>1.5xULN 
 
 
 
Total 
Bilirubin  
<Normal 
Normal  
>1xULN to 
≤1.5xULN  
>1.5xULN 
to ≤2xULN 
>2xULN 
 
 
Total 
Bilirubin 
accompany 
by ALT or 
AST>3xUL
N 
<Normal 
Normal  
>1xULN to 
≤1.5xULN  
>1.5xULN 
to ≤2xULN 
>2xULN 
 
 
eGFR 
 ≥90 
mL/min/1.7
3m2 
≥60 to <90 
mL/min/1.
73m2 
≥30 to <60 
mL/min/1.7
3m2 
<30 
mL/min/1.7
3m2 
 
 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 22 of 29 
 
Spaghetti plots of the individual patient data over time and boxplots of the values at baseline 
and each post-baseline visit will be presented by treatment for ALT, AST, CK, serum 
creatinine, total bilirubin, and alkaline phosphatase. Normal reference ranges will be 
plotted on these plots.   
The number and percentage of patients who meet ALT or AST >3xULN 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 these patients’ ALT, AST, ALP and total bilirubin 
data 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 left lower quadrant and Hy’s Law case candidates are in the upper 
right quadrant (ALT>3×ULN and total bilirubin>2×ULN). Subjects with Gilbert’s 
syndrome or cholestasis are typically found in the upper left quadrant, and subjects 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. 
3.8.3 
12-Lead Electrocardiogram 
ECG overall interpretation findings will be summarized by randomized treatment using 
descriptive statistics for the Safety Analysis Set. 
3.8.4 
Physical Examination 
The number and percentage of patients with physical examination findings will be 
presented for the Safety Analysis Set. 
3.8.5 
Vital Signs, Weight, Height, BMI 
Vital signs parameters will be summarized using descriptive statistics for the Safety 
Analysis Set. The change from baseline will also be presented. 
3.8.6 
Other Safety Parameters 
Other safety data will be listed. 
3.9 
Analysis of Pharmacokinetic/Pharmacodynamic Data 
Population PK and PK/PD data will be analyzed and reported separately. 
 
 
 
 
 
 
 
 
3.10 
Interim Analysis 
No interim analysis was planned for this study. 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 23 of 29 
 
4. 
SAMPLE SIZE DETERMINATION 
Approximately 630 patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L) will be randomized in a 2:1 ratio into one of the following 
treatment groups: K-877 0.2 mg twice daily or identical matching placebo twice daily. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
PROGRAMMING SPECIFICATIONS 
Statistical analyses will be performed using SAS® (Cary, NC) version 9.3 or above. All 
available data will be presented in subject data listings, which will be sorted by site number, 
unique subject identifier and where appropriate, visit number and visit/assessment date. 
The programming specification, including the mock-up validity listings, analysis tables, 
figures, and data listings, as well as the derived database specification, will be prepared in 
stand-alone documents. The programming specification document will be finalized prior to 
the database lock and unblinding the treatment code. 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 24 of 29 
 
6. 
REFERENCES 
Glynn R., Laird N., Rubin DB (1986). Selection Modeling Versus Mixture Modeling with 
Nonignorable Nonresponse. Drawing Inferences from Self-Selected Samples. pp 115-142. 
 
Hogan J. W., Roy J., and Korkontzelou C.. Handling Drop-out in Longitudinal Studies. 
Statistical Medicine, 23:1455–1497. 2004;  
 
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 
 
Little, R., Yau, L. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. 
Biometrics, 1996, vol. 52, 1324-1333. 
 
Ratitch B.; and O’Kelly M.; Implementation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedures. PharmaSUG2011 - Paper SP04, 2011 
 
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 
 
Rubin, D.B. Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & 
Sons, Inc. 1987 
 
Tangen, C.M. and Koch, G.G.. Nonparametric Analysis of Covariance for Hypothesis 
Testing with Logrank and Wilcoxon scores and Survival-rate estimation in a Randomized 
Clinical Trial. Journal of Biopharmaceutical. Statistics, 9:2, 307-338, 1999. 
 
Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using Controlled Clinical 
Trials to Learn More About Drug-Induced Liver Injury. Hepatology. 2008, 48:1680-1689.  
 
Woolson, R.F., and Lachenbruch, P.A.. Rank Analysis of Covariance with Right-censored 
Data. Biometrics, 39:727-733, 1983 
 
Yang, Y.. Sensitivity Analysis in Multiple Imputation for Missing Data. SAS Global Forum 
2014-SAS270, 2014.  
.


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 25 of 29 
 
7. 
APPENDIX  
Appendix 1 Primary Analysis Imputation Method for Missing Week 12 Efficacy Data 
– A Pattern Mixture Model 
Pattern mixture model was first introduced by Glynn et al (1986) and Little (1993). Later 
Little and Yau (1993) suggested control based pattern mixture models, which assume that 
after discontinuation, subjects on the experimental treatment who withdraw will tend to 
have efficacy close to subjects on the control treatment. The imputation model for this study 
will impute missing Week 12 fasting TG measurements as follows: 
I. 
For patients who do not adhere to therapy and who do not have Week 12 fasting TG 
measurements, the missing data imputation method will use patients in the same 
treatment arm who do not adhere to therapy and have Week 12 fasting TG 
measurements. 
Patients without Week 12 fasting TG measurements and patients with Week 12 
fasting TG measurements but discontinue treatment prior to Week 12 will be 
selected.  
DATA DATAIN1; 
SET ALLTG;  
IF TRTCOMPL=’N’ THEN OUTPUT DATAIN1; /*output patients who did not complete 12-week 
treatment and have Week-12 TG and those missing Week 12*/ 
RUN;  
 
Missing Week 12 TG data will be imputed using PROC MI procedure with a 
multivariate imputation by fully conditional specification methods to create 100 
datasets. In the imputation model, patient demographics (age, sex, ethnicity, 
country, and baseline BMI), current statin therapy use (not on statin therapy versus 
currently receiving statin therapy), disease status (baseline systolic and diastolic 
blood pressures, baseline eGFR), and baseline TG. The FCS statement will be used. 
This statements calls a multivariate imputation by fully conditional specification 
methods. 
 
PROC MI DATA=DATAIN1 OUT=IMOUT1 MINIMUM=0 SEED=98547 NIMPUTE=100; 
BY TRT; 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN; 
FCS; /* fully conditional specification method*/ 
TRANSFORM LOG(BASE) LOG(WEEK12); 
RUN; 
 
 
II. 
If there are no or very few patients in the same treatment arm who do not adhere to 
therapy and have Week 12 TG measurements, missing Week 12 TG measurements 
will be imputed as follows: 
a. For the K-877 arm, the treatment effect is considered washed out and 
baseline TG measurements of all K-877 patients will be used to impute the 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 26 of 29 
 
Week 12 TG measurements. Missing Week 12 TG values will be imputed 
by using the method which was proposed by Ratitch et al (2013). 
DATA DATA21; 
SET ALLTG; 
IF TRT=’K-877’;  /*Select patients from the K-877 arm*/ 
              RUN;  
 
DATA DATA21a; 
LENGTH SUBJID2 $8 ; 
SET DATA21(RENAME=(WEEK12=WEEK12A)); 
SUBJID2 ="ORI"; 
WEEK12 = BASE; 
OUTPUT; 
IF WEEK12A =. THEN DO  ;  
SUBJID2 ="IMP"; 
WEEK12 = .; 
IF TRTCOMPFL= ‘Y’ and SUBJID2 = ‘IMP’ then delete; /*These will be imputed in step III*/ 
OUTPUT; 
END; 
RUN; 
 
PROC MI DATA= DATA21a OUT=IMOUT1a MINIMUM=0 SEED=68756 NIMPUTE=100; 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN TRTCOMPFL 
WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN TRTCOMPFL; 
FCS; /* fully conditional specification method*/ 
TRANSFORM LOG(WEEK12); 
RUN; 
 
DATA IMOUT1a; 
SET IMOUT1a; 
IF WEEK12A^=. THEN WEEK12=WEEK12A; /*set Week12 back to use the observed Week 12 
values for those not missing Week 12*/ 
IF TRTCOMPFL = “N” 
IF SUBJID2= “IMP” or (SUBJID2= “ORI” and WEEK12A^=.); /*keep imputed records of only 
for K-877 subjects who did not complete the treatment period*/ 
RUN; 
 
b. For the placebo arm, missing Week 12 TG values will be imputed assuming 
missing at random, including patient demographics, disease status, and 
baseline and post-baseline efficacy data from the placebo arm including 
patients who completed the efficacy period and have a valid Week 12 TG 
value. 
           DATA DATA22; 
             SET ALLTG; 
             IF TRT=”PLACEBO”; /*select patients from the Placebo arm*/ 
             IF TRTCOMPL=’N’ OR (TRTCOMPL=’Y’ AND WEEK12 ^= .); /*Include Placebo patients who  
                                                 did not adhere to therapy as well as patients who adhered to therapy and have 
                                                 a non-missing Week 12 TG value */ 
             RUN; 
 
PROC MI DATA=DATA22 OUT=IMOUT22 MINIMUM=0 SEED=63546 NIMPUTE=100; 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 27 of 29 
 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK 4 WEEK8 
WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN; 
FCS;/* fully conditional specification method*/ 
TRANSFORM LOG(BASE) LOG(WEEK4) LOG(WEEK8) LOG(WEEK12); 
RUN; 
 
III. 
For patients who adhere to therapy (complete the 12 week efficacy treatment) and 
who do not have Week 12 fasting TG measurements, the missing data imputation 
method will use patients in the same treatment arm who adhere to therapy and have 
Week 12 fasting TG measurements. i.e. Missing at random assumption will be used. 
DATA DATA21c; 
SET ALLTG; 
IF (WEEK12=. & TRTCOMPL=’Y’)  |  (WEEK12^=. & TRTCOMPL=’Y’); 
RUN; 
 
PROC MI DATA= DATA21c OUT=IMOUT1c MINIMUM=0 SEED=745369 NIMPUTE=100; 
BY TRT; 
VAR AGE SEX ETHNICITY COUNTRY BMI SBP DBP EGFR STATIN BASE WEEK4 WEEK8 
WEEK12; 
CLASS SEX ETHNICITY COUNTRY STATIN; 
FCS; /* fully conditional specification method*/ 
TRANSFORM LOG(BASE) LOG(WEEK4) LOG(WEEK8) LOG(WEEK12); 
RUN; 
             
If there are no patients who adhere to therapy and miss Week 12 fasting TG 
measurement in DATA21c, 100 datasets will be created from DATA21c in order to 
merge with the 100 imputed datasets from the others. 
If there are not enough observations to fit regression models for missing Week 12               
values with a FCS regression method specified in steps II (a and b) and III, a correlation 
test between baseline TG measurements and the covariates will be performed based on the 
Full Analysis Set. The covariate with the lowest absolute value of Spearman correlation 
coefficient will be removed from the model in step II, while on the other hand, the one with 
the largest absolute value of that will be removed from the model in step III. And then the 
analysis will be performed. If the model still does not fit, the variable with the next lowest 
value of Spearman correlation coefficient will be removed. This process will be repeated 
until the regression model fits successfully.   
After imputation step, percentage change in TG will be calculated and each of the 100 
multiply imputed datasets for FAS patients will be analyzed by either PROC NPAR1WAY 
procedure or PROC MIXED procedure. The estimate and standard error for treatment effect 
from the analysis will be analyzed by PROC MIANALYZE to obtain the overall estimate 
of treatment difference, as well as the confidence interval and p-value. 
For example, the primary analysis method will output the Hodges-Lehmann estimation and 
asymptotic standard error from PROC NPAR1WAY procedure. 
PROC MIANALYZE DATA=DIFF;  


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 28 of 29 
 
MODELEFFECTS ESTIMATE;  
STDERR STDERR;  
 RUN;  
 
The SAP could be updated as a result of a blind review of the data and will be finalized 
before breaking the blind. Final imputed values will be saved in analysis database when the 
SAP is finalized as well as when the blind is subsequently broken. 
 
 


Kowa Research Institute, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol: K-877-301 
V2.0 
21 June 2019 
 
Page 29 of 29 
 
Appendix 2 Sensitivity Imputation Method: Probabilities of Missing Estimated by 
Logistic Regressions 
Below is a summary of steps/description of the imputation with probabilities of missing 
estimated by logistic regressions with the imputation forward for an early withdrew 
subject i: 
Step 1: To calculate the probabilities for missing data for Visit 5, a logit model is 
performed with treatment, baseline TG value, country, and baseline current statin 
therapy use (not on statin therapy versus currently receiving statin therapy) in the 
model. Percent change in TG at Visit 5 is calculated based on the formula below. 
PCHG5i = (1 – P5i) x (the median PCHG from the control group at Visit 5). 
TG5i = BTGi + (PCHG5i /100) x BTGi 
Step 2: Imputed Percent change in TG at Visit 5 is put into the data for those with missing 
Visit 5 to calculate the probabilities for missing data for Visit 6 using the same 
logit model with treatment, baseline value, country, and baseline current statin 
therapy use and Visit 5 TG as covariates. 
PCHG6i = (1 – P6i) x PCHG5i. 
TG6i = BTGi + (PCHG6i /100) x BTGi; 
Step 3: Imputed Percent change in TG at Visit 6 is put into the data for those with missing 
Visit 7 to calculate the probabilities for missing data for Visit 7 using the same 
logit model with treatment, baseline value, country, and baseline current statin 
therapy use and Visit 6 TG as covariates. 
PCHG7i = (1 – P7i) x PCHG6i. 
TG7i = BTGi + (PCHG7i /100) x BTGi; 
Where for subject i, 
PCHG5i PCHG6i PCHG7i = percent change in TG at Visit 5(Week 4), Visit 
6(Week 8), Visit 7(Week 12) respectively, 
TG5i TG6i TG7i = TG at Visit 5(Week 4), Visit 6(Week 8), Visit 7(Week 12) 
respectively, 
BTGi =baseline TG 
P5i P6i P7i = probability of missing estimated from the logistic regression 
respectively, 
 
Firth’s penalized likelihood approach will be used to address any issues of separability. 
 

Prot_001.pdf: 
CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877
 
18 Aug 2017 v2.0  
i12 
 
 
CONFIDENTIAL 
 
A Phase 3, Multi-Center, Placebo-Controlled, Randomized, 
Double-Blind, 12-Week Study With a 40-Week, Active-Controlled, 
Double-Blind Extension to Evaluate the Efficacy and Safety of K-877 in 
Adult Patients With Fasting Triglyceride Levels 500 mg/dL and 
<2000 mg/dL and Normal Renal Function 
Clinical Study Protocol 
Drug Name:  
K-877 
Study Number: 
K-877-301 
U.S. IND Number: 
109388 
EudraCT Number: 
2015-003511-37 
Protocol Version Date: 
18 Aug 2017 
Version Number: 
2.0 
Name of Sponsor: 
Kowa Research Institute, Inc.  
Address: 
430 Davis Drive, Suite 200 
Morrisville, NC 27560 
United States of America 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
ii12 
 
 
INVESTIGATOR’S STATEMENT 
I, the Investigator, understand that all information concerning the product supplied to me 
by Kowa Research Institute, Inc. (KRI) and 
 in connection with 
this study and not previously published is confidential information. This information 
includes the Investigator’s Brochure, protocol, case report forms, assay methods, technical 
methodology, and basic scientific data. 
I understand that any changes to the protocol must be approved in writing by KRI, 
 
and the Institutional Review Board/Ethics Committee (IRB/EC) before implementation, 
except where necessary to eliminate apparent immediate hazards to the patients. 
I confirm that I will report all adverse events (AEs) following the regulations indicated in 
the protocol. 
I confirm that I will conduct this study in conformance with the principles of the 
Declaration of Helsinki, Health Insurance Portability and Accountability Act (HIPAA), 
Food and Drug Administration (FDA) Good Clinical Practice (GCP), regulations (Code of 
Federal Regulations [CFR] Title 21 Parts 11, 50, 54, 56, and 312), International Council 
for Harmonisation (ICH) Guideline for GCP (E6/R1), local laws, and the laws and 
regulations of the country where the study is to be conducted. 
I confirm that I am informed of the need for record retention and that no data can be 
destroyed. 
By my signature below, I hereby attest that I have read, understood, and agree to abide by 
all conditions, instructions, and restrictions contained in this version of the protocol dated 
18 August 2017. 
 
Investigator’s Signature: 
 
Date:  
 
 
 
 
mm/dd/yyyy 
Printed Name: 
 
 
 
 
 
 
 
 




CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
iv12 
 
PROTOCOL SYNOPSIS 
 
Name of Sponsor Company: 
Kowa Research Institute, Inc.  
Drug Under Study: 
K-877 
Title of Protocol: 
A Phase 3, Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With a 
40-Week, Active-Controlled, Double-Blind Extension to Evaluate the Efficacy and Safety of K-877 in 
Adult Patients With Fasting Triglyceride Levels 500 mg/dL and <2000 mg/dL and Normal Renal 
Function 
Protocol Number: 
K-877-301 
Phase: 
3 
Indication: 
Dyslipidemia 
Study Design: 
Study K-877-301 is a Phase 3, multi-center, randomized, double-blind study to confirm the efficacy and 
safety of K-877 0.2 mg twice daily compared to matching placebo (in the 12-week Efficacy Period) and 
an active comparator, fenofibrate (in the 40-week Extension Period), in patients with fasting triglyceride 
(TG) levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) and normal renal function. 
Eligible patients will enter a 4- to 6-week lifestyle stabilization period (4-week stabilization for patients 
not requiring washout and 6-week washout and stabilization for patients on lipid-altering therapy other 
than statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors). The 
stabilization period will be followed by a 2-week TG qualifying period (Visits 2 [Week -2] and 
3 [Week -1]), and patient eligibility will be assessed based on the mean TG value from these 2 visits. If 
the patient’s mean TG level during the TG qualifying period is 450 mg/dL (5.09 mmol/L) and 
<500 mg/dL (5.65 mmol/L), an additional TG measurement can be taken 1 week later at Visit 3.1. The 
mean of all 3 TG measurements will be used to determine eligibility for the study. After confirmation of 
qualifying fasting TG values, eligible patients will enter a 12-week, randomized, double-blind Efficacy 
Period. At Visit 4 (Day 1), patients will be randomly assigned in a 2:1 ratio to K-877 0.2 mg twice daily 
or identical matching placebo tablets twice daily. During the 12-week Efficacy Period, patients will 
return to the site at Visit 5 (Week 4), Visit 6 (Week 8), and Visit 7 (Week 12) for efficacy and safety 
evaluations. 
Patients who successfully complete the 12-week Efficacy Period are eligible to continue in a 40-week, 
double-blind, active-controlled Extension Period after completing the Visit 7 (Week 12) procedures. 
Patients randomized to receive K-877 0.2 mg twice daily in the 12-week Efficacy Period will continue 
to receive K-877 0.2 mg twice daily, as well as placebo matching fenofibrate 145 mg once daily, in the 
40-week Extension Period. Patients randomized to receive placebo matching K-877 0.2 mg twice daily 
in the 12-week Efficacy Period will receive fenofibrate 145 mg once daily and placebo matching 
K-877 0.2 mg twice daily in the 40-week Extension Period. 
From Visit 7 (Week 12), patients not on statins, ezetimibe, or PCSK9 inhibitors may initiate therapy, 
and patients receiving statins, ezetimibe, or PCSK9 inhibitors may alter their dose, as indicated by 
guidelines or local standard of care. 
After Visit 8 (Week 16), patients are to return to the site every 12 weeks until the last visit (Visit 11 
[Week 52]). 
Primary Objective: 
The primary objective of the study is to demonstrate the efficacy of K-877 0.2 mg twice daily compared 
to placebo from baseline to Week 12 in lowering fasting TG levels in patients with fasting TG levels 
500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
v12 
 
Secondary Objectives: 
The secondary objectives of the study are the following: 
 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 52 in lowering 
fasting TG levels in patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L);  
 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 12 and Week 52 
in altering lipid parameters in patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L);  
 
To evaluate the safety and tolerability of K-877 0.2 mg twice daily in patients with fasting 
TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L); and 
 
To determine the plasma concentrations of K-877 for the purpose of use in population 
pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) analysis. 
Exploratory Objective: 
 
 
 
Patient Population: 
The study population will consist of male and female patients 18 years of age with fasting TG levels 
500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) after washout from background 
lipid-altering therapy other than statins, ezetimibe, or PCSK9 inhibitors and with normal renal function. 
Stable therapy with statins, ezetimibe, or PCSK9 inhibitors will be allowed. The 40-week, 
active-controlled Extension Period population will consist of patients completing the 12-week 
placebo-controlled Efficacy Period. Patients in the 40-week, active-controlled Extension Period will be 
allowed to continue in the study even if the background lipid-altering therapy with statins, ezetimibe, or 
PCSK9 inhibitors requires adjustment. 
Number of Patients: 
Approximately 630 patients (420 patients receiving 
K-877; 210 patients receiving placebo/fenofibrate) 
Number of Centers: 
Approximately 200 sites globally 
Dose Levels: 
12-week Efficacy Period 
 K-877: 0.2 mg twice daily  
 Placebo: twice daily 
40-week Extension Period 
 K-877: 0.2 mg twice daily/fenofibrate matching 
placebo: once daily 
 Fenofibrate: 145 mg once daily/K-877 matching 
placebo: twice daily 
Route of Administration: 
Oral 
Duration of Treatment: 
This study consists of a 12-week, double-blind, placebo-controlled Efficacy Period, followed by a 
40-week, double-blind, active-controlled Extension Period, for a total of 52 weeks on study drug. 
Criteria for Evaluation: 
Efficacy: 
The primary efficacy endpoint is the percent change in fasting TG from baseline to Week 12. Baseline 
for TG will be defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either 
Visit 3 [Week -1] or Visit 3.1, if required) measurements.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
vi12 
 
The secondary efficacy endpoints for the 12-week Efficacy Period include the following: 
 
Percent change from baseline to Week 12 in remnant cholesterol (calculated as total cholesterol 
[TC] – low-density lipoprotein C [LDL-C] – high-density lipoprotein C [HDL-C]), HDL-C, 
apolipoprotein (Apo) A1, and non-HDL-C: 
o 
Low-density lipoprotein cholesterol will be determined by preparative ultracentrifugation; 
 
Percent change from baseline to Week 12 in TC, LDL-C, free fatty acids (FFAs), Apo A2, 
Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; 
 
Change from baseline to Week 12 in fibroblast growth factor 21 (FGF21) and high-sensitivity 
C-reactive protein (hsCRP), and percent change from baseline to Week 12 in ion mobility 
analysis and lipoprotein fraction (nuclear magnetic resonance [NMR]); and  
 
Percent change from baseline to Week 12 in the lipid and lipoprotein ratios of TG:HDL-C, 
TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and Apo C3:Apo C2. 
The secondary efficacy endpoints for the 40-week Extension Period include the following: 
 
Percent change from baseline to Week 52 in fasting TG; 
 
Percent change from baseline to Week 52 in remnant cholesterol (calculated as 
TC − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o 
Low-density lipoprotein cholesterol will be determined by preparative ultracentrifugation; 
 
Percent change from baseline to Week 52 in TC, LDL-C, FFAs, Apo A2, Apo B, Apo B48, 
Apo B100, Apo C2, Apo C3, and Apo E; 
 
Change from baseline to Week 52 in FGF21 and hsCRP, and percent change from baseline to 
Week 52 in ion mobility analysis and lipoprotein fraction (NMR); and  
 
Percent change from baseline to Week 52 in the lipid and lipoprotein ratios of TG:HDL-C, 
TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and Apo C3:Apo C2. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be defined as the mean 
of Visit 4 (Day 1) and the preceding TG qualifying visit (either Visit 3 [Week -1] or Visit 3.1, if required) 
measurements. Baseline for all other efficacy and safety variables will be defined as Visit 4 (Day 1). If 
the measurement at this visit is missing, the last measurement prior to the first dose of randomized study 
drug will be used.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
Safety assessments include adverse events (AEs), clinical laboratory measurements (chemistry, 
hematology, coagulation profile, 
 and urinalysis), 12-lead electrocardiograms (ECGs), 
vital signs (heart rate, respiratory rate, and blood pressure), and physical examinations. 
Pharmacokinetics/Pharmacodynamics: 
Pharmacokinetic concentrations collected during the 12-week Efficacy Period will be used for 
population PK analysis and PK/PD analysis. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
vii12 
 
Criteria for Inclusion:  
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Able to understand and willing to comply with all study requirements and procedures 
throughout the duration of the study and give written informed consent; 
2. Aged 18 years; 
3. Patients receiving moderate- or high-intensity statin therapy must meet one of the following 
criteria1 unless they have any exceptional conditions (see inclusion criterion 4): 
a. 
Aged  years with clinical atherosclerotic cardiovascular disease (ASCVD) (history of 
acute coronary syndrome or myocardial infarction, stable or unstable angina, coronary or 
other arterial revascularization, stroke, transient ischemic attack [TIA] presumed to be of 
atherosclerotic origin, or peripheral arterial disease or revascularization), on a 
high-intensity statin (or moderate-intensity statin if not a candidate for high-intensity statin 
due to safety concerns); 
b. Aged years with a history of LDL-C190 mg/dL, which is not due to secondary 
modifiable causes, on a high-intensity statin (or moderate-intensity statin if not a candidate 
for high-intensity statin due to safety concerns); 
c. 
Aged 40 to 75 years, inclusive, without clinical ASCVD but with diabetes and a history of 
LDL-C of 70 to 189 mg/dL, inclusive, on a moderate- or high-intensity statin; or 
d. Aged 40 to 75 years, inclusive, without clinical ASCVD or diabetes, with a history of 
LDL-C of 70 to 189 mg/dL, inclusive, with estimated 10-year risk for ASCVD of7.5% 
by the Pooled Cohort Equation on a moderate- or high-intensity statin; 
4. Patients currently on a low-intensity statin or not on a statin, must meet one of the following 
criteria: 
a. 
Patient does not meet any criteria for moderate- or high-intensity statin therapy listed above 
(see inclusion criteria 3.a. through 3.d.); 
b. Patient does meet one or more criteria for moderate- or high-intensity statin therapy listed 
above (see inclusion criteria 3.a. through 3.d.); but the patient is not a candidate for 
moderate  or high-intensity statin due to safety concerns, or due to partial or complete statin 
intolerance; or 
c. 
Patient does meet one or more criteria for moderate- or high-intensity statin therapy listed 
above (see inclusion criteria 3.b. through 3.d., except for 3.a.); but the patient is not a 
candidate for moderate- or high-intensity statin for primary prevention after considering 
individual risk evaluation (e.g. current LDL-C 70mg/dL) and patient preference; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
viii12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criteria for Exclusion: 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Patients who will require lipid-altering treatments other than study drugs (K-877 or fenofibrate), 
statins, ezetimibe, or PCSK9 inhibitors during the course of the study. These include bile acid 
sequestrants, non-study fibrates, niacin (>100 mg/day), omega-3 fatty acids (>1000 mg/day), 
or any supplements used to alter lipid metabolism including, but not limited to, red rice yeast 
supplements, garlic supplements, soy isoflavone supplements, sterol/stanol products, or 
policosanols; 
2. Body mass index (BMI) >45 kg/m2 at Visit 1 (Week -8 or Week -6); 
3. Patients with type 1 diabetes mellitus; 
4. Patients with newly diagnosed (within 3 months prior to Visit 2 [Week -2]) or poorly controlled 
type 2 diabetes mellitus (T2DM), defined as hemoglobin A1c >9.5% at Visit 1 (Week -8 or 
Week -6); 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
ix12 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
x12 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Sample Size Justification: 
Approximately 630 patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L) will be randomized in a 2:1 ratio into one of the following treatment groups: 
K-877 0.2 mg twice daily or identical matching placebo twice daily. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis: 
Efficacy: 
In order to control the family-wise Type I error at a 0.05 level, a fixed sequential testing procedure will 
be implemented. In a hierarchical step-down manner, the primary endpoint will be tested first, followed 
by secondary endpoints, tested in the following hierarchical manner: percent change from baseline to 
Week 12 in a fixed sequence of (1) remnant cholesterol (calculated as TC − LDL-C − HDL-C), 
(2) HDL-C, (3) Apo A1, and (4) non-HDL-C. Each test is planned to be performed at a 0.05 significance 
level. Inferential conclusions about these efficacy endpoints will require statistical significance of the 
previous one. 
For other efficacy endpoints, nominal p-values and 95% confidence intervals (CIs) will be presented, 
but should not be considered as confirmatory. 
The primary efficacy analysis will be based on Hodges-Lehmann estimator with pattern-mixture model 
imputation based on the Full Analysis Set (FAS). The pattern-mixture model will be used as the primary 
imputation method as part of the primary analysis for the percent change in fasting TGs from baseline 
to Week 12. This imputation model will include factors such as patient demographics, disease status, 
and baseline TG, as well as adherence to therapy. The imputation model will impute missing Week 12 
TG values as follows: 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
xi12 
 
 
For patients who do not adhere to therapy and who do not have a Week 12 measurement, the 
missing data imputation method will use patients in the same treatment arm who do not adhere 
to therapy and have a Week 12 measurement; and  
 
If there are no patients in the same treatment arm who do not adhere to therapy and have a 
Week 12 measurement, missing Week 12 TG values will be imputed as follows: 
o 
For the K-877 arm, the treatment effect is considered washed out and baseline TG values 
will be used to impute the Week 12 TG values; and  
o 
For the placebo arm, missing Week 12 TG values will be imputed assuming missing at 
random, including patient demographics, disease status, and baseline and post-baseline 
efficacy data from the placebo arm.  
After the multiple imputation step, each imputed dataset will be analyzed by the nonparametric 
Hodges-Lehmann method and the Hodges-Lehmann estimator and standard error will be combined to 
produce treatment difference estimate and 95% CI and p-value. 
 
 
 
 
 
 
The primary efficacy analysis will be repeated on the Per-Protocol Set. 
Summary statistics (number of patients, mean, standard deviation, median, minimum, maximum, 
25th percentile, and 75th percentile) at baseline, each scheduled visit, and change and percent change in 
fasting TG from baseline to each scheduled visit will be provided. 
Secondary efficacy endpoints included in the hierarchical step-down testing procedure include percent 
change from baseline to Week 12 in a fixed sequence of (1) remnant cholesterol, (2) HDL-C, (3) Apo A1, 
and (4) non-HDL-C. 
The secondary and exploratory efficacy endpoints during the 12-week Efficacy Period will be analyzed 
using an ANCOVA model with the same imputation method used for the primary analysis. The 
ANCOVA model will include country, current statin therapy use (not on statin therapy versus currently 
receiving statin therapy), and treatment as factors; baseline value as a covariate. If the normality 
assumption is not met, the Hodges-Lehmann estimator with the same imputation method used for the 
primary analysis will be used. 
The secondary efficacy endpoint of percent change in fasting TG from baseline to Week 52 will be 
summarized descriptively. 
 
 Other efficacy endpoints during the 40-week 
Extension Period will be summarized descriptively. No hypothesis testing will be performed. 
 
 
 
Safety: 
The safety endpoint data will be summarized for the Safety Analysis Set for the 12-week Efficacy Period, 
40-week Extension Period, and overall. 
The AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities. A 
general summary of the AEs and serious AEs (SAEs) will be summarized by overall number of AEs, 
severity, and relationship to study drug per treatment group. The number of AEs leading to withdrawal 
and SAEs leading to death will also be summarized. The incidence of AEs will be summarized by body 
system and treatment group. The incidence of treatment-emergent AEs will also be summarized by 
system organ class and preferred term. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
xii12 
 
The safety laboratory data will be summarized by visit and by treatment group, along with changes from 
the baseline. The values that are below the lower limit or above the upper limit of the reference range 
will be flagged. Those values or changes in values that are identified as being clinically significant will 
be flagged. Laboratory abnormalities of special interest, such as liver function tests and pancreatitis 
events, will be summarized. 
Vital signs and 12-lead ECGs will also be summarized by visit and by treatment group, along with the 
changes from baseline. 
Pharmacokinetics: 
Population PK and PK/PD data will be analyzed and reported separately. 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
xiii6 
 
TABLE OF CONTENTS 
INVESTIGATOR’S STATEMENT ............................................................................................. ii 
SIGNATURE PAGE ..................................................................................................................... iii 
PROTOCOL SYNOPSIS ............................................................................................................. iv 
TABLE OF CONTENTS ........................................................................................................... xiii 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ xvi 
 
INTRODUCTION AND RATIONALE FOR DOSE SELECTION ............................ 1 
1.1 
BACKGROUND INFORMATION ................................................................................... 1 
1.2 
RATIONALE ...................................................................................................................... 1 
 
STUDY OBJECTIVES ..................................................................................................... 5 
2.1 
PRIMARY OBJECTIVE .................................................................................................... 5 
2.2 
SECONDARY OBJECTIVES............................................................................................ 5 
2.3 
EXPLORATORY OBJECTIVE ......................................................................................... 5 
2.4 
PRIMARY EFFICACY ENDPOINT ................................................................................. 5 
2.5 
SECONDARY EFFICACY ENDPOINTS ......................................................................... 5 
2.6 
EXPLORATORY EFFICACY ENDPOINTS .................................................................... 7 
2.7 
SAFETY ENDPOINTS ...................................................................................................... 7 
2.8 
PHARMACOKINETIC/PHARMACODYNAMIC ENDPOINTS .................................... 7 
 
STUDY DESCRIPTION .................................................................................................. 8 
3.1 
STUDY DESIGN ............................................................................................................... 8 
 
PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA ................................. 12 
4.1 
INCLUSION CRITERIA ................................................................................................. 12 
4.2 
EXCLUSION CRITERIA ................................................................................................ 14 
4.3 
STUDY DRUG DISCONTINUATION CRITERIA ........................................................ 17 
4.4 
WITHDRAWAL CRITERIA ........................................................................................... 18 
4.5 
RE-SCREENING OF SCREEN FAILURES ................................................................... 19 
4.6 
STUDY DRUG DISCONTINUATION FOR PERSISTENT ABNORMAL CLINICAL 
LABORATORY VALUES .............................................................................................. 20 
4.7 
SURVEILLANCE FOR POSSIBLE PANCREATITIS ................................................... 20 
 
PROCEDURES FOR EFFICACY, SAFETY, AND PHARMACOKINETIC 
EVALUATIONS ............................................................................................................. 21 
5.1 
EFFICACY EVALUATIONS .......................................................................................... 21 
5.2 
SAFETY EVALUATIONS .............................................................................................. 21 
 
Adverse Events ................................................................................................................. 21 
 
Clinical Laboratory Tests .................................................................................................. 21 
 Liver Function Test Elevations ......................................................................................... 22 
 Creatine Kinase Elevations ............................................................................................... 23 
 Triglyceride Elevations ..................................................................................................... 23 
 Estimated Glomerular Filtration Rate Decrease ............................................................... 24 
 
Electrocardiogram and Vital Signs ................................................................................... 24 
 
Physical Examination ....................................................................................................... 24 
 
Demographics and Medical History ................................................................................. 24 
 
Body Weight, Height, Body Mass Index, and Waist Circumference ............................... 24 
5.3 
PHARMACOKINETIC EVALUATIONS ....................................................................... 25 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
xiv6 
 
 
5.4 
DATA MONITORING COMMITTEE ............................................................................ 26 
5.5 
PANCREATITIS ADJUDICATION COMMITTEE ....................................................... 26 
 
CONDUCT OF THE STUDY ........................................................................................ 27 
6.1 
STUDY BLINDING AND RANDOMIZATION ............................................................ 27 
6.2 
PATIENT INFORMED CONSENT................................................................................. 28 
6.3 
STUDY VISITS ................................................................................................................ 28 
6.4 
COMPLIANCE WITH THE PROTOCOL ...................................................................... 35 
6.5 
TERMINATION OF THE STUDY.................................................................................. 36 
 
Site Termination ............................................................................................................... 36 
 
Study Termination ............................................................................................................ 36 
6.6 
LABORATORY ALERT RELATED TO HIGH TRIGLYCERIDES ............................. 36 
 
INVESTIGATIONAL DRUG........................................................................................ 37 
7.1 
DESCRIPTION OF STUDY DRUGS .............................................................................. 37 
7.2 
DRUG PACKAGING ....................................................................................................... 37 
7.3 
DRUG LABELING .......................................................................................................... 37 
7.4 
DRUG STORAGE ............................................................................................................ 38 
7.5 
DISPENSING AND ADMINISTRATION OF TREATMENT ....................................... 38 
 
Drug Administration ......................................................................................................... 38 
7.6 
COMPLIANCE WITH PRESCRIBED STUDY DRUG DOSING REGIMEN .............. 39 
7.7 
DRUG ACCOUNTABILITY ........................................................................................... 39 
7.8 
PROCEDURE FOR UNBLINDING ................................................................................ 39 
 
CONCOMITANT MEDICATION ............................................................................... 40 
8.1 
GENERAL CONSIDERATIONS .................................................................................... 40 
 
 
8.3 
PROHIBITED MEDICATION ........................................................................................ 40 
8.4 
PERMITTED MEDICATION .......................................................................................... 41 
8.5 
PATIENT RESTRICTIONS ............................................................................................. 42 
 
Therapeutic Lifestyle Changes ......................................................................................... 42 
 
ADVERSE EVENTS ...................................................................................................... 43 
9.1 
ADVERSE EVENT DEFINITION .................................................................................. 43 
9.2 
ADVERSE DRUG REACTIONS .................................................................................... 43 
9.3 
REPORTING ADVERSE EVENTS ................................................................................ 43 
9.4 
FOLLOW-UP OF ADVERSE EVENTS .......................................................................... 46 
 
SERIOUS ADVERSE EVENTS .................................................................................... 48 
10.1 
LIFE-THREATENING ADVERSE EVENT ................................................................... 48 
10.2 
HOSPITALIZATION OR PROLONGATION OF EXISTING HOSPITALIZATION .. 48 
10.3 
PREGNANCY .................................................................................................................. 48 
10.4 
PATIENT WITHDRAWAL ............................................................................................. 49 
10.5 
SERIOUS UNEXPECTED SUSPECTED ADVERSE REACTIONS............................. 49 
10.6 
REPORTING SERIOUS ADVERSE EVENTS, URGENT SAFETY ISSUES, AND 
SERIOUS BREACHES .................................................................................................... 50 
 Serious Adverse Events .................................................................................................... 50 
 Initial Reports ................................................................................................................... 50 
 Follow-Up Reports ........................................................................................................... 50 
 Urgent Safety Issues and Serious Breaches of Clinical Trial Regulation ......................... 51 
 
STATISTICAL METHODS AND DATA ANALYSIS ............................................... 52 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
xv6 
 
11.1 
SAMPLE SIZE JUSTIFICATION ................................................................................... 52 
11.2 
ANALYSIS POPULATIONS .......................................................................................... 52 
 Full Analysis Set ............................................................................................................... 52 
 Per-Protocol Set ................................................................................................................ 52 
 Safety Analysis Set ........................................................................................................... 53 
 Pharmacokinetic Analysis Set........................................................................................... 53 
11.3 
DEMOGRAPHIC/BASELINE INFORMATION ............................................................ 53 
11.4 
STUDY DRUG EXPOSURE, COMPLIANCE, AND CONCOMITANT THERAPIES 53 
11.5 
ANALYSIS OF EFFICACY ............................................................................................ 54 
 Hypothesis Testing Procedure .......................................................................................... 54 
 Analysis of Primary Efficacy Parameters ......................................................................... 54 
 Analysis of Secondary and Exploratory Efficacy Parameters .......................................... 55 
 
11.6 
ANALYSIS OF SAFETY DATA .................................................................................... 55 
11.7 
ANALYSIS OF PHARMACOKINETIC DATA ............................................................. 56 
11.8 
INTERIM ANALYSIS ..................................................................................................... 56 
 
STUDY MANAGEMENT AND DATA COLLECTION ............................................ 57 
12.1 
ETHICAL CONDUCT OF THE TRIAL ......................................................................... 57 
12.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE ..................................... 57 
12.3 
PATIENT INFORMED CONSENT................................................................................. 57 
12.4 
AMENDMENTS TO THE PROTOCOL ......................................................................... 58 
12.5 
STUDY INITIATION ...................................................................................................... 58 
12.6 
STUDY MONITORING .................................................................................................. 58 
12.7 
CASE REPORT FORM .................................................................................................... 59 
12.8 
VERIFICATION PROCEDURES.................................................................................... 59 
12.9 
RETENTION OF RECORDS........................................................................................... 60 
12.10 INSURANCE AND INDEMNITY .................................................................................. 60 
12.11 AUDIT .............................................................................................................................. 60 
 
USE OF INFORMATION ............................................................................................. 61 
13.1 
GENERAL ASPECTS ...................................................................................................... 61 
13.2 
PATIENT CONFIDENTIALITY AND DATA PROTECTION ..................................... 61 
13.3 
FINAL REPORT AND PUBLICATION POLICY .......................................................... 61 
 
REFERENCES ................................................................................................................ 63 
 
APPENDICES ................................................................................................................. 66 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
xvi6 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Apo  
Apolipoprotein 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CK 
Creatine kinase 
 
 
Cmax 
Maximum plasma pharmacokinetic concentration 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
EC 
Ethics Committee 
EC50 
Half-maximal effective concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFA 
Free fatty acid 
FGF21 
Fibroblast growth factor 21 
 
 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
 
 
 
 
HDL-C 
High-density lipoprotein cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
HOMA-β 
Homeostatic model assessment for beta-cell function 
HOMA-IR 
Homeostatic model assessment for insulin resistance 
hsCRP 
High-sensitivity C-reactive protein 
HTG 
Hypertriglyceridemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
18 Aug 2017 v2.0 
xvii6 
 
ID 
Identification 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KRI 
Kowa Research Institute, Inc. 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
 
 
MMRM 
Mixed effect model repeat measurement 
 
 
NCEP 
National Cholesterol Education Program 
NMR 
Nuclear magnetic resonance 
OATP 
Organic anion-transporting polypeptide 
PAC 
Pancreatitis Adjudication Committee 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPAR 
Peroxisome proliferator-activated receptor 
QUICKI 
Quantitative insulin sensitivity check index 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SHTG 
Severe hypertriglyceridemia  
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
T2DM 
Type 2 diabetes mellitus 
 
 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
TIA 
Transient ischemic attack 
TLC 
Therapeutic Lifestyle Changes 
Tmax 
Time to maximum plasma concentration 
 
 
 
 
ULN 
Upper limit of normal 
VLDL 
Very low-density lipoprotein  
WOCBP 
Women of childbearing potential 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 1 of 78 
 
INTRODUCTION AND RATIONALE FOR DOSE SELECTION 
1.1 
BACKGROUND INFORMATION 
K-877 is a potent and selective peroxisome proliferator-activated receptor (PPAR) 
modulator, which is several thousand times more selective for the PPARα receptor than the 
PPARγ or PPARδ receptor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 
RATIONALE 
A variety of primary disorders of lipoprotein metabolism have been described which may 
lead to elevated levels of the atherogenic lipoproteins (VLDL, remnant particles, 
LDL, etc.) or reduced levels of the anti-atherogenic high-density lipoprotein, any or all of 
which can confer increased risk of coronary artery disease. Of greater concern, elevated 
levels of TG, in particular TG levels 500 mg/dL (5.65 mmol/L), confer an increased risk 
of acute pancreatitis. 2 , 3 Acute pancreatitis caused by hypertriglyceridemia (HTG) is 
associated with increased severity and rates of complications compared to pancreatitis with 
causes other than HTG.4,5  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 2 of 78 
Fibrates improve TG and HDL-C by activating PPARα, 6  and are labeled in the 
United States for the treatment of severe HTG (SHTG). In the United States, fenofibrate, 
fenofibric acid, and gemfibrozil are available. Fibrates available in Europe are bezafibrate, 
ciprofibrate, fenofibrate, and gemfibrozil. In Japan, bezafibrate, clinofibrate, clofibrate, 
and fenofibrate are available.  
The United States Adult Treatment Panel III National Cholesterol Education Program 
(NCEP) guidelines7 recommend reduction of TG through lifestyle, diet, and pharmacologic 
methods as the first priority of therapy when serum TG are 500 mg/dL. Treatment with 
omega-3 fatty acids, such as those found in fish oils, has been shown to effectively decrease 
TG levels up to 30%; however, for individuals with SHTG (serum TG 500 mg/dL), 
increasing omega-3 fatty acid intake does not adequately manage TG levels.8 
The European Society for Cardiology and European Atherosclerosis Society consensus 
guidelines note that patients can develop pancreatitis with TG concentrations between 
5 and 10 mmol/L (440 and 880 mg/dL).9 These guidelines also recommend initiating 
fibrates to prevent acute pancreatitis. 
Most fibrates are contraindicated or require careful administration in patients with renal 
dysfunction. Furthermore, coadministration of these drugs with statins is contraindicated 
in patients with severe renal dysfunction. Thus, there are restrictions in the use of existing 
PPARα agonists.10,11,12,13,14,15,16,17 
K-877 is a selective PPARα agonist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 3 of 78 
 
 
 
 
 
 
 
 
 
 
 
 Therefore, K-877 is expected to exhibit not only a potent lipid 
metabolism-improving effect but also to serve as a drug with a broad therapeutic range 
with fewer restrictions in patients with renal dysfunction or with concomitant drugs than 
existing PPARα agonists.  
Fenofibrate (145 mg once daily) was chosen as the active comparator for the 40-week 
Extension Period of this study based on current guidelines for the management of SHTG. 
The present study is a Phase 3 multi-center, placebo-controlled, randomized, double-blind, 
12-week study with a 40-week, active-controlled, double-blind extension designed to 
evaluate the efficacy and safety of K-877 0.2 mg twice daily in adult patients with fasting 
TG levels 500 mg/dL and <2000 mg/dL and normal renal function. The results of this 
study will provide a better understanding of the efficacy and safety of K-877 0.2 mg twice 
daily in patients with SHTG. 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
18 Aug 2017 v2.0 
Page 4 of 78 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 5 of 78 
 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to demonstrate the efficacy of K-877 0.2 mg twice 
daily compared to placebo from baseline to Week 12 in lowering fasting TG levels in 
patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L). 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are the following: 
 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 52 in 
lowering fasting TG levels in patients with fasting TG levels 500 mg/dL 
(5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L); 
 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 12 and 
Week 52 in altering lipid parameters in patients with fasting TG levels 500 mg/dL 
(5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L);  
 
To evaluate the safety and tolerability of K-877 0.2 mg twice daily in patients with 
fasting TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L); 
and 
 
To determine the plasma concentrations of K-877 for the purpose of use in 
population pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) 
analysis. 
2.3 
EXPLORATORY OBJECTIVE 
 
 
 
2.4 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the percent change in fasting TG from baseline to 
Week 12. Baseline for TG will be defined as the mean of Visit 4 (Day 1) and the preceding 
TG qualifying visit (either Visit 3 [Week -1] or Visit 3.1, if required) measurements.  
2.5 
SECONDARY EFFICACY ENDPOINTS 
The secondary efficacy endpoints for the 12-week Efficacy Period include the following: 
 
Percent change from baseline to Week 12 in remnant cholesterol (calculated as total 
cholesterol [TC] − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 6 of 78 
 
Percent change from baseline to Week 12 in TC, LDL-C, free fatty acids (FFAs), 
Apo A2, Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; 
 
Change from baseline to Week 12 in FGF21 and high-sensitivity C-reactive protein 
(hsCRP), and percent change from baseline to Week 12 in ion mobility analysis 
and lipoprotein fraction (nuclear magnetic resonance [NMR]); and  
 
Percent change from baseline to Week 12 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and 
Apo C3:Apo C2. 
The secondary efficacy endpoints for the 40-week Extension Period include the following: 
 
Percent change from baseline to Week 52 in fasting TG; 
 
Percent change from baseline to Week 52 in remnant cholesterol (calculated as 
TC − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 
 
Percent change from baseline to Week 52 in TC, LDL-C, FFAs, Apo A2, Apo B, 
Apo B48, Apo B100, Apo C2, Apo C3, and Apo E;  
 
Change from baseline to Week 52 in FGF21 and hsCRP, and percent change from 
baseline to Week 52 in ion mobility analysis and lipoprotein fraction (NMR); and  
 
Percent change from baseline to Week 52 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and 
Apo C3:Apo C2. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either Visit 3 
[Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy and safety 
variables will be defined as Visit 4 (Day 1). If the measurement at this visit is missing, the 
last measurement prior to the first dose of randomized study drug will be used. 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 7 of 78 
2.6 
EXPLORATORY EFFICACY ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
 
2.7 
SAFETY ENDPOINTS 
Safety assessments include adverse events (AEs), clinical laboratory measurements 
(chemistry, hematology, coagulation profile, 
 and urinalysis), 12-lead 
electrocardiograms (ECGs), vital signs (heart rate, respiratory rate, and blood pressure), 
and physical examinations. 
2.8 
PHARMACOKINETIC/PHARMACODYNAMIC ENDPOINTS 
Pharmacokinetic concentrations collected during the 12-week Efficacy Period will be used 
for population PK analysis and PK/PD analysis. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 8 of 78 
 
STUDY DESCRIPTION 
3.1 
STUDY DESIGN 
This is a Phase 3, multi-center, randomized, double-blind study to confirm the efficacy and 
safety of K-877 0.2 mg twice daily compared to matching placebo (in the 12-week 
Efficacy Period) and an active comparator, fenofibrate (in the 40-week Extension Period), 
in patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L) and normal renal function. 
Eligible patients will enter a 4- to 6-week lifestyle stabilization period (4-week stabilization 
for patients not requiring washout and 6-week washout and stabilization for patients on 
lipid-altering therapy other than statins, ezetimibe, or proprotein convertase 
subtilisin/kexin type 9 [PCSK9] inhibitors). The stabilization period will be followed by a 
2-week TG qualifying period (Visits 2 [Week -2] and 3 [Week -1]), and patient eligibility 
will be assessed based on the mean TG value from these 2 visits. If the patient’s mean TG 
level during the TG qualifying period is 450 mg/dL (5.09 mmol/L) and <500 mg/dL 
(5.65 mmol/L), an additional TG measurement can be taken 1 week later at Visit 3.1. The 
mean of all 3 TG measurements will be used to determine eligibility for the study. After 
confirmation of qualifying fasting TG values, eligible patients will enter a 12-week, 
randomized, double-blind Efficacy Period. At Visit 4 (Day 1), patients will be randomly 
assigned in a 2:1 ratio to K-877 0.2 mg twice daily or identical matching placebo tablets 
twice daily. During the 12-week Efficacy Period, patients will return to the site at Visit 5 
(Week 4), Visit 6 (Week 8), and Visit 7 (Week 12) for efficacy and safety evaluations. 
Patients who successfully complete the 12-week Efficacy Period are eligible to continue in 
a 40-week, double-blind, active-controlled Extension Period after completing the Visit 7 
(Week 12) procedures. Patients randomized to receive K-877 0.2 mg twice daily in the 
12-week Efficacy Period will continue to receive K-877 0.2 mg twice daily, as well as 
placebo matching fenofibrate 145 mg once daily, in the 40-week Extension Period. Patients 
randomized to receive placebo matching K-877 0.2 mg twice daily in the 12-week 
Efficacy Period will receive fenofibrate 145 mg once daily and placebo matching K-877 
0.2 mg twice daily in the 40-week Extension Period.  
From Visit 7 (Week 12), patients not on statins, ezetimibe, or PCSK9 inhibitors may initiate 
therapy, and patients receiving statins,  ezetimibe, or PCSK9 inhibitors may alter their dose, 
as indicated by guidelines or local standard of care. 
After Visit 8 (Week 16), patients are to return to the site every 12 weeks until the last visit 
(Visit 11 [Week 52]). 
Table 2 presents the clinical evaluation schedule performed during the study.  
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
18 Aug 2017 v2.0 
Page 9 of 78 
Table 2: 
Clinical Evaluation Schedule 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 
Lifestyle 
Stabilization/
Washout 
Period 
Triglyceride 
Qualifying Period [1] 
12-Week Efficacy Period 
40-Week Extension Period [2] 
Time 
Week -8 or -6 
Week -2 
±3 days 
Week -1 
±3 days 
Day 1 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Week 28 
±7 days 
Week 40 
±7 days 
Week 52 
±7 days or ET 
Visit Number 
1 [3] 
2 
3 [1] 
4 
5 
6 
7 
8 
9 
10 
11 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, and family history, 
and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
Vital signs (heart rate, respiratory rate, 
and blood pressure) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height [4], weight, and waist 
circumference 
X 
 
 
X 
 
 
X 
 
 
 
X 
Register screening number with IRT 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug and blood alcohol screen [5] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase and lipase 
X 
 
 
X 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Insulin, glycated albumin, HOMA-IR, 
HOMA-β, and QUICKI 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Serum pregnancy test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for WOCBP 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry, hematology, coagulation, 
and urinalysis 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Plasma Population PK sampling [8] 
PK/PD sampling [9] 
TG, TC, HDL-C, non-HDL-C, LDL-C, 
and remnant cholesterol [10] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*footnotes on following page 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol  
 
K-877 
18 Aug 2017 v2.0 
Page 10 of 78 
Table 2: 
Clinical Evaluation Schedule (Continued) 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 
Lifestyle 
Stabilization/
Washout 
Period 
Triglyceride 
Qualifying Period [1] 
12-Week Efficacy Period 
40-Week Extension Period [2] 
Time 
Week -8 or -6 
Week -2 
±3 days 
Week -1 
±3 days 
Day 1 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Week 28 
±7 days 
Week 40 
±7 days 
Week 52 
±7 days or ET 
Visit Number 
1 [3] 
2 
3 [1] 
4 
5 
6 
7 
8 
9 
10 
11 
Apo A1, Apo A2, Apo B, Apo B48, 
Apo B100, Apo C2, Apo C3, and Apo E 
 
 
 
X 
X 
 
X 
 
X 
 
X 
FFAs 
 
 
 
X 
 
 
X 
 
X 
 
X 
Ion mobility analysis and lipoprotein 
fraction (NMR) 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Withdraw lipid-altering medication(s) 
other than statins, ezetimibe, or PCSK9 
inhibitors, if applicable 
X 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
X 
 
 
X 
 
 
 
X 
Physical examination 
X 
 
 
X 
 
 
X 
 
 
 
X 
Assess and record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLC counseling [13] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Dispense study drug (efficacy period) 
 
 
 
X 
X 
X 
 
 
 
 
 
Dispense study drug (extension period) 
 
 
 
 
 
 
X 
X 
X 
X 
 
Collect study drug and record 
accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
1. 
Triglyceride levels are based on the mean of the Visit 2 (Week -2) and Visit 3 (Week -1) values. In cases in which a patient’s mean TG level from Visit 2 (Week -2) and Visit 3 (Week -1) falls outside the required range 
for entry into the study but is 450 mg/dL (5.09 mmol/L) and <500 mg/dL (5.65 mmol/L), an additional TG measurement can be collected 1 week (±3 days) later (Visit 3.1). If Visit 3.1 is required, the TG qualifying 
period will be extended, and Visit 4 will occur 1 week (±3 days) after Visit 3.1. If a third sample is collected, entry into the 12-week Efficacy Period is based on the mean of the values from Visit 2 (Week -2), Visit 3 
(Week -1), and Visit 3.1. 
2. 
The 40-week Extension Period will begin at Week 12 following the completion of Visit 7 (Week 12) study procedures (i.e., end of the Efficacy Period). 
3. 
Visit 1 for patients who require a washout is at Week -8. Visit 1 for patients who do not require a washout is at Week -6. Patients with an eGFR 90 mL/min/1.73 m2 at Visit 1 will proceed to Visit 2. Patients with an 
eGFR <90 mL/min/1.73 m2 but 30 mL/min/1.73 m2 at Visit 1 will be screen failures for this study 
 
. If the Visit 1 eGFR is <30 mL/min/1.73 m2, the patient will be a screen failure. 
4. 
Height is measured at Visit 1 (Week -8 or Week -6) only. 
*footnotes continued on following page 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol  
 
K-877 
18 Aug 2017 v2.0 
Page 11 of 78 
Table 2: 
Clinical Evaluation Schedule (Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
10. All lipid laboratory blood specimens must be obtained under fasting conditions (i.e., after the patient has fasted for at least 10 hours). 
 
 
 
 
13. TLC counseling can be provided by the Investigator or designee (see Section 8.5.1). 
AE = adverse event; Apo = apolipoprotein; eGFR = estimated glomerular filtration rate; ET = Early Termination; FFA = free fatty acid; 
; HbA1c = hemoglobin A1c; HDL-C = high-density 
lipoprotein cholesterol; HOMA-β = homeostasis model assessment for beta-cell function; HOMA-IR = homeostasis model assessment for insulin resistance; ICF = Informed consent form; IRT = Interactive Response 
Technology; LDL-C = low-density lipoprotein cholesterol; 
 NMR = nuclear magnetic resonance; PCSK9 = proprotein convertase subtilisin/kexin type 9; 
PD = pharmacodynamic; PK = pharmacokinetic; QUICKI = quantitative insulin sensitivity check index; 
 TC = total cholesterol; TG = triglycerides; TLC = therapeutic lifestyle changes; Tmax = time to 
maximum plasma concentration; 
 WOCBP = women of childbearing potential. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 12 of 78 
 
PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA 
4.1 
INCLUSION CRITERIA 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Able to understand and willing to comply with all study requirements and 
procedures throughout the duration of the study and give written informed consent; 
2. Aged 18 years; 
3. Patients receiving moderate- or high-intensity statin therapy must meet one of the 
following criteria1 unless they have any exceptional conditions (see inclusion 
criterion 4): 
a. 
Aged 21 years with clinical atherosclerotic cardiovascular disease (ASCVD) 
(history of acute coronary syndrome or myocardial infarction, stable or 
unstable angina, coronary or other arterial revascularization, stroke, transient 
ischemic attack [TIA] presumed to be of atherosclerotic origin, or peripheral 
arterial disease or revascularization), on a high-intensity statin (or 
moderate-intensity statin if not a candidate for high-intensity statin due to 
safety concerns – including, but not limited to, examples in Appendix 
Table B3);  
b. 
Aged 21 years with a history of LDL-C 190 mg/dL, which is not due to 
secondary modifiable causes, on a high-intensity statin (or moderate intensity 
statin if not a candidate for high-intensity statin due to safety 
concerns – including, but not limited to, examples in Appendix Table B3);  
c. 
Aged 40 to 75 years, inclusive, without clinical ASCVD but with diabetes and 
a history of LDL C of 70 to 189 mg/dL, inclusive, on a moderate- or 
high-intensity statin; or  
d. 
Aged 40 to 75 years, inclusive, without clinical ASCVD or diabetes, with a 
history of LDL-C of 70 to 189 mg/dL, inclusive, with estimated 10-year risk 
for ASCVD of 7.5% by the Pooled Cohort Equation (see Appendix C) on a 
moderate- or high-intensity statin;  
4. Patients currently on a low-intensity statin or not on a statin, must meet one of the 
following criteria: 
a. 
Patient does not meet any criteria for moderate- or high-intensity statin 
therapy listed above (see inclusion criteria 3.a. through 3.d.); 
b. 
Patient does meet one or more criteria for moderate- or high-intensity statin 
therapy listed above (see inclusion criteria 3.a. through 3.d.); but the patient 
is not a candidate for moderate- or high-intensity statin due to safety concerns 
(including, but not limited to, examples in Appendix B), or due to partial or 
complete statin intolerance; 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 13 of 78 
c. 
Patient does meet one or more criteria for moderate- or high-intensity statin 
therapy listed above (see inclusion criteria 3.b. through 3.d., except for 3.a.); 
but the patient is not a candidate for moderate- or high-intensity statin for 
primary prevention after considering individual risk evaluation (e.g., current 
LDL-C 70mg/dL) and patient preference (see Appendix B); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 14 of 78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from participation in the 
study: 
1. Patients who will require lipid-altering treatments other than study drugs (K-877 
or fenofibrate), statins, ezetimibe, or PCSK9 inhibitors during the course of the 
study. These include bile acid sequestrants, non-study fibrates, niacin 
(>100 mg/day), omega-3 fatty acids (>1000 mg/day), or any supplements used to 
alter lipid metabolism including, but not limited to, red rice yeast supplements, 
garlic supplements, soy isoflavone supplements, sterol/stanol products, or 
policosanols; 
2. Body mass index (BMI) >45 kg/m2 at Visit 1 (Week -8 or Week -6); 
3. Patients with type 1 diabetes mellitus; 
4. Patients with newly diagnosed (within 3 months prior to Visit 2 [Week -2]) or 
poorly controlled type 2 diabetes mellitus (T2DM), defined as hemoglobin A1c 
(HbA1c) >9.5% at Visit 1 (Week -8 or Week -6); 
 
 
  
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 15 of 78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 16 of 78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 17 of 78 
 
 
 
 
4.3 
STUDY DRUG DISCONTINUATION CRITERIA 
It will be necessary to make a distinction between patients who prematurely discontinue 
study drug treatment and those who withdraw from the study for any reason.  
If the patient discontinues study drug, the reason should be captured and could include the 
following: 
1. The patient requests discontinuation of the study drug; 
2. The patient begins to take any medication(s) that is contraindicated by the protocol; 
3. The patient develops an AE that, in the opinion of the Investigator, would 
compromise the patient’s safety to continue the study drug; 
4. The patient meets any of the criteria specified in Section 4.6;  
5. A female patient becomes pregnant during the study; 
6. In the Investigator’s judgment, it is in the patient’s best interests; or 
7. The patient is unblinded. 
During the 12-week Efficacy Period, patients who discontinue study drug prematurely will 
remain in the study until Visit 7 (Week 12). However, patients who discontinue study drug 
during the 40-week Extension Period will be required to withdraw from the study and 
requested to complete the full panel of assessments scheduled for the Early Termination 
(ET) Visit (see Section 4.4). If a patient who has discontinued study drug fails to attend 
any follow-up appointments, reasonable efforts (telephone calls to family members or 
friends, e-mail contacts, etc.) will be made in order to encourage the patient to complete 
the study visits. 
Although a patient is not obligated to give his/her reason for discontinuing study drug, the 
Investigator will make a reasonable effort to obtain the reason while fully respecting the 
patient’s rights. The reason for discontinuation of study drug must be documented in the 
electronic case report form (eCRF). The Clinical Study Report (CSR) will include the 
reason(s) for discontinuation of study drug. 
Patients will not be allowed to restart the study drug in the event of discontinuation; 
however, study drug may be restarted in cases of study drug interruption due to temporary 
use of prohibited medication(s) and AEs. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 18 of 78 
4.4 
WITHDRAWAL CRITERIA 
The patient has the right to withdraw from the study at any time. Nevertheless, in this study, 
every attempt will be made to prevent missing data and to obtain complete follow-up of all 
patients during the 12-week Efficacy Period. Investigators will be trained to minimize full 
withdrawals from the 12-week Efficacy Period wherever possible. Patients who 
discontinue study drug during the first 12 weeks are not required to withdraw from the 
study. These patients will be encouraged to remain in the study and asked to conduct the 
remaining study visits as outlined in the protocol through Visit 7 (Week 12). At a minimum, 
measurements of lipid parameters at key time points, particularly Visit 7 (Week 12), should 
be taken for all study patients, regardless of adherence to therapy or study protocol. If a 
patient fails to actively maintain contact with the Investigator, reasonable efforts (telephone 
calls to family members or friends, e-mail contacts, etc.) will be made in order to encourage 
the patient to complete the study visits. 
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 of the study 
drug during the 40-week Extension Period; 
2. The patient begins to take any medication(s) during the 40-week Extension Period 
that is prohibited by the protocol; 
3. The patient develops an AE that, in the opinion of the Investigator, would 
compromise the patient’s safety by continuing in the study; 
4. The patient meets any of the criteria specified in Section 4.6 during the 40-week 
Extension Period; 
5. A female patient becomes pregnant during the study; 
6. 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; 
7. In the Investigator’s judgment, it is in the patient’s best interests; 
8. 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;  
9. The patient is unblinded during the 40-week Extension Period; or 
10. 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. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 19 of 78 
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 CSR will include the reason(s) 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 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, other than failing the TG criteria, can be re-screened once 
at a future date if they are then deemed eligible. Before each patient is re-screened, the 
Investigator should discuss the case with the Medical Monitor. It is acceptable to re-test 
only the out-of-range result, with the approval of the Medical Monitor. 
Patients who were screen failures under the previous version of this protocol (Version 1.0) 
can be re-screened once again for this amended protocol (Version 2.0), only if the 
eligibility criteria determining the original screen failure have been revised in this 
amendment (for example, the criteria relating to eGFR, statin treatment, insulin treatment, 
 or blood pressure). 
Patients who are screen failures only due to the eGFR criteria will undergo the following 
procedures: 
 Patients with an eGFR <90 mL/min/1.73 m2 but 30 mL/min/1.73 m2 at Visit 1 will 
be screen failures for this study 
 
 
 and 
 Patients with an eGFR <30 mL/min/1.73 m2, at Visit 1 will be screen failures. 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 20 of 78 
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, 
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 
(INR) >1.5, confirmed on repeat;  
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 at or after Visit 7 (Week 12), confirmed on 
repeat. 
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 at Visit 7 (Week 12) or any subsequent visit, the study site will 
receive an alert from the central laboratory. 
For further details regarding study drug discontinuation for persistent abnormal clinical 
laboratory tests, see Section 5.2.2.  
4.7 
SURVEILLANCE FOR POSSIBLE PANCREATITIS 
Investigators should be vigilant for potential cases of pancreatitis. If a patient experiences 
abdominal pain or unexplained gastrointestinal symptoms (e.g., nausea, vomiting, or 
diarrhea), they should return to the site for an unscheduled visit as soon as possible. A 
history including symptoms, concomitant medication and dietary and alcohol intake, a 
physical examination, and laboratory evaluation of TG, amylase and lipase, as well as any 
other evaluations deemed necessary by the Investigator should be performed and 
documented on the appropriate eCRF. Patients who are diagnosed with pancreatitis; who 
have elevations of amylase or lipase, with or without symptoms; or who have severe 
abdominal pain, or sustained (>7 days), unexplained abdominal pain, even without 
elevations of amylase or lipase should have their cases submitted for adjudication of 
pancreatitis. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 21 of 78 
 
PROCEDURES FOR EFFICACY, SAFETY, AND 
PHARMACOKINETIC EVALUATIONS 
5.1 
EFFICACY EVALUATIONS 
Blood samples for the determination of laboratory analytes for efficacy assessment will be 
collected as specified in Table 2. All visits with laboratory sampling are fasting visits and 
blood specimens must be obtained under fasting conditions (i.e., after the patient has fasted 
[nothing by mouth except water] for at least 10 hours). 
The following parameters will be measured or derived to assess efficacy in this study: 
 Lipid parameters including HDL-C, LDL-C, TC, TG, non-HDL-C, free fatty acids, 
remnant cholesterol (calculated as TC – LDL-C – HDL-C), Apo A1, Apo A2, Apo 
B, Apo B48, Apo B100, Apo C2, Apo C3, Apo E, TG:HDL-C ratio, TC:HDL-C 
ratio, non-HDL-C:HDL-C ratio, LDL-C:Apo B ratio, Apo B:Apo A1 ratio, 
Apo C3:Apo C2 ratio, ion mobility analysis, and lipoprotein fraction (NMR); and 
 Biomarkers and exploratory parameters including FGF21, hsCRP, 
 
 
5.2 
SAFETY EVALUATIONS 
 Adverse Events 
The Investigator will determine at each study visit whether any AEs have occurred since 
the signing of informed consent. The patients will be questioned in a general way and no 
specific symptoms will be suggested. Section 9.0 presents further information with regard 
to AEs. 
 Clinical Laboratory Tests 
Blood and urine samples for the determination of laboratory analytes will be collected as 
specified in 
 
 All standard blood and 
urine tests will be performed by 
 All visits with 
laboratory sampling are fasting visits and blood specimens must be obtained under fasting 
conditions (i.e., after the patient has fasted [nothing by mouth except water] for at least 
10 hours).  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 22 of 78 
The following parameters will be measured or derived at the time points indicated in 
Table 2: 
 Serum chemistry – sodium, chloride, potassium, bicarbonate, calcium, inorganic 
phosphorus, blood urea nitrogen, creatinine, eGFR, uric acid, ALT, AST, alkaline 
phosphatase, gamma-glutamyl transpeptidase, total and direct bilirubin, albumin, 
total protein, lipase, amylase, CK, lactate dehydrogenase, glucose, insulin, HbA1c, 
glycated albumin, homeostatic model assessment for insulin resistance 
(HOMA-IR), homeostatic model assessment for beta-cell function (HOMA-β), 
quantitative insulin sensitivity check index (QUICKI), homocysteine, and alcohol; 
 Hematology – hematocrit, hemoglobin, platelets, red blood cell count, and white 
blood cell count and differential; 
 Coagulation – fibrinogen, activated partial thromboplastin time, INR, and 
prothrombin time;  
 
 
 Urinalysis – bilirubin, blood, glucose, ketones, leukocyte esterase, microscopy (as 
needed based on dipstick results), nitrite, pH, protein, specific gravity, urobilinogen, 
urine albumin, urine creatinine, urine albumin:creatinine ratio, and 
 
 and  
 
 
See Appendix A for a complete list of clinical laboratory analytes to be measured.  
The Investigator or a delegated physician will evaluate all laboratory test results for their 
clinical significance and review, sign, and date all laboratory reports. 
For WOCBP, serum pregnancy tests will be analyzed by 
 at Visit 1 (Week -8 or 
Week -6). 
 will provide urine pregnancy test kits to the 
investigative sites so that sites may conduct urine pregnancy tests at Visit 4 (Day 1), Visit 7 
(Week 12), Visit 9 (Week 28), and Visit 11 (Week 52) or the ET Visit. 
 
Liver Function Test Elevations 
With any of the following liver function test elevations, patients should undergo repeat 
laboratory measurements as soon as possible, preferably within 72 hours (unless otherwise 
specified), and no later than 1 week. Local laboratory measurements may be used to 
facilitate follow-up: 
 
ALT or AST >8 × ULN; 
 
ALT or AST >3 × ULN and bilirubin >2 × ULN or INR >1.5 × ULN; 
 
ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%); and 
 
ALT or AST >5 × ULN, regardless of symptoms should be followed up within 
1 week. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 23 of 78 
Repeat evaluation should include AST, ALT, prothrombin time/INR, total bilirubin, 
alkaline phosphatase, gamma-glutamyltransferase, creatinine, CK, and complete viral 
hepatitis screen. The patient should be questioned regarding symptoms, as well as potential 
causative factors. This information, including results and normal ranges of any laboratory 
parameters collected at a local laboratory, should be collected on the appropriate eCRF. 
Hepatobiliary ultrasonography and/or consultation with a hepatologist should be 
considered if clinically indicated. 
Abnormal laboratory parameters should be followed at least weekly (more frequently as 
clinically indicated) until they have returned to baseline or have stabilized. 
 
Creatine Kinase Elevations 
In the event of a CK elevation >5 × ULN, the patient should return to the site within 1 week 
for evaluation.  
For a CK elevation >10 × ULN, study drug should be interrupted immediately while 
awaiting evaluation.  
Evaluation 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-MB, 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 D for a list of muscle AE definitions. 
Abnormalities should be followed until they have returned to baseline, or the Investigator 
considers them clinically stable. 
 
Triglyceride Elevations 
For alerts due to fasting TG levels >2000 mg/dL (22.60 mmol/L), the patient should return 
to the site within 1 week for clinical and laboratory assessments. Patients should be 
assessed for potential signs or symptoms of pancreatitis (including measurements of serum 
amylase and lipase), and a repeat assessment of fasting TG will be obtained. For patients 
with asymptomatic elevations of TG, compliance with study drug and lifestyle 
recommendations should be assessed and reinforced. Patients should be closely followed 
for the emergence of signs and symptoms of pancreatitis until TG levels are <2000 mg/dL 
(22.60 mmol/L). If 2 consecutive alerts for a patient are sent due to elevated TG levels 
>2000 mg/dL (22.60 mmol/L), the Investigator may contact the Medical Monitor to discuss 
study drug discontinuation and further monitoring. 
To maintain the integrity of the blind, TG values from post-randomization blood samples 
obtained prior to Visit 8 (Week 16), run by the central laboratory, will not be communicated 
to the sites (see Section 6.6). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 24 of 78 
 
Estimated Glomerular Filtration Rate Decrease 
For eGFR <30 mL/min/1.73 m2, the patient should return to the site within 1 week for 
repeat laboratory assessment. Abnormal laboratory parameters should be followed at least 
weekly (more frequently as clinically indicated) until they have returned to baseline or have 
stabilized. 
 Electrocardiogram and Vital Signs 
Twelve-lead ECGs will be performed at Visit 1 (Week -8 or Week -6), Visit 4 (Day 1), 
Visit 7 (Week 12), and Visit 11 (Week 52) or the ET Visit. Site personnel will make every 
attempt to perform a patient’s ECG using the same equipment at each visit. 
Vital signs (heart rate, respiratory rate, and blood pressure) will be assessed at all study 
visits. All blood pressure measurements will be obtained after a 5-minute rest in the sitting 
or supine position with a standard mercury sphygmomanometer or an automated 
oscillometric blood pressure monitor. The blood pressure should be taken in a consistent 
position for each patient throughout the study. Heart rate measurements will be made by 
counting events (heartbeats) for a period of 30 seconds and multiplying this value by 2 to 
obtain the rate per minute. Whenever possible, the same person will do all of the 
assessments for a given patient throughout the study. 
 Physical Examination 
A physical examination will be performed at Visit 1 (Week -8 or Week -6), Visit 4 (Day 1), 
Visit 7 (Week 12), and Visit 11 (Week 52) or the ET Visit. The physical examination will 
consist of an examination of the following body systems: general appearance; eyes, ears, 
nose, and throat; head and neck; chest and lungs; cardiovascular; abdomen; 
musculoskeletal; lymphatic; dermatological; neurological; mental status; and extremities. 
 Demographics and Medical History 
Demographics and brief, relevant medical/social and surgical history, as well as alcohol 
consumption, cigarette smoking, hypertension, diabetes history, and family history of heart 
disease will be taken at Visit 1 (Week -8 or Week -6) and recorded in the eCRF.  
 Body Weight, Height, Body Mass Index, and Waist Circumference 
Body weight, height, and waist circumference will be measured at Visit 1 (Week -8 or 
Week -6). Body weight and height will be used to calculate the BMI. Body weight and 
waist circumference will also be measured at Visit 4 (Day 1), Visit 7 (Week 12), and 
Visit 11 (Week 52) or the ET Visit. Waist circumference will be measured with a tape 
measure. Starting at the top of the hip bone then bringing the tape measure all the way 
around, level with the navel. The tape measure should be snug around the waist, but without 
compressing the skin, and parallel with the floor. Patients should not hold their breath while 
measuring waist circumference. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 25 of 78 
5.3 
PHARMACOKINETIC EVALUATIONS 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 26 of 78 
 
5.4 
DATA MONITORING COMMITTEE 
A data monitoring committee is not planned for this study. 
5.5 
PANCREATITIS ADJUDICATION COMMITTEE 
An external expert Pancreatitis Adjudication Committee (PAC) will blindly adjudicate all 
suspected pancreatitis events reported by Investigators. A PAC Charter will describe the 
operations of the PAC and definitions to be utilized for adjudication. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 27 of 78 
 
CONDUCT OF THE STUDY 
6.1 
STUDY BLINDING AND RANDOMIZATION 
This is a multi-center, placebo-controlled, randomized, double-blind 12-week study with a 
40-week, active-controlled, double-blind extension. Patients will be randomly assigned in 
a 2:1 ratio to treatment with either K-877 0.2 mg twice daily or a matching placebo twice 
daily. An Interactive Response Technology (IRT) system will be used to perform the 
randomization. At Visit 7 (Week 12), patients who were randomized to receive K-877 
0.2 mg twice daily during the 12-week Efficacy Period will continue to receive K-877 
0.2 mg twice daily and will also receive a placebo matching fenofibrate once daily. Patients 
who were randomized to receive placebo during the 12-week Efficacy Period will continue 
to receive placebo matching K-877 twice daily and will also receive fenofibrate 145 mg 
once daily. 
The Investigator or designee must contact the IRT system to register each patient. Patient 
numbers will consist of an 8-digit number and will be assigned based on the pre-printed 
value on the selected central laboratory requisition binder. Patient numbers will be 
composed of a 5-digit site identification (ID) plus a 3-digit patient ID, assigned sequentially 
starting at 101 for the first patient at each site. 
The patient number will be used to identify the patient throughout the study and will be 
entered on all documentation. 
A patient number will not be assigned to more than 1 patient. If a patient is not eligible to 
receive treatment, or should a patient discontinue from the study, the patient number cannot 
be reassigned to another patient. 
At Visit 4 (Day 1), qualified patients who meet all of the inclusion criteria and none of the 
exclusion criteria will receive the randomly assigned treatment. The Investigator or 
designee must contact the IRT system to randomize each patient. Randomization will be 
stratified by country and current statin therapy use (not on statin therapy versus currently 
receiving statin therapy). 
Investigators will be blinded to key results from lipid parameters, such as TG and LDL-C, 
obtained prior to Visit 8 (Week 16), in order to maintain the blind of the treatment 
assignments. Investigators are encouraged not to check lipid panels locally, especially 
during the 12-week Efficacy Period to avoid becoming unblinded. Beginning at Week 16, 
Investigators will receive unblinded lipid data. Investigators will receive an alert for 
TG levels >2000 mg/dL (22.60 mmol/L) at any time during the study. To ensure study 
blinding can be maintained, Investigators may receive a sham alert for TG elevation during 
the 12-week Efficacy Period (see Section 6.6). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 28 of 78 
6.2 
PATIENT INFORMED CONSENT 
Written consent will be obtained from the patient prior to any study-specific procedure or 
investigation. 
Information about the study will be given to the patient both verbally and in writing. The 
written patient information will explain the objectives of the study, its potential risks, and 
benefits and the impact of early withdrawal on the scientific validity of the study. The 
patient must have adequate time to read the information and to ask the Investigator any 
questions. The Investigator must be satisfied that the patient has understood the information 
provided before written consent is obtained. If there is any doubt as to whether the patient 
has understood the written and verbal information, the patient should not enter the study. 
Participating patients will be asked to sign and date an ICF, the original copy of which will 
be kept by the Investigator. A copy of the signed ICF will be given to the patient. A record 
will be made in the source document that the patient voluntarily agreed to participate in the 
study.  
 
 
 
  
6.3 
STUDY VISITS 
The procedures and assessments to be performed at each visit are indicated in Table 2. All 
visits with laboratory sampling are fasting visits and blood specimens must be obtained 
under fasting conditions (i.e., after the patient has fasted [nothing by mouth except water] 
for at least 10 hours). 
A detailed list of procedures to be conducted at each study visit is also described below. 
Visit 1: Screening/Lifestyle Stabilization/Washout Period (Week -8 or Week -6) 
Screening procedures that will be performed at Visit 1 (Week -8 or Week -6) include: 
 Obtain written informed consent; 
 Evaluate inclusion and exclusion criteria; 
 Obtain medical history (including information on prior and concomitant 
medications), surgical history, family history, and demographic information; 
 Assess vital signs, height, weight, and waist circumference; 
 Perform physical examination; 
 Perform 12-lead ECG; 
 Obtain fasting blood sample for the following assessments: 
o 
Serum chemistry (see Appendix A for a complete list of analytes); 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 29 of 78 
o 
Hematology (see Appendix A for a complete list of analytes); 
o 
Coagulation (see Appendix A for a complete list of analytes); 
 
 
 
 
 
o 
Lipid parameters (see Appendix A for a complete list of analytes); 
 
 
 
 
 
o 
Serum pregnancy test for WOCBP; 
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes); 
 
 
 
 
 Instruct the patient to discontinue all lipid-altering medications other than statins, 
ezetimibe, or PCSK9 inhibitors, if applicable; 
 Provide Therapeutic Lifestyle Changes (TLC) counseling (see Section 8.5.1); 
 Contact the IRT system to register the patient’s screening number;  
 Assess and record AEs; and 
 Schedule Visit 2 (4 weeks or 6 weeks ±3 days from Visit 1). 
 
 
  
Visit 2: Triglyceride Qualifying Period (Week -2) 
Procedures that will be performed at Visit 2 (Week -2) include: 
 Evaluate inclusion and exclusion criteria; 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
 Provide TLC counseling (see Section 8.5.1); 
 Assess and record AEs; and 
 Schedule Visit 3 (1 week ±3 days from Visit 2). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 30 of 78 
 
 
 
 
 
 
 
 
Visit 3: Triglyceride Qualifying Period (Week -1) 
Procedures that will be performed at Visit 3 (Week -1) include: 
 Evaluate inclusion and exclusion criteria; 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
 Provide TLC counseling (see Section 8.5.1); 
 Assess and record AEs; and 
 Schedule Visit 4 or Visit 3.1, if applicable (1 week ±3 days from Visit 3). 
Visit 3.1: Optional Triglyceride Qualifying Period (1 Week ±3 Days From Visit 3) 
Patients with a mean TG level 450 mg/dL (5.09 mmol/L) and <500 mg/dL (5.65 mmol/L) 
from Visit 2 (Week -2) and Visit 3 (Week -1) may have a third TG measurement collected 
1 week later at Visit 3.1. Visit 4 (Day 1) will be scheduled for 1 week (±3 days) after 
Visit 3.1. The following procedures will be performed at Visit 3.1: 
 Evaluate inclusion and exclusion criteria; 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
 Provide TLC counseling (see Section 8.5.1); 
 Assess and record AEs; and 
 Schedule Visit 4 (1 week ±3 days from Visit 3.1). 
Visit 4: Randomization (Day 1) 
Procedures that will be performed at Visit 4 (Day 1) include: 
 Evaluate inclusion and exclusion criteria; 
 Record concomitant medication(s); 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 31 of 78 
 Assess vital signs, weight, and waist circumference; 
 Perform 12-lead ECG; 
 Perform physical examination; 
 Obtain fasting blood sample for the following assessments: 
o 
Serum chemistry (see Appendix A for a complete list of analytes); 
o 
Hematology (see Appendix A for a complete list of analytes); 
o 
Coagulation (see Appendix A for a complete list of analytes);  
o 
Lipid parameters (see Appendix A for a complete list of analytes); 
 
 
 
 
 
 
 
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes) 
and urine pregnancy test (WOCBP only); 
 Provide TLC counseling (see Section 8.5.1); 
 Contact the IRT system to randomize the patient if all inclusion and exclusion 
criteria are met and the laboratory results and physical examination findings are 
acceptable; 
 Dispense study drug via the IRT system and provide instructions for proper use; 
 Assess and record AEs; and 
 Schedule Visit 5 (4 weeks ±3 days from Visit 4). 
Visit 5: Efficacy Period (Week 4) 
Procedures that will be performed at Visit 5 (Week 4) include: 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for the following assessments: 
o 
Serum chemistry (see Appendix A for a complete list of analytes); 
o 
Hematology (see Appendix A for a complete list of analytes); 
o 
Coagulation (see Appendix A for a complete list of analytes);  
o 
Lipid parameters (see Appendix A for a complete list of analytes); and 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 32 of 78 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes); 
 Provide TLC counseling (see Section 8.5.1); 
 Dispense study drug via the IRT system and provide instructions for proper use; 
 Collect study drug and assess study drug accountability; 
 Assess and record AEs; and 
 Schedule Visit 6 (8 weeks ±3 days from Visit 4). 
Visit 6: Efficacy Period (Week 8) 
Procedures that will be performed at Visit 6 (Week 8) include: 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
 
 
 
 
 
  
 Provide TLC counseling (see Section 8.5.1); 
 Dispense study drug via the IRT system and provide instructions for proper use; 
 Collect study drug and assess study drug accountability; 
 Assess and record AEs; and 
 Schedule Visit 7 (12 weeks ±3 days from Visit 4). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 33 of 78 
Visit 7: Efficacy Period (Week 12) 
Procedures that will be performed at Visit 7 (Week 12) include: 
 Record concomitant medication(s); 
 Assess vital signs, weight, and waist circumference; 
 Perform 12-lead ECG; 
 Perform physical examination; 
 Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes);  
o Lipid parameters (see Appendix A for a complete list of analytes); 
 
 
 
 
  
 
  
 
 
 
 
 
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes) 
and urine pregnancy test (WOCBP only); 
 Provide TLC counseling (see Section 8.5.1); 
 Dispense study drug via the IRT system and provide instructions for proper use; 
 Collect study drug and assess study drug accountability; 
 Assess and record AEs; and 
 Schedule Visit 8 (16 weeks ±3 days from Visit 4). 
Visit 8: Extension Period (Week 16) 
Procedures that will be performed at Visit 8 (Week 16) include: 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 34 of 78 
o Coagulation (see Appendix A for a complete list of analytes); and 
o Lipid parameters (see Appendix A for a complete list of analytes);  
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes); 
 Provide TLC counseling (see Section 8.5.1); 
 Dispense study drug via the IRT system and provide instructions for proper use; 
 Collect study drug and assess study drug accountability; 
 Assess and record AEs; and 
 Schedule Visit 9 (28 weeks ±7 days from Visit 4). 
Visit 9: Extension Period (Week 28) 
Procedures that will be performed at Visit 9 (Week 28) include: 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes); and 
o Lipid parameters (see Appendix A for a complete list of analytes);  
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes) 
and urine pregnancy test (WOCBP only); 
 Provide TLC counseling (see Section 8.5.1); 
 Dispense study drug via the IRT system and provide instructions for proper use; 
 Collect study drug and assess study drug accountability; 
 Assess and record AEs; and 
 Schedule Visit 10 (40 weeks ±7 days from Visit 4). 
Visit 10: Extension Period (Week 40) 
Procedures that will be performed at Visit 10 (Week 40) include: 
 Record concomitant medication(s); 
 Assess vital signs; 
 Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 35 of 78 
o Coagulation (see Appendix A for a complete list of analytes); and 
o Lipid parameters (see Appendix A for a complete list of analytes);  
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes); 
 Provide TLC counseling (see Section 8.5.1); 
 Dispense study drug via the IRT system and provide instructions for proper use; 
 Collect study drug and assess study drug accountability; 
 Assess and record AEs; and 
 Schedule Visit 11 (52 weeks ±7 days from Visit 4). 
Visit 11: Extension Period (Week 52) or Early Termination Visit 
Procedures that will be performed at Visit 11 (Week 52) include: 
 Record concomitant medication(s); 
 Assess vital signs, weight, and waist circumference; 
 Perform 12-lead ECG; 
 Perform physical examination; 
 Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes);  
o Lipid parameters (see Appendix A for a complete list of analytes);  
 
 
 
 
 
 
 
 Obtain urine sample for urinalysis (see Appendix A for a complete list of analytes) 
and urine pregnancy test (WOCBP only); 
 Provide TLC counseling (see Section 8.5.1); 
 Collect study drug and assess study drug accountability; and 
 Assess and record AEs. 
6.4 
COMPLIANCE WITH THE PROTOCOL 
The Investigator must agree to implement the study protocol as written and adhere to the 
guidelines given in the “Investigator’s Statement,” which will be signed by the Investigator 
prior to the start of the study. The study will be performed in accordance with Declaration 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 36 of 78 
of Helsinki, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, local laws, and other applicable guidance documents. Sites in the United States 
will also comply with the Health Insurance Portability and Accountability Act (HIPAA) 
and Food and Drug Administration (FDA) GCP regulations (21 Code of Federal 
Regulations [CFR] Parts 11, 50, 54, 56, and 312).  
Protocol noncompliance must be reported to 
 and Kowa Research Institute, Inc. 
(KRI). Each deviation and the reason for its occurrence must be documented. Kowa 
Research Institute, Inc. retains the right to require the withdrawal of any patient who 
violates the protocol. 
6.5 
TERMINATION OF THE STUDY 
 Site Termination 
If it becomes apparent that patient enrollment is unsatisfactory with respect to quality or 
quantity, or data recording is inaccurate or incomplete on a chronic basis, KRI has the right 
to terminate the study at an investigational site and remove all study materials from the 
investigational site. A written statement will be provided to the Investigator, the 
Institutional Review Board (IRB)/Ethics Committee (EC), and regulatory authorities, if 
required. In the event of any serious or non-serious AE(s) having occurred at a site, all 
documentation relating to the event(s) must be obtained. 
 Study Termination 
If, in the opinion of KRI, the clinical observations in the study suggest that it may be unwise 
to continue, the study may be terminated. In addition, KRI may terminate the study at any 
time. 
6.6 
LABORATORY ALERT RELATED TO HIGH TRIGLYCERIDES 
Sites will receive an alert for any reported TG level >2000 mg/dL (22.60 mmol/L) during 
the study. In order to maintain the study blind during the placebo-controlled 12-week 
Efficacy Period, sites may receive a sham alert. A sham alert is an alert which will be sent 
to a site for randomly selected patients who do not actually meet the alert criteria for TG 
levels >2000 mg/dL (22.60 mmol/L). These alerts will be programmed to occur in patients 
assigned to K-877, at the expected (low) frequency that they would occur in the placebo 
population, and will be indistinguishable from “true” alerts. Investigators are expected to 
respond to every alert (see Section 5.2.2.3).  
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 37 of 78 
 
INVESTIGATIONAL DRUG 
7.1 
DESCRIPTION OF STUDY DRUGS 
Kowa Research Institute, Inc. will supply sufficient K-877 0.2 mg film-coated tablets and 
matching placebo to allow for completion of the study. The lot numbers of the study drug 
will be recorded in the final study report.  
All K-877 and matching placebo tablets are 
 To 
ensure study blinding can be maintained, each tablet is indistinguishable by size, markings, 
or weight. Each K-877 tablet contains 0.2 mg of K-877; each K-877 and placebo tablet also 
contains the following excipients: 
 
 
 
 
 
Fenofibrate is supplied as a white to off-white bi-convex oblong tablet containing 145 mg 
fenofibrate, as well as the following excipients: anhydrous lactose, croscarmellose sodium, 
hypromellose, magnesium stearate, purified water, simethicone emulsion, sodium lauryl 
sulfate, polyvinyl alcohol, titanium dioxide, talc, soybean lecithin, and xanthan gum. To 
ensure study blinding can be maintained, each tablet will be over-encapsulated and 
backfilled with anhydrous lactose, and matching placebo capsules containing anhydrous 
lactose as a backfill will be manufactured by 
  
7.2 
DRUG PACKAGING 
Drug packaging will be completed by an 
 
  
Study drugs will be packaged in clear polyvinyl chloride/aluminum foil blisters within a 
child-resistant sleeve. Patients will have approximately a 1-month supply of study drug in 
each blister card. Study drug will be labeled in accordance with Section 7.3. Patients will 
receive an adequate supply of study drug at each visit to ensure proper dosing can occur 
until the next scheduled study visit.  
7.3 
DRUG LABELING 
Study drugs will be labeled according to country/state/province specific requirements. For 
example, the label will include the following information: 
 Name and address of Sponsor (i.e., KRI); 
 A study reference code (e.g., protocol number) allowing ID of the investigational 
site and Investigator; 
 Blank space for patient ID; 
 Blank space for site/Investigator ID; 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 38 of 78 
 Route of administration, quantity of dosage units, and pharmacological form as 
appropriate;  
 A code number that will allow appropriate blinded assignment of the correct 
clinical trial material kit via the randomization code; 
 Lot number (as required);  
 Directions for use;  
 The statement “Caution - New Drug - Limited by Federal (United States) Law to 
Investigational Use”; 
 The statement “Keep out of reach of children”;  
 The storage conditions; and 
 Expiration date (as required). 
7.4 
DRUG STORAGE 
K-877 0.2 mg tablets, fenofibrate 145 mg capsules, and matching placebos will be stored 
at controlled room temperatures of 20°C to 25°C (68°F to 77°F) in a secured area with 
access limited to the Investigator and the site staff. The permitted excursion temperature 
range is 15°C to 30°C (59°F to 86°F).  
7.5 
DISPENSING AND ADMINISTRATION OF TREATMENT 
Study drugs will be dispensed to eligible patients beginning at Visit 4 (Day 1) after 
randomization via the IRT system and at Visit 5 (Week 4), Visit 6 (Week 8), Visit 7 
(Week 12), Visit 8 (Week 16), Visit 9 (Week 28), and Visit 10 (Week 40). From Visit 4 
(Day 1) to Visit 6 (Week 8), an approximately 1-month supply of blinded study drug will 
be dispensed to patients at each visit. Each patient will receive 1 blister card of 
K-877 0.2  mg or matching placebo. At Visit 7 (Week 12), an approximately 1-month 
supply of blinded study drug will be dispensed. Each patient will receive 1 blister card of 
K-877 0.2 mg or matching placebo, and 1 blister card of fenofibrate 145 mg or matching 
placebo. From Visit 8 (Week 16) to Visit 10 (Week 40), an approximately 3-month supply 
of blinded study drug will be dispensed at each visit. Each patient will receive 3 blister 
cards of K-877 0.2 mg or matching placebo, and 3 blister cards of fenofibrate 145 mg or 
matching placebo. 
 Drug Administration 
Patients will receive an oral dose of K-877 0.2 mg or matching placebo twice daily starting 
at Visit 4 (Day 1) until Visit 7 (Week 12). Starting at Visit 7 (Week 12), patients will 
receive an oral dose of K-877 0.2 mg twice daily and placebo matching fenofibrate once 
daily, or fenofibrate 145 mg once daily and placebo matching K-877 twice daily. Patients 
may take study drug in a fed or fasted state (before or after meals); however, patients should 
be instructed that fed/fasted state and dosing time should remain consistent for all doses 
throughout the study. Study drug will be dispensed at Visit 4 (Day 1) through Visit 10 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 39 of 78 
(Week 40). Patients will be instructed by the site to follow dosing instructions on the drug 
packaging and to return the remaining study drug at the next visit. 
7.6 
COMPLIANCE WITH PRESCRIBED STUDY DRUG DOSING REGIMEN 
Study drug or placebo will be dispensed in excess of the amount required between study 
visits. Patients will be instructed to return all unused study drug at the next visit. The patient 
will be asked whether there have been any problems with taking the medication, and the 
Investigator will record any significant departure from the dosing instructions (e.g., misuse 
or overdose) as a protocol deviation. A record of the number of tablets/capsules dispensed, 
taken, and returned for each patient must be documented on the Drug Accountability Log 
and eCRF. Compliance will be assessed from information recorded in the eCRF, including 
study drug count and the start and end date of therapy. Patients will be considered 
compliant if they have taken between 80% and 120% of the intended regimen. 
During the treatment period, if compliance is not between 80% and 120%, inclusive, the 
patient will be counseled about the importance of compliance with the regimen. See 
Section 7.5.1 for study drug administration. 
7.7 
DRUG ACCOUNTABILITY 
Sites will be instructed to maintain drug accountability and retain all used, partially used, 
and unused study drug materials until the end of the study. 
7.8 
PROCEDURE FOR UNBLINDING 
As needed, the randomization code may be broken by the Investigator to manage an urgent 
medical event. If possible, the Medical Monitor will be contacted to discuss the case and 
ET assessments will be completed before the code is broken. 
For each patient, the treatment group can be unblinded using the IRT system and the site’s 
Emergency Unblinding IRT Code, provided with the site’s study start-up materials. Using 
the Emergency Unblinding IRT Code, the Investigator or designee will be able to unblind 
a patient by following the instructions on 
 When 
the unblinding is completed, the study’s Medical Monitor, the Clinical Trial Manager, and 
designated KRI personnel will be notified that the unblinding has taken place. 
If it becomes necessary to unblind treatment information during the study, the reason for 
unblinding must be documented in the eCRF. The Investigator must contact the Medical 
Monitor within one business day and explain the reason for the premature unblinding 
(e.g., unblinding due to a serious AE [SAE]). Patients whose treatment assignment is 
unblinded are no longer eligible to receive treatment. Patients unblinded during the 
12-week Efficacy Period should complete the 12-week Efficacy Period. Patients who are 
unblinded in the 40-week Extension Period must be discontinued from the study after ET 
assessments are completed (see Section 6.3). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 40 of 78 
 
CONCOMITANT MEDICATION 
All concomitant medications, both prescribed and over-the-counter, as well as dietary 
supplements, must be recorded in the eCRF. This includes drugs used on a chronic and 
as-needed basis. 
8.1 
GENERAL CONSIDERATIONS 
Patients shall be advised not to start any new medication, either prescribed or 
over-the-counter, without consulting the Investigator, unless the new medication is 
required for emergency use. 
 
 
 
 
 
 
 
 
 
8.3 
PROHIBITED MEDICATION 
The following medications and products (prescription and over-the-counter) must not be 
taken by the patient during the course of the study, except as noted: 
 Insulin or insulin analogues, except for fixed-dose regimens that have been stable 
for 4 weeks prior to Visit 1 (Week -8 or Week -6); 
 All systemic corticosteroids, except for local, topical, inhaled, or nasal 
corticosteroids; 
 Prescription or over-the-counter agents taken for the purpose of weight reduction; 
 Any non-study lipid-lowering treatments except for statins, ezetimibe, and PCSK9 
inhibitors including bile acid sequestrants, fibrates, niacin (>100 mg/day), omega-3 
fatty acids (>1000 mg/day), or any supplements used to alter lipid metabolism 
including but not limited to red rice yeast supplements, garlic supplements, soy 
isoflavone supplements, sterol/stanol products, or policosanols; 
 During the 12-week Efficacy Period, dietary fiber supplements cannot be increased 
or started; or 
 Cyclosporine, rifampin, or other inhibitors of OATP1B1 or OATP1B3 except for 
clarithromycin.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 41 of 78 
8.4 
PERMITTED MEDICATION 
The following frequently prescribed medications are permitted by the protocol, if the 
patient has been on a stable dose for 4 weeks prior to Visit 1 (Week -8 or Week -6) unless 
otherwise noted, and doses should remain stable throughout the duration of the study: 
 Fixed-dose insulin regimens; 
 Oral contraceptives and hormone replacement therapy; 
 Statins, ezetimibe, or PCSK9 inhibitors that have been at a stable dose for 6 weeks 
prior to Visit 1 (Week -8 or Week -6); 
o After completion of the 12-week Efficacy Period (Visit 7 [Week 12]), patients 
not on statins, ezetimibe, or PCSK9 inhibitors may initiate therapy, and 
patients receiving statins, ezetimibe, or PCSK9 inhibitors may alter their 
dose; and  
o Simvastatin 80 mg or Vytorin (ezetimibe/simvastatin) 10/80 mg are permitted 
if tolerated for 6 weeks prior to Visit 1 (Week -8 or Week -6). However, 
simvastatin 80 mg or Vytorin 10/80 mg cannot be started at any point during 
the study; 
 Dietary fiber supplements that are taken as part of the TLC diet during the lifestyle 
stabilization period may be used at a stable dose for the duration of the study. 
Dietary fiber supplements cannot be increased or started during the 12-week 
Efficacy Period; 
 Chronic prescription pharmacotherapy for metabolic or CVD management or risk 
factor modification; 
o During the 40-week Extension Period, patients not on chronic prescription 
pharmacotherapy for metabolic or CVD management (other than statins, 
ezetimibe, or PCSK9 inhibitors) or risk factor modification may initiate 
therapy, and patients receiving therapy may alter their dose, as indicated by 
guidelines or local standard of care; 
 Tamoxifen, estrogens, or progestins that have been at a stable dose for 4 weeks 
prior to the first TG qualifying visit (Visit 2 [Week -2]); 
 Thyroid replacement therapy that has been at a stable dose for 4 weeks prior to 
the first TG qualifying visit (Visit 2 [Week -2]); and 
 Local, topical, inhaled, or nasal corticosteroids. 
Note: Other than the prohibited medications (see Section 8.3), medications needed for 
chronic conditions and AEs are permitted. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 42 of 78 
8.5 
PATIENT RESTRICTIONS 
 Therapeutic Lifestyle Changes 
The Investigator or designee will provide TLC instructions based on the NCEP 
recommendations (see Appendix E) with implementation beginning at Visit 1 (Week -8 or 
Week -6). From Visit 4 (Day 1), the Investigator or designee will instruct patients to stably 
maintain these lifestyle changes. Goals and recommendations on diet, 18 weight loss, 
physical activity, and abstaining from alcohol will be reviewed at all study visits.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 43 of 78 
 
ADVERSE EVENTS 
9.1 
ADVERSE EVENT DEFINITION 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the pharmaceutical 
product. An AE can, therefore, be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not related 
to the medicinal product. Any worsening of the patient’s disease under study or other 
medical conditions will also be considered to be an AE, unless it is within the normal range 
of disease fluctuation for that patient. 
Clinically meaningful (for a given patient) changes in physical examination findings and 
abnormal objective test findings (e.g., clinical laboratory tests, ECGs) will also be recorded 
as AEs. The criteria for determining whether an abnormal objective test finding will be 
reported as an AE are as follows: 
1. Test result is associated with accompanying symptoms, and/or; 
2. Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or; 
3. Test result leads to a change in study drug dosing or discontinuation from the study, 
significant additional concomitant drug treatment or other therapy, and/or; 
4. Test result leads to any of the outcomes included in the definition of an SAE.  
Merely repeating a test, in the absence of any of the above conditions, does not meet 
condition number 2 above for reporting as an AE. 
Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
A treatment-emergent AE (TEAE) is defined as an AE that begins after the start of study 
drug or an event that begins before the start of the study drug and worsens in intensity after 
starting treatment with the study drug. 
9.2 
ADVERSE DRUG REACTIONS 
All noxious and unintended responses to a medicinal product related to any dose will be 
considered adverse drug reactions. The phrase “responses to a medicinal product” means 
that a causal relationship between a medicinal product and the AE is at least a reasonable 
possibility (see Section 9.3). 
9.3 
REPORTING ADVERSE EVENTS 
At each evaluation, the Investigator will determine whether any AEs have occurred. The 
patient will be questioned in a general way and no specific symptoms will be suggested. If 
any AEs have occurred, they will be recorded on the AE pages of the eCRF and in the 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 44 of 78 
patient’s medical record. If known, the diagnosis should be recorded, in preference to the 
listing of individual signs and symptoms. 
Adverse event assessment and reporting begins with the signing of informed consent, and 
occurs at every scheduled study visit through Visit 11 (Week 52), unless an unresolved AE 
is still being followed (see Section 9.4). 
The severity (intensity) of AEs will be classified as follows: 
 
Mild: An AE that is easily tolerated by the patient, causes minimal discomfort, and 
does not interfere with everyday activities;  
 
Moderate: An AE that causes enough discomfort to interfere with normal everyday 
activities and may require intervention; and 
 
Severe: An AE that prevents normal everyday activities;  
o Note: Treatment or intervention will usually be required.  
The Investigator will make a judgment regarding whether or not the AE was related to the 
study drug. The following factors should be considered: 
 
The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from 
study drug exposure to event should be evaluated in the clinical context of the 
event. 
 
Underlying, concomitant, intercurrent diseases- 
o 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 drugs- 
o 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- 
o Clinical and/or preclinical data may indicate whether a particular response is 
likely to be a class effect. 
 
Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the patient and 
provide a logical and better explanation for the event. 
 
The pharmacology and PK of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, 
and excretion) of the study drug should be considered. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 45 of 78 
The relationship of an AE to the administration of the study drug is to be assessed according 
to the following definitions: 
 
Definite: An AE which is consistent with the suspected type of reaction known for 
the drug, in line with the reasonable temporal order after treatment, and is alleviated 
or disappears upon discontinuation of the study drug; 
 
Probable: An AE which is consistent with the suspected type of reaction known for 
the drug, in line with the reasonable temporal order after treatment, alleviates or 
disappears upon discontinuation of the study drug, but could also be caused by the 
clinical conditions of the study patient or other factors;  
 
Possible: An AE which is consistent with the suspected type of reaction known for 
the drug, not in line with the reasonable temporal order after treatment, and could 
also be caused by the clinical conditions of the study patient or other factors;  
 
Improbable: An AE which is inconsistent with the suspected type of reaction known 
for the drug, not in line with the reasonable temporal order after treatment, and 
could also be caused by the clinical conditions of the study patient or other factors; 
and 
 
Not related: An AE which is inconsistent with the suspected type of reaction known 
for the drug, not in line with the reasonable temporal order from administration of 
the study drug, or that can be easily explained by other factors, such as underlying 
diseases, complication, concomitant drugs, and concurrent treatment.  
If the causality assessment for an individual event is “Definite,” “Probable,” or “Possible,” 
the event will be considered a suspected adverse drug reaction.  
The Investigator will evaluate any changes in laboratory values, make a determination as 
to whether or not the change is clinically important, and whether or not the changes were 
related to the study drug. However, even if the Investigator feels there is no relationship to 
the study drug, the AE or laboratory abnormality MUST be recorded in the eCRF. 
The Investigator will record the action taken to treat the AE, if any, the action taken with 
study treatment, and the outcome for each AE in the eCRF according to the following: 
Action taken to treat the AE 
 
None, 
 
Treatment required, 
 
Hospitalization, 
 
Patient withdrawn, or 
 
Other (specify). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 46 of 78 
Action taken with study treatment 
 
Dose not changed, 
 
Drug interrupted, 
 
Drug withdrawn, 
 
Not applicable, or 
 
Unknown. 
Outcome 
 
Resolved: The event has recovered;  
o Note: An SAE/AE stop date should be provided.  
 
Resolved with sequelae: The study patient has recovered as much as may be 
expected but is left with sequelae of the event that are not expected to recover 
further;  
o Note: If the sequelae are severe enough to represent a significant disability or 
incapacity then the event should be reported as an SAE. 
 
Resolving: Can be used in cases where study patient is known to be clearly 
recovering from the event at the end of a study, although the event is not yet 
resolved, and the Investigator and Medical Monitor agree that further follow-up is 
not necessary; 
 
Death: The study patient died as a result of the AE;  
o Note: Death is considered an outcome of an AE rather than an AE in its own 
right, and the cause of death should be recorded as the AE. There may be rare 
circumstances where the cause of death is unknown and the death may have 
to be recorded as the event (e.g., “sudden cardiac death”). Adverse events 
resulting in death are SAEs. 
 
Not resolved: The patient has an AE that has not improved or recuperated at the 
time of the report; or 
o Note: The decision not to continue follow-up should be discussed between 
the Investigator and Medical Monitor and recorded in the source documents. 
 
Unknown: The outcome of the event is genuinely unknown in spite of efforts to 
contact the patient. 
9.4 
FOLLOW-UP OF ADVERSE EVENTS 
If any AEs are present when a patient completes the study, or if a patient is withdrawn from 
the study, the patient will be re-evaluated. At the Investigator’s discretion, clinically minor 
AEs can be re-evaluated via telephone and documented. If the AE is still not resolved, 
additional follow-up will be performed as appropriate. Every effort will be made by the 
Investigator or delegate to contact the patient until the AE is resolved or stabilized, or until 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 47 of 78 
the Medical Monitor and Investigator agree that further follow-up is not necessary. The 
follow-up of AEs will be documented in the patient’s study records. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 48 of 78 
 SERIOUS ADVERSE EVENTS 
An SAE is any untoward medical occurrence that at any dose: 
 
Results in death, 
 
Is life-threatening, 
 
Requires patient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity,  
 
Is a congenital anomaly/birth defect, or 
 
Is an important medical event. 
Medical and scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  
10.1 LIFE-THREATENING ADVERSE EVENT 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it were more severe. 
10.2 HOSPITALIZATION 
OR 
PROLONGATION 
OF 
EXISTING 
HOSPITALIZATION 
Hospitalization is defined as the patient being hospitalized overnight, or the patient’s 
hospital stay being prolonged for at least an additional overnight stay. An emergency room 
visit without hospital admission will not be recorded as an SAE under this criterion, nor 
will hospitalization for a procedure scheduled or planned before the signing of informed 
consent. However, unexpected complications and/or prolongation of hospitalization that 
occur during elective surgery should be recorded as AEs and assessed for seriousness. 
Admission to the hospital for social or situational reasons (i.e., no place to stay, live too far 
away to come for hospital visits) will not be considered inpatient hospitalizations. 
Twenty-three hour hospitalizations for observation should be discussed with the Medical 
Monitor to determine whether they are appropriate for SAE reporting. 
10.3 PREGNANCY 
If a patient becomes pregnant during the study or within 30 days of discontinuing study 
drug, the Investigator will report the pregnancy to 
 within 24 hours 
of being notified (see Section 10.6.1 for contact information). 
 will 
then forward the Exposure In Utero form to the Investigator for completion.  
A patient who becomes pregnant while on study drug will immediately be withdrawn from 
the study and ET study procedures will be performed. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 49 of 78 
The patient will be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator will notify 
 At the completion of the pregnancy, the Investigator will 
document the outcome of the pregnancy. 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 will follow the 
procedures for reporting an SAE (see Section 10.6). 
10.4 
PATIENT WITHDRAWAL 
If a patient experiences an AE that leads to discontinuation of study drug treatment and/or 
withdrawal from the study, the eCRF will identify the AE as the reason for study drug 
discontinuation or withdrawal. 
10.5 
SERIOUS UNEXPECTED SUSPECTED ADVERSE REACTIONS 
According to FDA CFR 312.32(a), FDA Guidance “Safety Reporting Requirements for 
Investigational New Drugs (INDs) and Bioavailability/Bioequivalence (BA/BE) Studies” 
finalized December 2012, European Directives 2001/20/EC and CT-3 Guideline, suspected 
adverse reaction means any AE for which there is a reasonable possibility that the 
medicinal product caused the AE. The phrase “reasonable possibility” means there is 
evidence to suggest a causal relationship between the AE and the medicinal product 
(see Section 9.3). 
The following are examples of types of evidence that would suggest a causal relationship 
between the drug and the AE: 
 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome); or 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug 
(e.g., tendon rupture).  
A suspected adverse reaction is considered “unexpected” if it is not listed in the Reference 
Safety Information in Section 6 of the K-877 Investigator’s Brochure or is not listed at the 
specificity or severity that has been described in the K-877 Investigator’s Brochure or the 
approved package insert of fenofibrate. Study sites will be provided with the current 
version of the fenofibrate package insert. 
The Sponsor will report suspected unexpected serious adverse reactions (SUSARs) to 
Investigators, Competent Authorities, and IRB/ECs in an expedited manner according to 
national requirements. Fatal and life-threatening SUSARs will be reported within 
7 calendar days of Day 0, where Day 0 is defined as the day on which the information 
containing the minimum reporting criteria is received by the Sponsor. All other SUSARs 
will be reported within 15 calendar days of Day 0. All cases will be unblinded for reporting 
purposes, as required.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 50 of 78 
10.6 REPORTING SERIOUS ADVERSE EVENTS, URGENT SAFETY ISSUES, 
AND SERIOUS BREACHES 
 Serious Adverse Events 
 Initial Reports  
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to 
 within 24 hours 
of the knowledge of the occurrence (this refers to any AE that meets any of the 
aforementioned serious criteria). All SAEs that the Investigator considers related to study 
drug occurring after the 30 day follow-up period must be reported to the Sponsor. 
To report the SAE, complete the SAE form electronically in the electronic data capture 
(EDC) system for the study. When the form is completed, 
 will 
be notified electronically 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 
 
 
 and fax the completed paper SAE form to 
 
 within 24 hours of awareness. When the EDC system becomes available, the 
SAE information must be entered within 24 hours. 
Safety Contact Information: 
 
 
 
 
 
 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. Written confirmation that these 
serious, unexpected, and related AEs have been submitted to the IRB/EC must be 
forwarded to KRI and kept in the Investigator files. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 51 of 78 
 Urgent Safety Issues and Serious Breaches of Clinical Trial Regulation 
 or any Investigator become aware of an actual 
or potential urgent safety issue or a serious breach of clinical trial regulations, the Medical 
Monitor and the Sponsor must be immediately contacted so that agreement can be made 
on appropriate urgent safety measures. An urgent safety issue is defined as: 
 
An immediate hazard to the health or safety of study patients participating in a 
clinical trial, or 
 
A serious risk to human health or potentially a serious risk to human health. 
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, intercurrent illness (including pandemic infections), concomitant 
medications, concurrent medical conditions, or any other issues related to the safe conduct 
of the study or that pose a risk to study patients. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, 
 may take urgent safety measures before informing the 
Sponsor, but the Sponsor must be informed immediately after the hazard has been resolved. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 52 of 78 
 STATISTICAL METHODS AND DATA ANALYSIS 
11.1 
SAMPLE SIZE JUSTIFICATION 
Approximately 630 patients with fasting TG levels 500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L) will be randomized in a 2:1 ratio into one of the following 
treatment groups: K-877 0.2 mg twice daily or identical matching placebo twice daily. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2 
ANALYSIS POPULATIONS 
The study population will consist of male and female patients 18 years of age with fasting 
TG levels 500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) after washout 
from background lipid-altering therapy other than statins, ezetimibe, or PCSK9 inhibitors 
and with normal renal function. Stable therapy with statins, ezetimibe, or PCSK9 inhibitors 
will be allowed. The 40-week, active-controlled Extension Period population will consist 
of patients completing the 12-week placebo-controlled Efficacy Period. Patients in the 
40-week, active-controlled Extension Period will be allowed to continue in the study even 
if the background lipid-altering therapy with statins, ezetimibe, or PCSK9 inhibitors 
requires adjustment. 
 Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized patients who take at least 1 dose 
of double-blind study drug and have a baseline TG measurement. The FAS Population is 
the primary analysis population. All efficacy analyses will be performed on the FAS 
Population. 
 Per-Protocol Set 
The Per-Protocol Set will include all FAS patients for the 12-week Efficacy Period who 
complete the 12-week, placebo-controlled Efficacy Period without any major protocol 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 53 of 78 
deviations and have valid baseline and Week 12 fasting serum TG measurements. Major 
protocol deviations will be pre-specified prior to unblinding the study. The Per-Protocol 
Set will be used to assess robustness of the primary analysis results during the 12-week 
Efficacy Period. 
 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. 
 Pharmacokinetic Analysis Set 
The PK Analysis Set will include all patients from the Safety Analysis Set who have at 
least 1 PK sample.  
11.3 
DEMOGRAPHIC/BASELINE INFORMATION 
Summary statistics will be provided by treatment group for demographics (e.g., age, gender, 
race, and ethnicity).  
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either Visit 3 
[Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy and safety 
variables will be defined as Visit 4 (Day 1). If the measurement at this visit is missing, the 
last measurement prior to the first dose of randomized study drug will be used. 
 
 
 
11.4 
STUDY DRUG EXPOSURE, COMPLIANCE, AND CONCOMITANT 
THERAPIES 
Days of exposure to randomized study drug and study drug for the 12-week Efficacy Period 
and the 40-week Extension Period will be summarized with descriptive statistics by 
treatment for the Safety Analysis Set. Exposure in days is defined as the date of last dose 
of study drug minus the date of first dose of study drug plus 1. 
Patient compliance with the study drug will be summarized by treatment group in each 
period. 
Prior/concomitant medications will be coded with Anatomical Therapeutic Chemical 
(ATC) class and preferred term (defined by the most recent version of the World Health 
Organization Drug Dictionary) and summarized by ATC class and preferred term for each 
treatment group for the Safety Analysis Set. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 54 of 78 
11.5 
ANALYSIS OF EFFICACY  
 Hypothesis Testing Procedure 
In order to control the family-wise Type I error at a 0.05 level, a fixed sequential testing 
procedure will be implemented. In a hierarchical step-down manner, the primary endpoint 
will be tested first, followed by secondary endpoints, tested in the following hierarchical 
manner: percent change from baseline to Week 12 in a fixed sequence of (1) remnant 
cholesterol (calculated as TC − LDL-C − HDL-C), (2) HDL-C, (3) Apo A1, and 
(4) non-HDL-C. Each test is planned to be performed at a 0.05 significance level. 
Inferential conclusions about these efficacy endpoints will require statistical significance 
of the previous one. 
For other efficacy endpoints, nominal p-values and 95% confidence intervals (CIs) will be 
presented, but should not be considered as confirmatory. 
 Analysis of Primary Efficacy Parameters 
The primary efficacy analysis will be based on Hodges-Lehmann estimator with 
pattern-mixture model imputation based on the FAS. The pattern-mixture model will be 
used as the primary imputation method as part of the primary analysis for the percent 
change in fasting TGs from baseline to Week 12. This imputation model will include 
factors such as patient demographics, disease status, and baseline TG, as well as adherence 
to therapy. The imputation model will impute missing Week 12 TG values as follows: 
 
For patients who do not adhere to therapy and who do not have a Week 12 
measurement, the missing data imputation method will use patients in the same 
treatment arm who do not adhere to therapy and have a Week 12 measurement; and 
 
If there are no patients in the same treatment arm who do not adhere to therapy and 
have a Week 12 measurement, missing Week 12 TG values will be imputed as 
follows: 
o For the K-877 arm, the treatment effect is considered washed out and baseline 
TG values will be used to impute the Week 12 TG values; and 
o For the placebo arm, missing Week 12 TG values will be imputed assuming 
missing at random, including patient demographics, disease status, and 
baseline and post-baseline efficacy data from the placebo arm.  
After the multiple imputation step, each imputed dataset will be analyzed by the 
nonparametric Hodges-Lehmann method and the Hodges-Lehmann estimator and standard 
error will be combined to produce treatment difference estimate and 95% CI and p-value. 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 55 of 78 
The primary efficacy analysis will be repeated on the Per-Protocol Set. 
Summary statistics (number of patients, mean, standard deviation, median, minimum, 
maximum, 25th percentile, and 75th percentile) at baseline, each scheduled visit, and change 
and percent change in fasting TG from baseline to each scheduled visit will be provided. 
 Analysis of Secondary and Exploratory Efficacy Parameters 
Secondary efficacy endpoints included in the hierarchical step-down testing procedure 
include percent change from baseline to Week 12 in a fixed sequence of (1) remnant 
cholesterol, (2) HDL-C, (3) Apo A1, and (4) non-HDL-C. 
The secondary and exploratory efficacy endpoints during the 12-week Efficacy Period will 
be analyzed using an ANCOVA model with the same imputation method used for the 
primary analysis. The ANCOVA model will include country, current statin therapy use 
(not on statin therapy versus currently receiving statin therapy), and treatment as factors; 
baseline value as a covariate. If the normality assumption is not met, the Hodges-Lehmann 
estimator with the same imputation method used for the primary analysis will be used. 
The secondary efficacy endpoint of percent change in fasting TG from baseline to Week 52 
will be summarized descriptively. 
 
 Other efficacy 
endpoints during the 40-week Extension Period will be summarized descriptively. No 
hypothesis testing will be performed. 
 
 
 
 
 
11.6 
ANALYSIS OF SAFETY DATA 
The safety endpoint data will be summarized for the Safety Analysis Set for the 12-week 
Efficacy Period, 40-week Extension Period, and overall. 
The AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities. A general summary of the AEs and SAEs will be summarized by overall number 
of AEs, severity, and relationship to study drug per treatment group. The number of AEs 
leading to withdrawal and SAEs leading to death will also be summarized. The incidence 
of AEs will be summarized by body system and treatment group. The incidence of TEAEs 
will also be summarized by system organ class and preferred term. 
The safety laboratory data will be summarized by visit and by treatment group, along with 
changes from the baseline. The values that are below the lower limit or above the upper 
limit of the reference range will be flagged. Those values or changes in values that are 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 56 of 78 
identified as being clinically significant will be flagged. Laboratory abnormalities of 
special interest, such as liver function tests and pancreatitis events, will be summarized. 
Vital signs and 12-lead ECGs will also be summarized by visit and by treatment group, 
along with the changes from baseline. 
11.7 
ANALYSIS OF PHARMACOKINETIC DATA 
Population PK and PK/PD data will be analyzed and reported separately. 
 
 
 
 
 
 
 
 
 
11.8 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 57 of 78 
 STUDY MANAGEMENT AND DATA COLLECTION 
12.1 
ETHICAL CONDUCT OF THE TRIAL 
This study will be conducted according to the protocol; FDA GCP, as described in 21 CFR 
Parts 11, 50, 54, 56, and 312 and HIPAA (in the United States) or Directive 2001/20/EC; 
the World Medical Association Declaration of Helsinki; ICH GCP (E6/R1), and the laws 
and regulations of the country where the study is to be conducted. Each Investigator will 
also conduct the study according to applicable local or regional regulatory requirements. 
12.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
The IRB/EC must be constituted according to the applicable state, federal, and local 
requirements of each participating location, and those of the ICH GCP guidance and, in the 
United States, FDA GCP regulations. 
It is the responsibility of each investigational site to submit the protocol, Investigator’s 
Brochure, patient informed consent, patient recruitment materials (if applicable), and other 
required documentation to the IRB/EC for review and approval. Copies of the written 
approvals must be provided to 
 The documentation should clearly mention the 
approval/favorable opinion of the protocol, the patient ICF, and patient recruitment 
materials (if applicable). The respective version dates are to be included. The written 
approvals and a list of the voting members, their titles or occupations, and their institutional 
affiliations must be obtained from the IRB/EC and provided to
 prior to the release 
of clinical study supplies to the investigational site and commencement of the study. If any 
member of the IRB/EC has direct participation in the study, written notification regarding 
his or her abstinence from voting must also be obtained. 
Sites must adhere to all requirements stipulated by the IRB/EC. This includes notification 
to the IRB/EC regarding protocol amendments; updates to the patient informed consent 
and recruitment materials intended for viewing by patients; IND safety reports; serious and 
unexpected AEs; updates regarding the ongoing review of the study at intervals specified 
by the IRB/EC; and final study reports or summaries. 
It is the responsibility of each investigational site to submit information to the appropriate 
IRB/EC for annual review and annual re-approval. 
12.3 
PATIENT INFORMED CONSENT 
Prior to the implementation of study procedures, patients and persons conducting the 
consent discussion will be required to sign and date the IRB/EC-approved ICF, and each 
patient will be given a copy. In addition, this information will be recorded in the patient’s 
medical record (i.e., source document). 
The written consent document will embody the elements of informed consent as described 
in HIPAA, World Medical Association Declaration of Helsinki, FDA 21 CFR Part 50.25, 
ICH GCP, and in accordance with any local regulations. The Investigator is responsible for 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 58 of 78 
the preparation, content, and IRB/EC approval of the ICF. The ICF must be approved by 
the site-designated IRB/EC and be acceptable to KRI and 
 
The ICF must be written in a language fully comprehensible to the prospective patient. The 
Investigator or designee will give the patient adequate opportunity to read it before it is 
signed and dated. Information provided will be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the IRB/EC. Patients must be 
given ample opportunity to inquire about study details. 
12.4 
AMENDMENTS TO THE PROTOCOL 
An amendment must be agreed to in writing by KRI and 
 submitted as an IND 
application amendment in the United States, and submitted to and approved by the 
respective IRB/EC for each investigational site, and an applicable regulatory authority 
before it is implemented. Written approval of a protocol amendment is not required prior 
to implementation for changes to the protocol that eliminate immediate hazard to the 
patient; however, approval must be obtained as soon as possible thereafter. Approved 
amendments must also be signed by the Investigator. 
12.5 
STUDY INITIATION 
The Investigator must not enroll any patients prior to the completion of a formal meeting 
conducted by a representative of 
 or KRI. This meeting will include a detailed 
review of the study protocol and eCRFs. Study drug will not be supplied to an Investigator 
until all the necessary pre-study requirements have been completed and essential signed 
documents are received by 
 and KRI. 
12.6 
STUDY MONITORING 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance 
with the protocol, ICH/FDA GCPs, other applicable regional or local regulatory 
requirements, HIPAA, and the current Declaration of Helsinki. Valid data are to be entered 
into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same 
time, 
 and KRI in the maintenance of accurate, complete, legible, well-organized, 
and easily retrievable data. The monitor will review the protocol with the Investigator. In 
addition, the monitor will explain the Investigator’s reporting responsibilities and all 
applicable regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of KRI and 
 to monitor the study 
as frequently as 
 or KRI deems is necessary to determine that data recording and 
protocol adherence are acceptable. The eCRFs and related source documents will be 
reviewed in detail by the monitor at each visit, in accordance with relevant Standard 
Operating Procedures (SOPs), ICH GCP guidance, and FDA GCP regulations. This 
includes results of tests performed as a requirement for participation in this study and any 
other medical records required to confirm information contained in the eCRFs, such as 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 59 of 78 
medical history and secondary diagnoses. The Investigator and staff will be expected to 
cooperate with the monitor and provide any missing information, whenever possible. 
All monitoring activities will be summarized in a report, which will be filed in the Trial 
Master File. In addition, performance of monitoring visits will be acknowledged at the 
investigational site by the monitor’s signature and date on the study-specific monitoring 
log. 
12.7 
CASE REPORT FORM 
All patient data generated during the study will be recorded on the eCRF. Data will be 
reviewed by the KRI or 
 Clinical Research Associate (CRA) during monitoring 
visits. The CRA will verify the accuracy of data recorded on the eCRF using source 
documents.  
The Investigator will ensure that all data are entered promptly, legibly, and completely, in 
accordance with specific instructions accompanying the eCRFs, which will be designed for 
this study and supplied by 
 for each patient. The Investigator will also ensure that 
all applicable entries agree with the source data. 
 will only consider the eCRFs to be complete after they are reviewed and signed 
by the Investigator, indicating his/her assurance of the accuracy of all recorded data. It is 
expected that the Investigator and staff will cooperate with the monitoring team and 
provide missing data in a timely manner. 
12.8 
VERIFICATION PROCEDURES 
In fulfillment of their obligations to KRI and to verify compliance with this protocol, 
ICH GCP guidance, FDA GCP regulations (in the United States), local regulations, and 
regulations in the countries in which the study is conducted, the Investigator will permit 
 the IRB/EC, the monitor, the auditors, and regulatory authorities to have direct 
access to the patient’s medical records. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the 
patient’s medical record. The patient’s medical record will be considered the source 
document and must include the following information: medical history/concomitant 
disease, patient ID number, confirmation of informed consent and the date of study 
enrollment, visit dates, administration of study drugs, AEs (start and stop dates), and all 
concomitant medications (start and stop dates). This information may not be recorded 
directly into the eCRF. 
The Investigator will maintain a Patient ID Code List to enable unambiguous ID of the 
patients (patient names and corresponding patient numbers).  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 60 of 78 
12.9 
RETENTION OF RECORDS 
All documentation pertaining to the study will be retained by KRI in accordance with 
regulatory requirements and the ICH GCP guidance document. 
will provide each Investigator with a study file, which will be used to file the 
Investigator’s Brochure; protocol; drug accountability records; correspondence with the 
IRB/EC, KRI, and 
 and other study-related documents. 
The Investigator agrees to keep records and those documents that include (but are not 
limited to) the ID of all participating patients, medical records, study-specific source 
documents, source worksheets, all original signed and dated ICFs, copies of all eCRFs, 
query responses, and detailed records of drug disposition, to enable evaluations or audits 
from regulatory authorities and KRI or its designees. 
The Investigator will retain records required to be maintained under federal regulations for 
a period of 2 years following the date a marketing application is approved for the drug for 
the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. However, these documents will be retained for a longer 
period if required by the applicable regulatory requirement(s) or if needed by KRI. In 
addition, the Investigator must make provision for the patient’s medical records to be kept 
for the same period of time. 
Patients’ medical records and other original data will be archived in accordance with 
applicable regulations and requirements established by the investigational sites. 
12.10 INSURANCE AND INDEMNITY 
Kowa Research Institute, Inc.’s obligations regarding insurance and indemnification are 
described in other documents or agreements. 
12.11 AUDIT 
It is the responsibility of 
 and KRI to perform audits (if applicable), as part of 
implementing quality assurance. The purpose of an audit, which is independent of and 
separate from routine monitoring or quality control functions, is to evaluate trial conduct 
and compliance with the protocol, SOPs, ICH/FDA GCPs, HIPAA, and other applicable 
regulatory requirements. The auditor and regulatory authorities will require direct access 
to the patients’ medical records. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 61 of 78 
 USE OF INFORMATION 
13.1 
GENERAL ASPECTS 
All information concerning 
 and KRI, such as patent applications, formula, 
manufacturing processes, basic scientific data or formulation information supplied by KRI 
and not previously published, are considered confidential and will remain the sole property 
of KRI. The Investigator agrees to use this information only in accomplishing this study 
and will not use it for other purposes without the written consent of KRI, except for official 
representatives, such as regulatory authorities. 
It is understood by the Investigator that the information developed in this clinical study, in 
connection with the development of K-877 will be used by KRI and, therefore, may be 
disclosed by KRI as required to other clinical Investigators, other pharmaceutical 
companies, and to other government agencies. In order to allow for the use of the 
information derived from clinical studies, it is understood that there is an obligation to 
provide to KRI complete test results and all data compiled in this study. 
13.2 
PATIENT CONFIDENTIALITY AND DATA PROTECTION 
Kowa Research Institute, Inc. and its designees affirm and uphold the principle of the 
patient’s right to protection against invasion of privacy. Throughout this study, all data will 
be linked to the eCRF via a unique ID number. The data will be blinded correspondingly 
in all data analyses. 
However, in compliance with the guidelines and regulations of the United States FDA 
concerning the acceptance of clinical studies in support of IND applications and the ICH 
GCP (whether performed in the United States or elsewhere), and in fulfillment of its 
obligations to KRI to verify compliance with this protocol, KRI’s designee requires that 
the Investigator permit its monitor, representatives from the FDA, KRI’s designated 
auditors, IRBs/ECs, and other governmental regulatory authorities to review the patient’s 
primary medical records (source data or documents) including, but not limited to laboratory 
test result reports, ECG reports, admission and discharge summaries for hospital 
admissions occurring during a patient’s study participation, and autopsy reports related to 
deaths occurring during the study. 
Should access to such medical records require a waiver or authorization separate from the 
statement of informed consent, the Investigator will obtain such permission in writing from 
the patient before the patient is entered into the study. 
13.3 
FINAL REPORT AND PUBLICATION POLICY 
All information regarding this study will be kept strictly confidential. All data derived from 
the study will be the property of KRI. The Investigator must undertake not to submit any 
part of the data from this study for publication without prior consent of KRI. Kowa 
Research Institute, Inc. may disclose data derived from the study to other Investigators and 
drug regulatory authorities. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 62 of 78 
After completion of the study, and as agreed by the Investigator and KRI, the Investigator 
may send a draft manuscript to KRI to be reviewed in order to reach an agreement regarding 
publication. The Investigator must receive written approval from KRI before the final 
version of the manuscript is submitted for publication. 
At the conclusion of the study, after the data are analyzed, KRI or its designee will prepare 
a final CSR. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 63 of 78 
 REFERENCES


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 64 of 78 
1  Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the 
Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in 
Adults; A Report of the American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines. Circulation. 2014;129:S1-S45. 
2  Miller M, Stone NJ, Ballantyne C, et al. American Heart Association Clinical 
Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, 
Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and 
Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in 
Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific 
statement from the American Heart Association. Circulation. 
2011;123(20):2292-2333. 
3  Scherer J, Singh VP, Pitchumoni CS, Yadav D. Issues in hypertriglyceridemic 
pancreatitis: an update. J Clin Gastroenterol. 2014;48(3):195-203. 
4  Anderson F, Thomson SR, Clarke DL, Buccimazza I. Dyslipidaemic pancreatitis 
clinical assessment and analysis of disease severity and outcomes. Pancreatology. 
2009;9(3):252-257. 
5  Deng LH, Xue P, Xia Q, Yang NX, Wan MH. Effect of admission 
hypertriglyceridemia on the episodes of severe acute pancreatitis. World J 
Gastroenterol. 2008;14(28):4558-4561. 
6  Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. 
Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 
1998;98:2088-2093. 
7  National Institutes of Health, National Heart, Lung, and Blood Institute. 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. 2002;pII-1-61;September 2002. 
8  Pirillo A, Catapano AL. Update on the management of severe hypertriglyceridemia – 
focus on free fatty acid forms of omega-3. Drug Des Devel Ther. 2015;9:2128-2137. 
9  Task Force for the management of dyslipidaemias of the European Society of 
Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS 
Guidelines for the management of dyslipidaemias. Eur Heart J. 2011;32:1769-1818. 
10  Package insert for Lipidil® Tablets, revised in May 2012 (2nd edition). 
11  Package insert for Bezatol® SR Tablets, revised in June 2009 (12th edition). 
12  Package insert for Clofibrate Capsules, revised in July 2009 (6th edition). 
13  Ciprofibrate 100 mg tablets, Summary of Product Characteristics at eMedicines 
Compendium. 
14  Lopid 300 mg capsules and 600 mg tablets, Summary of Product Characteristics at 
eMedicines Compendium. 
15  Package insert for Tricor® tablets, revised in September 2011. 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 65 of 78 
 
16  Package insert for Trilipix® capsule, revised in September 2012. 
17  Package insert for Lopid® tablets, revised in September 2010. 
18  US Department of Health and Human Services; National Institutes of Health; and 
National Heart, Lung and Blood Institute. Your Guide to Lowering Your Cholesterol 
With Therapeutic Lifestyle Changes. NIH Publication. December 2005; No. 06-5235.  
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
18 Aug 2017 v2.0 
Page 66 of 78 
 APPENDICES 
APPENDIX A: CLINICAL LABORATORY PARAMETERS 
Chemistry 
Sodium  
Chloride 
Potassium 
Bicarbonate 
Calcium 
Inorganic phosphorus 
 
Blood urea nitrogen 
Creatinine 
Estimated glomerular filtration rate (eGFR) 
Uric acid 
 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase 
Gamma-glutamyl transpeptidase (GGT) 
Total bilirubin 
Direct bilirubin 
Albumin 
Total protein 
 
Lipase (Visits 1 and 4 only) 
Amylase (Visits 1 and 4 only) 
 
Creatine kinase (CK) 
Lactate dehydrogenase 
 
 
Glucose 
 
Insulin (Visits 4, 7, 9, 10, and 11 only) 
Glycosylated hemoglobin (HbA1c) (Visits 1, 4, 7, 9, 10, and 11 only) 
Glycated albumin (Visits 4, 7, 9, 10, and 11 only) 
Homeostasis model assessment for insulin resistance (Visits 4, 7, 9, 10, and 11 only) 
Homeostasis model assessment for beta-cell function (Visits 4, 7, 9, 10, and 11 only) 
Quantitative insulin sensitivity check index (Visits 4, 7, 9, 10, and 11 only) 
Homocysteine 
 
 
 
 
 
Hematology 
Hematocrit 
 
Hemoglobin 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 67 of 78 
Platelets 
 
Red blood cell count 
 
White blood cell count and differential [1] 
Mean corpuscular hemoglobin 
Mean corpuscular volume 
Mean corpuscular hemoglobin concentration  
 
1. Manual microscopic review is performed only if white blood cell count and/or 
differential values are out of reference range. 
 
Coagulation 
Fibrinogen 
Activated partial thromboplastin time 
 
International Normalized Ratio (INR) 
 
Prothrombin time 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
Bilirubin 
 
Blood 
 
Glucose 
 
Ketones 
 
Leukocyte esterase 
 
Microscopy [1] 
 
Nitrite 
 
pH 
 
Protein 
 
Specific gravity 
 
Urobilinogen 
 
Urine albumin [2] 
 
Urine creatinine [2] 
 
1. Microscopy is performed only as needed based on positive dipstick test 
results. 
2. Urine albumin:creatinine ratio will be derived based on laboratory values 
obtained at that particular visit. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 68 of 78 
  
 
 
 
 
 
  
 
 
 
 
 
 
Pregnancy Test 
Serum (× 1; Visit 1) and urine (× 4; Visits 4, 7, 9, and 11) pregnancy tests will be 
administered to all female patients of childbearing potential. 
 
Lipid Parameters 
The following laboratory tests will be performed to assess efficacy in this study: 
High-density lipoprotein cholesterol (HDL-C) 
Low-density lipoprotein cholesterol (LDL-C) 
Total cholesterol (TC) 
Triglycerides (TG) 
Non-HDL-C 
Free fatty acids (Visits 4, 7, 9, and 11 only) 
Lipoprotein fraction (via nuclear magnetic resonance) (Visits 4, 7, and 11 only) 
Ion mobility analysis (Visits 4, 7, and 11 only) 
Apolipoprotein (Apo) A1 (Visits 4, 5, 7, 9, and 11 only) 
Apo A2 (Visits 4, 5, 7, 9, and 11 only) 
Apo B (Visits 4, 5, 7, 9, and 11 only) 
Apo B48 (Visits 4, 5, 7, 9, and 11 only) 
Apo B100 (Visits 4, 5, 7, 9, and 11 only) 
Apo C2 (Visits 4, 5, 7, 9, and 11 only) 
Apo C3 (Visits 4, 5, 7, 9, and 11 only) 
Apo E (Visits 4, 5, 7, 9, and 11 only) 
The following values will be derived based on laboratory values obtained at that 
particular visit:  
Remnant cholesterol (calculated as TC – LDL-C – HDL-C) 
TG:HDL-C ratio 
TC:HDL-C ratio 
Non-HDL-C:HDL-C ratio 
LDL-C:Apo B ratio 
Apo B:Apo A1 ratio 
Apo C3:Apo C2 ratio 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 69 of 78 
Biomarkers and Exploratory Parameters 
The following laboratory tests will be performed to assess efficacy in this study: 
Fibroblast growth factor 21 (Visits 4, 7, and 11 only) 
High-sensitivity C-reactive protein (Visits 4, 7, and 11 only) 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 70 of 78 
APPENDIX B: ASSESSING STATIN ELIGIBILITY CRITERIA AND 
MONITORING STATIN USE DURING THE STUDY  
Table B1: Recommendations for Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults - Statin Treatment 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
Secondary Prevention 
 
1. High-intensity statin therapy should be initiated or continued as 
first-line therapy in women and men 75 years of age who have 
clinical ASCVD*, unless contraindicated. 
A (Strong) 
I 
A 
2. Individuals with clinical ASCVD* in whom high-intensity statin 
therapy would otherwise be used, when high-intensity statin therapy is 
contraindicated† or when characteristics predisposing to 
statin-associated adverse effects are present, moderate-intensity statin 
should be used as the second option if tolerated. 
A (Strong) 
I 
A 
3. In individuals with clinical ASCVD* >75 years of age, it is reasonable 
to evaluate the potential for ASCVD risk-reduction benefits and for 
adverse effects and drug-drug interactions and to consider patient 
preferences when initiating a moderate- or high-intensity statin. It is 
reasonable to continue statin therapy in those who are tolerating it. 
E (Expert Opinion) 
IIa 
B 
Primary Prevention in Individuals 21 Years of Age with LDL-C 190 mg/dL 
1. Individuals with LDL-C 190 mg/dL or TG 500 mg/dL should be 
evaluated for secondary causes of hyperlipidemia. 
B (Moderate) 
I‡ 
B 
2. Adults 21 years of age with primary LDL-C 190 mg/dL should be 
treated with statin therapy (10-year ASCVD risk estimation is not 
required): 
 Use high-intensity statin therapy unless contraindicated; and  
 For individuals unable to tolerate high-intensity statin therapy, 
use the maximum tolerated statin intensity. 
B (Moderate) 
I§ 
B 
3. For individuals 21 years of age with an untreated primary LDL-C 
190 mg/dL, it is reasonable to intensify statin therapy to achieve at 
least a 50% LDL-C reduction. 
E (Expert Opinion) 
IIa 
B 
4. For individuals 21 years of age with an untreated primary LDL-C of 
190 mg/dL, after the maximum intensity of statin therapy has been 
achieved, addition of a non-statin drug may be considered to further 
lower LDL-C. Evaluate the potential for ASCVD risk-reduction 
benefits, adverse effects, and drug-drug interactions, and consider 
patient preferences. 
E (Expert Opinion) 
IIb 
C 
Primary Prevention in Individuals With Diabetes and LDL-C 70-189 mg/dL 
1. Moderate-intensity statin therapy should be initiated or continued for 
adults 40-75 years of age with diabetes. 
A (Strong) 
I 
A 
2. High-intensity statin therapy is reasonable for adults 40-75 years of age 
with diabetes with a 7.5% estimated 10-year ASCVD‖ risk unless 
contraindicated. 
E (Expert Opinion) 
IIa 
B 
Footnotes are located at the end of the table on a later page. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 71 of 78 
Table B1: Recommendations for Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults - Statin Treatment (Continued) 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
Primary Prevention in Individuals With Diabetes and LDL-C 70-189 mg/dL 
3. In adults with diabetes, who are <40 years of age or >75 years of age, 
or with LDL <70 mg/dL it is reasonable to evaluate the potential for 
ASCVD benefits and for adverse effects and drug-drug interactions 
and to consider patient preferences when deciding to initiate, 
continue, or intensify statin therapy.  
E (Expert Opinion) 
IIa 
C 
Primary Prevention in Individuals Without Diabetes and LDL-C 70-189 mg/dL 
 
1. The Pooled Cohort Equations should be used to estimate 10-year 
ASCVD‖ risk for individuals with LDL-C 70-189 mg/dL without 
clinical ASCVD* to guide initiation of statin therapy for the primary 
prevention of ASCVD. 
E (Expert Opinion) 
I 
B 
2. Adults 40-75 year of age with LDL-C 70-189 mg/dL, without 
clinical ASCVD* or diabetes and with an estimated 10-year ASCVD‖ 
risk of 7.5% should be treated with moderate- to high-intensity 
statin therapy. 
A (Strong) 
I 
A 
3. It is reasonable to offer treatment with a moderate-intensity statin to 
adults 40-75 years of age, with LDL-C 70-189 mg/dL, without 
clinical ASCVD* or diabetes, and with an estimated 10-year 
ASCVD‖ risk of 5 to <7.5%.  
C (Weak) 
IIa 
B 
4. Before initiation of statin therapy for the primary prevention of 
ASCVD in adults with LDL-C 70-189 mg/dL without clinical 
ASCVD* or diabetes, it is reasonable for clinicians and patients to 
engage in a discussion that considers the potential for ASCVD 
risk-reduction benefits and for adverse effects and drug-drug 
interactions, as well as patient preferences for treatment. 
E (Expert Opinion) 
IIa 
C 
5. In adults with LDL-C <190 mg/dL who are not otherwise identified 
in a statin benefit group, or for whom after quantitative risk 
assessment a risk-based treatment decision is uncertain, additional 
factors may be considered to inform treatment decision making. In 
these individuals, statin therapy for primary prevention may be 
considered after evaluation of the potential for ASCVD 
risk-reduction benefits, adverse effects, and drug-drug interactions 
and consider patient preferences.  
E (Expert Opinion) 
IIb 
C 
Footnotes are located at the end of the table on the following page. 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 72 of 78 
Table B1: Recommendations for Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults - Statin Treatment (Continued) 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
*Clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial 
revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin. 
†Contraindications, warnings, and precautions are defined for each statin according to the manufacturer’s prescribing information. 
‡Individuals with secondary causes of hyperlipidemia were excluded from RCTs reviewed. A TG level 500 mg/dL was an exclusion 
criterion for almost all RCTs. Therefore, ruling out secondary causes is necessary to avoid inappropriate statin therapy.  
§No RCTs included only individuals with LDL-C 190 mg/dL. However, many trials did include individuals with 
LDL-C 190 mg/dL, and all of these trials consistently demonstrated a reduction in ASCVD events. In addition, the Cholesterol 
Treatment Trialists meta-analyses have shown that each 39-mg/dL reduction in LDL-C with statin therapy reduced ASCVD events 
by 22%, and the relative reductions in ASCVD events were consistent across the range of LDL-C levels. Therefore, individuals 
with primary LDL-C 190 mg/dL should be treated with stain therapy. 
‖Estimated 10-year or “hard” ASCVD risk includes first occurrence of nonfatal MI, coronary heart disease death, and nonfatal and 
fatal stroke as used by the Risk Assessment Work Group in developing the Pooled Cohort Equations. 
¶These factors may include primary LDL-C 160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature 
ASCVD with onset <55 years of age in a first degree male relative or <65 years of age in a first degree female relative; 
high-sensitivity C-reactive protein 2 mg/L; CAC score 300 Agatston units, or 75th percentile for age, sex, and ethnicity; 
ABI <0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the 
future.  
ABI = ankle-brachial index; ACC = American College of Cardiology; AHA = American Heart Association; 
ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcium; COR = Class of Recommendation; 
LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LOE = Level of Evidence; MI = myocardial 
infarction; NHLBI = National Heart, Lung, and Blood Institute; RCT = randomized controlled trials; TG = triglyceride; TIA = 
transient ischemic attack. 
Source: American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults; Table 4 (2013) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 73 of 78 
Table B2: High-, Moderate-, and Low-Intensity Statin Therapy (Used in the RCTs 
Reviewed by the Expert Panel)* 
High-Intensity Statin Therapy 
Moderate-Intensity Statin Therapy 
Low-Intensity Statin Therapy 
Daily dose lowers LDL-C, on average, 
by approximately 50% 
Daily dose lowers LDL-C, on average, by 
approximately 30% to <50% 
Daily dose lowers LDL-C, on average, 
by approximately <30%  
Atorvastatin (40†)-80 mg 
Atorvastatin 10 (20) mg 
Simvastatin 10 mg 
Rosuvastatin 20 (40) mg 
Rosuvastatin (5) 10 mg 
Pravastatin 10-20 mg 
 
Simvastatin 20-40 mg‡ 
Lovastatin 20 mg 
 
Pravastatin 40 (80) mg 
Fluvastatin 20-40 mg 
 
Lovastatin 40 mg 
Pitavastatin 1 mg 
 
Fluvastatin XL 80 mg 
 
 
Fluvastatin 40 mg BID 
 
 
Pitavastatin 2-4 mg 
 
Boldface type indicates specific statins and doses that were evaluated in RCTs included in CQ1, CQ2, and the Cholesterol 
Treatment Trialists 2010 meta-analysis included in CQ3. All of these RCTs demonstrated a reduction in major cardiovascular 
events.  
Italic type indicates statins and doses that have been approved by the FDA but were not tested in the RCTs reviewed.  
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a 
biological basis for a less-than-average response. 
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the Incremental Decrease through 
Aggressive Lipid Lowering study. 
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by 
the FDA because of the increased risk of myopathy, including rhabdomyolysis.  
BID = twice daily; FDA = Food and Drug Administration; LDL-C = low-density lipoprotein cholesterol; CQ = critical question; 
RCT = randomized controlled trials. 
Source: American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults; Table 5 (2013) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 74 of 78 
Table B3: Characteristics Predisposing Individuals to Statin Adverse Effects 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
Safety 
1. To maximize the safety of statins, selection of the appropriate statin 
and dose in men and nonpregnant/nonnursing women should be based 
on patient characteristics, level of ASCVD* risk, and potential for 
adverse effects. Moderate-intensity statin therapy should be used in 
individuals in whom high-intensity statin therapy would otherwise be 
recommended 
when 
characteristics 
predisposing 
them 
to 
statin-associated adverse effects are present. 
Characteristics predisposing individuals to statin adverse effects 
include but are not limited to: 
 Multiple or serious comorbidities, including impaired renal or 
hepatic function; 
 History of previous statin intolerance or muscle disorders; 
 Unexplained ALT elevations 3 times ULN; 
 Patient characteristics or concomitant use of drugs affecting statin 
metabolism; 
 Age >75 years; and 
 Additional characteristics that could modify the decision to use 
higher statin intensities might include but are not limited to: 
o 
History of hemorrhagic stroke, and  
o 
Asian ancestry. 
A (Strong) 
I 
B 
*Based on the presence of clinical ASCVD, diabetes, LDL-C 190 mg/dL, or level of estimated 10-year ASCVD risk. 
ACC = American College of Cardiology; AHA = American Heart Association; ALT = alanine aminotransferase; 
ASCVD = atherosclerotic cardiovascular disease; COR = Class of Recommendation; NHLBI = National Heart, Lung, and Blood 
Institute; LDL-C = low-density lipoprotein cholesterol; LOE = Level of Evidence; ULN = upper limit of normal. 
Source: American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults; Table 8 (2013) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 75 of 78 
Statin Intolerance 
Statin intolerance occurs when a patient is unable to continue statin therapy due to a 
negative side effect or because creatine kinase (elevations >10 × upper limit of normal 
[ULN]) and/or hepatic transaminases (alanine aminotransferase and aspartate 
aminotransferase; elevations >3 × ULN) are sufficiently abnormal to cause concern for 
muscle and liver function, respectively. Intolerance can be partial (statin-specific and/or 
specific doses) or complete (all statins at any dose).  
Myalgia is the most common presentation of statin intolerance, which can occur in up to 
15% of treated patients. Other common presentations of statin intolerance include 
myopathy and rhabdomyolysis (see Appendix D for muscle event definitions). Table B4 
contains a complete list of potential adverse effects due to statin therapy.  
Table B4: Potential Adverse Effects of Statins 
Adverse Effects for Which There is Good 
Supportive Evidence 
Adverse Effects for Which There is Little or No 
Supportive Evidence 
Myopathy (muscle aches/cramps, myositis, 
rhabdomyolysis) 
Cancer 
Increase in liver function enzymes 
Intracerebral hemorrhage (bleeding stroke) 
New-onset diabetes mellitus 
Cognitive decline (Alzheimer disease) 
 
Lung disease 
 
Erectile dysfunction 
 
Fatigue, headaches, or dizziness 
 
Psychiatric illness 
 
Cataracts 
 
Rheumatoid arthritis 
 
Gastrointestinal upset, abdominal cramping 
 
Permanent liver or kidney damage 
Source: Cardiology Patient Page. Statin Intolerance. Circulation. 2015;131(13)e389-391; Table 2 
 
Statin intolerance will be managed by reducing the dose of statin to the maximum tolerated 
statin intensity per Table B1 and in accordance with the study design (see Section 8.4). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 76 of 78 
APPENDIX C: POOLED COHORT EQUATION 
The Pooled Cohort Equation for estimating atherosclerotic cardiovascular disease 
(ASCVD) risk in qualified patients will be entered using the ASVCD risk estimator and 
recorded in the electronic data capture system (see Figure C1).  
Figure C1: ASCVD Risk Estimator 
 
HDL-Cholesterol = High-density lipoprotein cholesterol. 
Source: American College of Cardiology Atherosclerotic Cardiovascular Disease Risk Estimator: 
http://tools.acc.org/ASCVD-Risk-Estimator/#page_calc  
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 77 of 78 
APPENDIX D: MUSCLE ADVERSE EVENT DEFINITIONS 
Spectrum of Muscle Adverse Events 
 
Myalgia 
Unexplained muscle discomfort often described as “flu-like” symptoms with normal 
creatine kinase (CK) level. The spectrum of myalgia complaints includes: 
Muscle aches, 
Muscle soreness, 
Muscle stiffness, 
Muscle tenderness, and 
Muscle cramps with or shortly after exercise (not nocturnal cramping). 
 
Myopathy 
Muscle weakness (not attributed to pain and not necessarily associated with elevated 
CK). 
 
Myositis 
Muscle inflammation. 
 
Myonecrosis 
Muscle enzyme elevations or hyperCKemia. 
o 
Mild = >3-fold upper limit of normal. 
o 
Moderate = 10-fold upper limit of normal. 
o 
Severe = 50-fold upper limit of normal. 
 
Myonecrosis with myoglobinuria or acute renal failure (increase in serum creatinine 0.5 mg/dL 
(clinical rhabdomyolysis). 
CK = Creatine kinase. 
Source: Adapted from the National Lipid Association Task Force on Statin Safety – 2014 Update 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
18 Aug 2017 v2.0 
Page 78 of 78 
APPENDIX E: THERAPEUTIC LIFESTYLE CHANGES (TLC) 
Table E1: Summary of Lifestyle Management 
Lifestyle  
Recommended Management [1,2] 
Diet 
Maintenance of the diet outlined in Table E2 
Physical activity 
Encourage 30 minutes of moderate exercise on most, if not all, days  
Smoking  
Support cessation from using tobacco products or e-cigarettes 
Alcohol consumption 
Support abstinence from use of alcohol 
Weight management 
Provide support to patients to maintain or attain a healthy weight 
1. At each study visit, patients will be counseled on the importance of maintaining the lifestyle management 
guidelines (see Section 8.5.1). 
2. From Visit 4 (Day 1), the Investigator or designee will instruct patients to stably maintain these lifestyle changes. 
Source: National Institutes of Health, National Heart, Lung, and Blood Institute (2002)7 
 
 
Table E2: Summary of the TLC Diet for High Cholesterol 
TLC Diet for High Cholesterol 
Total fat 
25% - 35% total calories [1] 
Saturated fat 
<7% total calories 
Polyunsaturated fat 
up to 10% total calories 
Monounsaturated fat 
up to 20% total calories 
Carbohydrates 
50% - 60% total calories 
Protein 
~15% total calories 
Cholesterol 
<200 mg/dL 
Plant sterols 
2 g 
Soluble fiber such as psyllium 
10 g - 25 g 
1. For subjects with triglycerides >1000 mg/dL, it is recommended that <15% of total calories 
come from total fat. 
TLC = Therapeutic Lifestyle Changes. 
Source: National Heart, Lung, and Blood Institute (2005)18  
 
 

Prot_000.pdf: 
CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877
 
13 Sep 2016 v1.0  
i11 
 
 
CONFIDENTIAL 
 
A Phase 3, Multi-Center, Placebo-Controlled, Randomized, 
Double-Blind, 12-Week Study With a 40-Week, Active-Controlled, 
Double-Blind Extension to Evaluate the Efficacy and Safety of K-877 in 
Adult Patients With Fasting Triglyceride Levels ≥500 mg/dL and 
<2000 mg/dL and Normal Renal Function 
Clinical Study Protocol 
Drug Name:  
K-877 
Study Number: 
K-877-301 
U.S. IND Number: 
109388 
EudraCT Number: 
2015-003511-37 
Protocol Version Date: 
13 Sep 2016 
Version Number: 
1.0 
Name of Sponsor: 
Kowa Research Institute, Inc.  
Address: 
430 Davis Drive, Suite 200 
Morrisville, NC 27560 
United States of America 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
ii11 
 
 
INVESTIGATOR’S STATEMENT 
I, the Investigator, understand that all information concerning the product supplied to me 
by Kowa Research Institute, Inc. (KRI) and 
 in connection with 
this study and not previously published is confidential information. This information 
includes the Investigator’s Brochure, protocol, case report forms, assay methods, 
technical methodology, and basic scientific data. 
I understand that any changes to the protocol must be approved in writing by KRI, 
, and the Institutional Review Board/Ethics Committee (IRB/EC) before 
implementation, except where necessary to eliminate apparent immediate hazards to the 
patients. 
I confirm that I will report all adverse events (AEs) following the regulations indicated in 
the protocol. 
I confirm that I will conduct this study in conformance with the principles of the 
Declaration of Helsinki, Health Insurance Portability and Accountability Act (HIPAA), 
Food and Drug Administration (FDA) Good Clinical Practice (GCP), regulations (Code 
of Federal Regulations [CFR] Title 21 Parts 11, 50, 54, 56, and 312), International 
Council for Harmonisation (ICH) Guideline for GCP (E6/R1), local laws, and the laws 
and regulations of the country where the study is to be conducted. 
I confirm that I am informed of the need for record retention and that no data can be 
destroyed. 
By my signature below, I hereby attest that I have read, understood, and agree to abide by 
all conditions, instructions, and restrictions contained in this version of the protocol dated 
13 September 2016. 
 
Investigator’s Signature: 
 
Date:  
 
 
 
 
mm/dd/yyyy 
Printed Name: 
 
 
 
 
 
 
 
 




CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
iv11 
 
PROTOCOL SYNOPSIS 
 
Name of Sponsor Company: 
Kowa Research Institute, Inc.  
Drug Under Study: 
K-877 
Title of Protocol: 
A Phase 3, Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With a 
40-Week, Active-Controlled, Double-Blind Extension to Evaluate the Efficacy and Safety of K-877 in 
Adult Patients With Fasting Triglyceride Levels ≥500 mg/dL and <2000 mg/dL and Normal Renal 
Function 
Protocol Number: 
K-877-301 
Phase: 
3 
Indication: 
Dyslipidemia 
Study Design: 
Study K-877-301 is a Phase 3, multi-center, randomized, double-blind study to confirm the efficacy and 
safety of K-877 0.2 mg twice daily compared to matching placebo (in the 12-week Efficacy Period) and 
an active comparator, fenofibrate (in the 40-week Extension Period), in patients with fasting triglyceride 
(TG) levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) and normal renal function. 
Eligible patients will enter a 4- to 6-week lifestyle stabilization period (4-week stabilization for patients 
not requiring washout and 6-week washout and stabilization for patients on lipid-altering therapy other 
than statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors). The 
stabilization period will be followed by a 2-week TG qualifying period (Visits 2 [Week -2] and 
3 [Week -1]), and patient eligibility will be assessed based on the mean TG value from these 2 visits. If 
the patient’s mean TG level during the TG qualifying period is ≥450 mg/dL (5.09 mmol/L) and 
<500 mg/dL (5.65 mmol/L), an additional TG measurement can be taken 1 week later at Visit 3.1. The 
mean of all 3 TG measurements will be used to determine eligibility for the study. After confirmation of 
qualifying fasting TG values, eligible patients will enter a 12-week, randomized, double-blind Efficacy 
Period. At Visit 4 (Day 1), patients will be randomly assigned in a 2:1 ratio to K-877 0.2 mg twice daily 
or identical matching placebo tablets twice daily. During the 12-week Efficacy Period, patients will return 
to the site at Visit 5 (Week 4), Visit 6 (Week 8), and Visit 7 (Week 12) for efficacy and safety 
evaluations. 
Patients who successfully complete the 12-week Efficacy Period are eligible to continue in a 40-week, 
double-blind, active-controlled Extension Period after completing the Visit 7 (Week 12) procedures. 
Patients randomized to receive K-877 0.2 mg twice daily in the 12-week Efficacy Period will continue to 
receive K-877 0.2 mg twice daily, as well as placebo matching fenofibrate 145 mg once daily, in the 
40-week Extension Period. Patients randomized to receive placebo matching K-877 0.2 mg twice daily in 
the 12-week Efficacy Period will receive fenofibrate 145 mg once daily and placebo matching 
K-877 0.2 mg twice daily in the 40-week Extension Period. 
From Visit 7 (Week 12), patients not on statins, ezetimibe, or PCSK9 inhibitors may initiate therapy, and 
patients receiving statins, ezetimibe, or PCSK9 inhibitors may alter their dose, as indicated by guidelines 
or local standard of care. 
After Visit 8 (Week 16), patients are to return to the site every 12 weeks until the last visit (Visit 11 
[Week 52]). 
Primary Objective: 
The primary objective of the study is to demonstrate the efficacy of K-877 0.2 mg twice daily compared 
to placebo from baseline to Week 12 in lowering fasting TG levels in patients with fasting TG levels 
≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
v11 
 
Secondary Objectives: 
The secondary objectives of the study are the following: 
• 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 52 in lowering 
fasting TG levels in patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L);  
• 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 12 and Week 52 in 
altering lipid parameters in patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L);  
• 
To evaluate the safety and tolerability of K-877 0.2 mg twice daily in patients with fasting 
TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L); and 
• 
To determine the plasma concentrations of K-877 for the purpose of use in population 
pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) analysis. 
Exploratory Objective: 
 
 
Patient Population: 
The study population will consist of male and female patients ≥18 years of age with fasting TG levels 
≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) after washout from lipid-altering therapy 
other than statins, ezetimibe, or PCSK9 inhibitors and with normal renal function. Stable therapy with 
statins, ezetimibe, or PCSK9 inhibitors will be allowed. The 40-week, active-controlled Extension Period 
population will consist of patients completing the 12-week placebo-controlled Efficacy Period. Patients in 
the 40-week, active-controlled Extension Period will be allowed to continue in the study even if the 
background lipid-altering therapy with statins, ezetimibe, or PCSK9 inhibitors requires adjustment. 
Number of Patients: 
Approximately 630 patients (420 patients receiving 
K-877; 210 patients receiving placebo/fenofibrate) 
Number of Centers: 
Approximately 160 sites globally 
Dose Levels: 
12-week Efficacy Period 
• K-877: 0.2 mg twice daily  
• Placebo: twice daily 
40-week Extension Period 
• K-877: 0.2 mg twice daily/fenofibrate matching 
placebo: once daily 
• Fenofibrate: 145 mg once daily/K-877 matching 
placebo: twice daily 
Route of Administration: 
Oral 
Duration of Treatment: 
This study consists of a 12-week, double-blind, placebo-controlled Efficacy Period, followed by a 
40-week, double-blind, active-controlled Extension Period, for a total of 52 weeks on study drug. 
Criteria for Evaluation: 
Efficacy: 
The primary efficacy endpoint is the percent change in fasting TG from baseline to Week 12. Baseline for 
TG will be defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either Visit 3 
[Week -1] or Visit 3.1, if required) measurements.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
vi11 
 
The secondary efficacy endpoints for the 12-week Efficacy Period include the following: 
• 
Percent change from baseline to Week 12 in remnant cholesterol (calculated as total cholesterol 
[TC] – low-density lipoprotein C [LDL-C] – high-density lipoprotein C [HDL-C]), HDL-C, 
apolipoprotein (Apo) A1, and non-HDL-C; 
o 
Low-density lipoprotein cholesterol will be determined by preparative ultracentrifugation; 
• 
Percent change from baseline to Week 12 in TC, LDL-C, free fatty acids (FFAs), Apo A2, 
Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; 
• 
Change from baseline to Week 12 in fibroblast growth factor 21 (FGF21) and high-sensitivity 
C-reactive protein (hsCRP), and percent change from baseline to Week 12 in ion mobility 
analysis and lipoprotein fraction (nuclear magnetic resonance [NMR]); and  
• 
Percent change from baseline to Week 12 in the lipid and lipoprotein ratios of TG:HDL-C, 
TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and Apo C3:Apo C2. 
The secondary efficacy endpoints for the 40-week Extension Period include the following: 
• 
Percent change from baseline to Week 52 in fasting TG; 
• 
Percent change from baseline to Week 52 in remnant cholesterol (calculated as 
TC − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o 
Low-density lipoprotein cholesterol will be determined by preparative ultracentrifugation; 
• 
Percent change from baseline to Week 52 in TC, LDL-C, FFAs, Apo A2, Apo B, Apo B48, 
Apo B100, Apo C2, Apo C3, and Apo E; 
• 
Change from baseline to Week 52 in FGF21 and hsCRP, and percent change from baseline to 
Week 52 in ion mobility analysis and lipoprotein fraction (NMR); and  
• 
Percent change from baseline to Week 52 in the lipid and lipoprotein ratios of TG:HDL-C, 
TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, and Apo C3:Apo C2. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be defined as the mean 
of Visit 4 (Day 1) and the preceding TG qualifying visit (either Visit 3 [Week -1] or Visit 3.1, if required) 
measurements. Baseline for all other efficacy and safety variables will be defined as Visit 4 (Day 1). If the 
measurement at this visit is missing, the last measurement prior to the first dose of randomized study drug 
will be used.  
 
 
 
 
 
 
 
 
 
 
 
Safety: 
Safety assessments include adverse events (AEs), clinical laboratory measurements (chemistry, 
hematology, coagulation profile, 
 and urinalysis), 12-lead electrocardiograms (ECGs), vital 
signs (heart rate, respiratory rate, and blood pressure), and physical examinations. 
Pharmacokinetics/Pharmacodynamics: 
Pharmacokinetic concentrations collected during the 12-week Efficacy Period will be used for population 
PK analysis and PK/PD analysis. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
vii11 
 
Criteria for Inclusion:  
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Able to understand and willing to comply with all study requirements and procedures throughout 
the duration of the study and give written informed consent; 
2. Aged ≥18 years; 
3. Patients receiving statin therapy must meet one of the following criteria1: 
o 
Aged ≥21 years with clinical atherosclerotic cardiovascular disease (ASCVD) (history of 
acute coronary syndrome or myocardial infarction, stable or unstable angina, coronary 
revascularization, stroke, transient ischemic attack [TIA] presumed to be of atherosclerotic 
origin, or peripheral arterial disease or revascularization), on a high-intensity statin (or 
moderate-intensity statin if not a candidate for high-intensity statin due to safety concerns); 
o 
Aged ≥21 years with a history of LDL-C ≥190 mg/dL, which is not due to secondary 
modifiable causes, on a high-intensity statin (or moderate-intensity statin if not a candidate 
for high-intensity statin due to safety concerns); 
o 
Aged 40 to 75 years, inclusive, without clinical ASCVD but with diabetes and a history of 
LDL-C of 70 to 189 mg/dL, inclusive, on a moderate- or high-intensity statin; or 
o 
Aged 40 to 75 years, inclusive, without clinical ASCVD or diabetes, with a history of 
LDL-C of 70 to 189 mg/dL, inclusive, with estimated 10-year risk for ASCVD of ≥7.5% by 
the Pooled Cohort Equation on a moderate- or high-intensity statin; 
4. Patients not currently on statins, must not meet the criteria for statin therapy listed above (see 
inclusion criterion 3); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
viii11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criteria for Exclusion: 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Patients who will require lipid-altering treatments other than study drugs (K-877 or fenofibrate), 
statins, ezetimibe, or PCSK9 inhibitors during the course of the study. These include bile acid 
sequestrants, non-study fibrates, niacin (>100 mg/day), omega-3 fatty acids (>1000 mg/day), or 
any supplements used to alter lipid metabolism including, but not limited to, red rice yeast 
supplements, garlic supplements, soy isoflavone supplements, sterol/stanol products, or 
policosanols; 
2. Body mass index (BMI) >45 kg/m2 at Visit 1 (Week -8 or Week -6); 
3. Patients with type 1 diabetes mellitus; 
4. Patients with newly diagnosed (within 3 months prior to Visit 2 [Week -2]) or poorly controlled 
type 2 diabetes mellitus (T2DM), defined as hemoglobin A1c >9.5% at Visit 1 (Week -8 or 
Week -6); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
ix11 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
Sample Size Justification: 
Approximately 630 patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L) will be randomized in a 2:1 ratio into one of the following treatment groups: 
K-877 0.2 mg twice daily or identical matching placebo twice daily. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
x11 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis: 
Efficacy: 
In order to control the family-wise Type I error at a 0.05 level, a fixed sequential testing procedure will be 
implemented. In a hierarchical step-down manner, the primary endpoint will be tested first, followed by 
secondary endpoints, tested in the following hierarchical manner: percent change from baseline to 
Week 12 in a fixed sequence of (1) remnant cholesterol (calculated as TC − LDL-C − HDL-C), 
(2) HDL-C, (3) Apo A1, and (4) non-HDL-C. Each test is planned to be performed at a 0.05 significance 
level. Inferential conclusions about these efficacy endpoints will require statistical significance of the 
previous one. 
For other efficacy endpoints, nominal p-values and 95% confidence intervals (CIs) will be presented, but 
should not be considered as confirmatory. 
The primary efficacy analysis will be based on Hodges-Lehmann estimator with pattern-mixture model 
imputation based on the Full Analysis Set (FAS). The pattern-mixture model will be used as the primary 
imputation method as part of the primary analysis for the percent change in fasting TGs from baseline to 
Week 12. This imputation model will include factors such as patient demographics, disease status, and 
baseline TG, as well as adherence to therapy. The imputation model will impute missing Week 12 TG 
values as follows: 
• 
For patients who do not adhere to therapy and who do not have a Week 12 measurement, the 
missing data imputation method will use patients in the same treatment arm who do not adhere to 
therapy and have a Week 12 measurement; and  
• 
If there are no patients in the same treatment arm who do not adhere to therapy and have a 
Week 12 measurement, missing Week 12 TG values will be imputed as follows: 
o 
For the K-877 arm, the treatment effect is considered washed out and baseline TG values 
will be used to impute the Week 12 TG values; and  
o 
For the placebo arm, missing Week 12 TG values will be imputed assuming missing at 
random, including patient demographics, disease status, and baseline and post-baseline 
efficacy data from the placebo arm.  
After the multiple imputation step, each imputed dataset will be analyzed by the nonparametric 
Hodges-Lehmann method and the Hodges-Lehmann estimator and standard error will be combined to 
produce treatment difference estimate and 95% CI and p-value. 
 
 
 
 
 
 
The primary efficacy analysis will be repeated on the Per-Protocol Set. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
xi11 
 
Summary statistics (number of patients, mean, standard deviation, median, minimum, maximum, 
25th percentile, and 75th percentile) at baseline, each scheduled visit, and change and percent change in 
fasting TG from baseline to each scheduled visit will be provided. 
Secondary efficacy endpoints included in the hierarchical step-down testing procedure include percent 
change from baseline to Week 12 in a fixed sequence of (1) remnant cholesterol, (2) HDL-C, (3) Apo A1, 
and (4) non-HDL-C. 
The secondary and exploratory efficacy endpoints during the 12-week Efficacy Period will be analyzed 
using an ANCOVA model with the same imputation method used for the primary analysis. The 
ANCOVA model will include country, current statin therapy use (not on statin therapy versus currently 
receiving statin therapy), and treatment as factors; baseline value as a covariate. If the normality 
assumption is not met, the Hodges-Lehmann estimator with the same imputation method used for the 
primary analysis will be used. 
The secondary efficacy endpoint of percent change in fasting TG from baseline to Week 52 will be 
summarized descriptively.
 
 Other efficacy endpoints during the 40-week 
Extension Period will be summarized descriptively. No hypothesis testing will be performed. 
 
 
 
Safety: 
The safety endpoint data will be summarized for the Safety Analysis Set for the 12-week Efficacy Period, 
40-week Extension Period, and overall. 
The AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities. A 
general summary of the AEs and serious AEs (SAEs) will be summarized by overall number of AEs, 
severity, and relationship to study drug per treatment group. The number of AEs leading to withdrawal 
and SAEs leading to death will also be summarized. The incidence of AEs will be summarized by body 
system and treatment group. The incidence of treatment-emergent AEs will also be summarized by 
system organ class and preferred term. 
The safety laboratory data will be summarized by visit and by treatment group, along with changes from 
the baseline. The values that are below the lower limit or above the upper limit of the reference range will 
be flagged. Those values or changes in values that are identified as being clinically significant will be 
flagged. Laboratory abnormalities of special interest, such as liver function tests and pancreatitis events, 
will be summarized. 
Vital signs and 12-lead ECGs will also be summarized by visit and by treatment group, along with the 
changes from baseline. 
Pharmacokinetics: 
Population PK and PK/PD data will be analyzed and reported separately. 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
xii6 
 
TABLE OF CONTENTS 
INVESTIGATOR’S STATEMENT ............................................................................................. ii 
SIGNATURE PAGE ..................................................................................................................... iii 
PROTOCOL SYNOPSIS ............................................................................................................. iv 
TABLE OF CONTENTS ............................................................................................................ xii 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. xv 
 
INTRODUCTION AND RATIONALE FOR DOSE SELECTION ............................ 1 
1.1 
BACKGROUND INFORMATION ................................................................................... 1 
1.2 
RATIONALE ...................................................................................................................... 1 
 
STUDY OBJECTIVES ..................................................................................................... 5 
2.1 
PRIMARY OBJECTIVE .................................................................................................... 5 
2.2 
SECONDARY OBJECTIVES............................................................................................ 5 
2.3 
EXPLORATORY OBJECTIVE ......................................................................................... 5 
2.4 
PRIMARY EFFICACY ENDPOINT ................................................................................. 5 
2.5 
SECONDARY EFFICACY ENDPOINTS ......................................................................... 6 
2.6 
EXPLORATORY EFFICACY ENDPOINTS .................................................................... 7 
2.7 
SAFETY ENDPOINTS ...................................................................................................... 7 
2.8 
PHARMACOKINETIC/PHARMACODYNAMIC ENDPOINTS .................................... 7 
 
STUDY DESCRIPTION .................................................................................................. 8 
3.1 
STUDY DESIGN ............................................................................................................... 8 
 
PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA ................................. 12 
4.1 
INCLUSION CRITERIA ................................................................................................. 12 
4.2 
EXCLUSION CRITERIA ................................................................................................ 14 
4.3 
STUDY DRUG DISCONTINUATION CRITERIA ........................................................ 16 
4.4 
WITHDRAWAL CRITERIA ........................................................................................... 17 
4.5 
RE-SCREENING OF SCREEN FAILURES ................................................................... 19 
4.6 
STUDY DRUG DISCONTINUATION FOR PERSISTENT ABNORMAL CLINICAL 
LABORATORY VALUES .............................................................................................. 19 
4.7 
SURVEILLANCE FOR POSSIBLE PANCREATITIS ................................................... 20 
 
PROCEDURES FOR EFFICACY, SAFETY, AND PHARMACOKINETIC 
EVALUATIONS ............................................................................................................. 21 
5.1 
EFFICACY EVALUATIONS .......................................................................................... 21 
5.2 
SAFETY EVALUATIONS .............................................................................................. 21 
 
Adverse Events ................................................................................................................. 21 
 
Clinical Laboratory Tests .................................................................................................. 21 
  Liver Function Test Elevations ......................................................................................... 22 
  Creatine Kinase Elevations ............................................................................................... 23 
  Triglyceride Elevations ..................................................................................................... 23 
  Estimated Glomerular Filtration Rate Decrease ............................................................... 24 
 
Electrocardiogram and Vital Signs ................................................................................... 24 
 
Physical Examination ....................................................................................................... 24 
 
Demographics and Medical History ................................................................................. 24 
 
Body Weight, Height, Body Mass Index, and Waist Circumference ............................... 24 
5.3 
PHARMACOKINETIC EVALUATIONS ....................................................................... 25 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
xiii6 
 
 
 
5.4 
DATA MONITORING COMMITTEE ............................................................................ 26 
5.5 
PANCREATITIS ADJUDICATION COMMITTEE ....................................................... 26 
 
CONDUCT OF THE STUDY ........................................................................................ 27 
6.1 
STUDY BLINDING AND RANDOMIZATION ............................................................ 27 
6.2 
PATIENT INFORMED CONSENT ................................................................................. 28 
6.3 
STUDY VISITS ................................................................................................................ 28 
6.4 
COMPLIANCE WITH THE PROTOCOL ...................................................................... 35 
6.5 
TERMINATION OF THE STUDY .................................................................................. 36 
 
Site Termination ............................................................................................................... 36 
 
Study Termination ............................................................................................................ 36 
6.6 
LABORATORY ALERT RELATED TO HIGH TRIGLYCERIDES ............................. 36 
 
INVESTIGATIONAL DRUG ........................................................................................ 37 
7.1 
DESCRIPTION OF STUDY DRUGS .............................................................................. 37 
7.2 
DRUG PACKAGING ....................................................................................................... 37 
7.3 
DRUG LABELING .......................................................................................................... 37 
7.4 
DRUG STORAGE ............................................................................................................ 38 
7.5 
DISPENSING AND ADMINISTRATION OF TREATMENT ....................................... 38 
 
Drug Administration ......................................................................................................... 38 
7.6 
COMPLIANCE WITH PRESCRIBED STUDY DRUG DOSING REGIMEN .............. 39 
7.7 
DRUG ACCOUNTABILITY ........................................................................................... 39 
7.8 
PROCEDURE FOR UNBLINDING ................................................................................ 39 
 
CONCOMITANT MEDICATION ............................................................................... 40 
8.1 
GENERAL CONSIDERATIONS .................................................................................... 40 
 
 
8.3 
PROHIBITED MEDICATION ........................................................................................ 40 
8.4 
PERMITTED MEDICATION .......................................................................................... 41 
8.5 
PATIENT RESTRICTIONS ............................................................................................. 42 
 
Therapeutic Lifestyle Changes ......................................................................................... 42 
 
ADVERSE EVENTS ...................................................................................................... 43 
9.1 
ADVERSE EVENT DEFINITION .................................................................................. 43 
9.2 
ADVERSE DRUG REACTIONS .................................................................................... 43 
9.3 
REPORTING ADVERSE EVENTS ................................................................................ 43 
9.4 
FOLLOW-UP OF ADVERSE EVENTS .......................................................................... 47 
 
SERIOUS ADVERSE EVENTS .................................................................................... 48 
10.1 
LIFE-THREATENING ADVERSE EVENT ................................................................... 48 
10.2 
HOSPITALIZATION OR PROLONGATION OF EXISTING HOSPITALIZATION .. 48 
10.3 
PREGNANCY .................................................................................................................. 48 
10.4 
PATIENT WITHDRAWAL ............................................................................................. 49 
10.5 
SERIOUS UNEXPECTED SUSPECTED ADVERSE REACTIONS ............................ 49 
10.6 
REPORTING SERIOUS ADVERSE EVENTS, URGENT SAFETY ISSUES, AND 
SERIOUS BREACHES .................................................................................................... 50 
  Serious Adverse Events .................................................................................................... 50 
 Initial Reports ................................................................................................................... 50 
 Follow-Up Reports ........................................................................................................... 50 
  Urgent Safety Issues and Serious Breaches of Clinical Trial Regulation ......................... 51 
 
STATISTICAL METHODS AND DATA ANALYSIS ............................................... 52 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
xiv6 
 
11.1 
SAMPLE SIZE JUSTIFICATION ................................................................................... 52 
11.2 
ANALYSIS POPULATIONS .......................................................................................... 52 
  Full Analysis Set ............................................................................................................... 52 
  Per-Protocol Set ................................................................................................................ 52 
  Safety Analysis Set ........................................................................................................... 53 
  Pharmacokinetic Analysis Set ........................................................................................... 53 
11.3 
DEMOGRAPHIC/BASELINE INFORMATION ............................................................ 53 
11.4 
STUDY DRUG EXPOSURE, COMPLIANCE, AND CONCOMITANT THERAPIES 53 
11.5 
ANALYSIS OF EFFICACY ............................................................................................ 54 
  Hypothesis Testing Procedure .......................................................................................... 54 
  Analysis of Primary Efficacy Parameters ......................................................................... 54 
  Analysis of Secondary and Exploratory Efficacy Parameters .......................................... 55 
 
 
11.6 
ANALYSIS OF SAFETY DATA .................................................................................... 55 
11.7 
ANALYSIS OF PHARMACOKINETIC DATA ............................................................. 56 
11.8 
INTERIM ANALYSIS ..................................................................................................... 56 
 
STUDY MANAGEMENT AND DATA COLLECTION ............................................ 57 
12.1 
ETHICAL CONDUCT OF THE TRIAL ......................................................................... 57 
12.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE ..................................... 57 
12.3 
PATIENT INFORMED CONSENT ................................................................................. 57 
12.4 
AMENDMENTS TO THE PROTOCOL ......................................................................... 58 
12.5 
STUDY INITIATION ...................................................................................................... 58 
12.6 
STUDY MONITORING .................................................................................................. 58 
12.7 
CASE REPORT FORM .................................................................................................... 59 
12.8 
VERIFICATION PROCEDURES .................................................................................... 59 
12.9 
RETENTION OF RECORDS........................................................................................... 60 
12.10 
INSURANCE AND INDEMNITY .................................................................................. 60 
12.11 
AUDIT .............................................................................................................................. 60 
 
USE OF INFORMATION ............................................................................................. 61 
13.1 
GENERAL ASPECTS ...................................................................................................... 61 
13.2 
PATIENT CONFIDENTIALITY AND DATA PROTECTION ..................................... 61 
13.3 
FINAL REPORT AND PUBLICATION POLICY .......................................................... 61 
 
REFERENCES ................................................................................................................ 63 
 
APPENDICES ................................................................................................................. 65 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
xv6 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Apo  
Apolipoprotein 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CK 
Creatine kinase 
 
 
Cmax 
Maximum plasma pharmacokinetic concentration 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
EC 
Ethics Committee 
EC50 
Half-maximal effective concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFA 
Free fatty acid 
FGF21 
Fibroblast growth factor 21 
 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HDL-C 
High-density lipoprotein cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
HOMA-β 
Homeostatic model assessment for beta-cell function 
HOMA-IR 
Homeostatic model assessment for insulin resistance 
hsCRP 
High-sensitivity C-reactive protein 
HTG 
Hypertriglyceridemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IND 
Investigational New Drug 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
13 Sep 2016 v1.0 
xvi6 
 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KRI 
Kowa Research Institute, Inc. 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
MMRM 
Mixed effect model repeat measurement 
 
 
NCEP 
National Cholesterol Education Program 
NMR 
Nuclear magnetic resonance 
OATP 
Organic anion-transporting polypeptide 
PAC 
Pancreatitis Adjudication Committee 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPAR 
Peroxisome proliferator-activated receptor 
QUICKI 
Quantitative insulin sensitivity check index 
SAE 
Serious adverse event 
SHTG 
Severe hypertriglyceridemia  
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
T2DM 
Type 2 diabetes mellitus 
 
 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
TIA 
Transient ischemic attack 
TLC 
Therapeutic Lifestyle Changes 
Tmax 
Time to maximum plasma concentration 
 
 
 
 
ULN 
Upper limit of normal 
VLDL 
Very low-density lipoprotein  
WOCBP 
Women of childbearing potential 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 1 of 77 
 
INTRODUCTION AND RATIONALE FOR DOSE SELECTION 
1.1 
BACKGROUND INFORMATION 
K-877 is a potent and selective peroxisome proliferator-activated receptor (PPAR) 
modulator, which is several thousand times more selective for the PPARα receptor than 
the PPARγ or PPARδ receptor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 
RATIONALE 
A variety of primary disorders of lipoprotein metabolism have been described which may 
lead to elevated levels of the atherogenic lipoproteins (VLDL, remnant particles, 
LDL, etc.) or reduced levels of the anti-atherogenic high-density lipoprotein, any or all of 
which can confer increased risk of coronary artery disease. Of greater concern, elevated 
levels of TG, in particular TG levels ≥500 mg/dL (5.65 mmol/L), confer an increased risk 
of acute pancreatitis. 2 , 3 Acute pancreatitis caused by hypertriglyceridemia (HTG) is 
associated with increased severity and rates of complications compared to pancreatitis 
with causes other than HTG.4,5  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 2 of 77 
Fibrates improve TG and HDL-C by activating PPARα, 6  and are labeled in the 
United States for the treatment of severe HTG (SHTG). In the United States, fenofibrate, 
fenofibric acid, and gemfibrozil are available. Fibrates available in Europe are bezafibrate, 
ciprofibrate, fenofibrate, and gemfibrozil. In Japan, bezafibrate, clinofibrate, clofibrate, 
and fenofibrate are available.  
The United States Adult Treatment Panel III National Cholesterol Education Program 
(NCEP) guidelines 7  recommend reduction of TG through lifestyle, diet, and 
pharmacologic methods as the first priority of therapy when serum TG are ≥500 mg/dL. 
Treatment with omega-3 fatty acids, such as those found in fish oils, has been shown to 
effectively decrease TG levels up to 30%; however, for individuals with SHTG (serum 
TG ≥500 mg/dL), increasing omega-3 fatty acid intake does not adequately manage 
TG levels.8 
The European Society for Cardiology and European Atherosclerosis Society consensus 
guidelines note that patients can develop pancreatitis with TG concentrations between 
5 and 10 mmol/L (440 and 880 mg/dL).9 These guidelines also recommend initiating 
fibrates to prevent acute pancreatitis. 
Most fibrates are contraindicated or require careful administration in patients with renal 
dysfunction. Furthermore, coadministration of these drugs with statins is contraindicated 
in patients with severe renal dysfunction. Thus, there are restrictions in the use of existing 
PPARα agonists.10,11,12,13,14,15,16,17 
K-877 is a selective PPARα agonist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 3 of 77 
 
 
 
 
 
 
 
 
 
 
 
 Therefore, K-877 is expected to exhibit not only a potent lipid 
metabolism-improving effect but also to serve as a drug with a broad therapeutic range 
with fewer restrictions in patients with renal dysfunction or with concomitant drugs than 
existing PPARα agonists.  
Fenofibrate (145 mg once daily) was chosen as the active comparator for the 40-week 
Extension Period of this study based on current guidelines for the management of SHTG. 
The present study is a Phase 3 multi-center, placebo-controlled, randomized, 
double-blind, 12-week study with a 40-week, active-controlled, double-blind extension 
designed to evaluate the efficacy and safety of K-877 0.2 mg twice daily in patients with 
fasting TG levels ≥500 mg/dL and <2000 mg/dL and normal renal function. The results 
of this study will provide a better understanding of the efficacy and safety of 
K-877 0.2 mg twice daily in patients with SHTG. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 4 of 77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 5 of 77 
 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to demonstrate the efficacy of K-877 0.2 mg twice 
daily compared to placebo from baseline to Week 12 in lowering fasting TG levels in 
patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L). 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are the following: 
• 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 52 in 
lowering fasting TG levels in patients with fasting TG levels ≥500 mg/dL 
(5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L); 
• 
To evaluate the efficacy of K-877 0.2 mg twice daily from baseline to Week 12 
and Week 52 in altering lipid parameters in patients with fasting TG levels 
≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L);  
• 
To evaluate the safety and tolerability of K-877 0.2 mg twice daily in patients 
with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L); and 
• 
To determine the plasma concentrations of K-877 for the purpose of use in 
population pharmacokinetic (PK) analysis and PK/pharmacodynamic (PD) 
analysis. 
2.3 
EXPLORATORY OBJECTIVE 
 
 
 
2.4 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the percent change in fasting TG from baseline to 
Week 12. Baseline for TG will be defined as the mean of Visit 4 (Day 1) and the 
preceding TG qualifying visit (either Visit 3 [Week -1] or Visit 3.1, if required) 
measurements.  
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 6 of 77 
2.5 
SECONDARY EFFICACY ENDPOINTS 
The secondary efficacy endpoints for the 12-week Efficacy Period include the following: 
• 
Percent change from baseline to Week 12 in remnant cholesterol (calculated as 
total cholesterol [TC] − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 
• 
Percent change from baseline to Week 12 in TC, LDL-C, free fatty acids (FFAs), 
Apo A2, Apo B, Apo B48, Apo B100, Apo C2, Apo C3, and Apo E; 
• 
Change from baseline to Week 12 in FGF21 and high-sensitivity C-reactive 
protein (hsCRP), and percent change from baseline to Week 12 in ion mobility 
analysis and lipoprotein fraction (nuclear magnetic resonance [NMR]); and  
• 
Percent change from baseline to Week 12 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, 
and Apo C3:Apo C2. 
The secondary efficacy endpoints for the 40-week Extension Period include the 
following: 
• 
Percent change from baseline to Week 52 in fasting TG; 
• 
Percent change from baseline to Week 52 in remnant cholesterol (calculated as 
TC − LDL-C − HDL-C), HDL-C, Apo A1, and non-HDL-C; 
o Low-density lipoprotein cholesterol will be determined by preparative 
ultracentrifugation; 
• 
Percent change from baseline to Week 52 in TC, LDL-C, FFAs, Apo A2, Apo B, 
Apo B48, Apo B100, Apo C2, Apo C3, and Apo E;  
• 
Change from baseline to Week 52 in FGF21 and hsCRP, and percent change from 
baseline to Week 52 in ion mobility analysis and lipoprotein fraction (NMR); and  
• 
Percent change from baseline to Week 52 in the lipid and lipoprotein ratios of 
TG:HDL-C, TC:HDL-C, non-HDL-C:HDL-C, LDL-C:Apo B, Apo B:Apo A1, 
and Apo C3:Apo C2. 
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either 
Visit 3 [Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy 
and safety variables will be defined as Visit 4 (Day 1). If the measurement at this visit is 
missing, the last measurement prior to the first dose of randomized study drug will be 
used. 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 7 of 77 
2.6 
EXPLORATORY EFFICACY ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
2.7 
SAFETY ENDPOINTS 
Safety assessments include adverse events (AEs), clinical laboratory measurements 
(chemistry, hematology, coagulation profile, 
, and urinalysis), 12-lead 
electrocardiograms (ECGs), vital signs (heart rate, respiratory rate, and blood pressure), 
and physical examinations. 
2.8 
PHARMACOKINETIC/PHARMACODYNAMIC ENDPOINTS 
Pharmacokinetic concentrations collected during the 12-week Efficacy Period will be 
used for population PK analysis and PK/PD analysis. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 8 of 77 
 
STUDY DESCRIPTION 
3.1 
STUDY DESIGN 
This is a Phase 3, multi-center, randomized, double-blind study to confirm the efficacy 
and safety of K-877 0.2 mg twice daily compared to matching placebo (in the 12-week 
Efficacy Period) and an active comparator, fenofibrate (in the 40-week Extension Period), 
in patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL 
(22.60 mmol/L) and normal renal function. 
Eligible patients will enter a 4- to 6-week lifestyle stabilization period (4-week 
stabilization for patients not requiring washout and 6-week washout and stabilization for 
patients on lipid-altering therapy other than statins, ezetimibe, or proprotein convertase 
subtilisin/kexin type 9 [PCSK9] inhibitors). The stabilization period will be followed by a 
2-week TG qualifying period (Visits 2 [Week -2] and 3 [Week -1]), and patient eligibility 
will be assessed based on the mean TG value from these 2 visits. If the patient’s mean TG 
level during the TG qualifying period is ≥450 mg/dL (5.09 mmol/L) and <500 mg/dL 
(5.65 mmol/L), an additional TG measurement can be taken 1 week later at Visit 3.1. The 
mean of all 3 TG measurements will be used to determine eligibility for the study. After 
confirmation of qualifying fasting TG values, eligible patients will enter a 12-week, 
randomized, double-blind Efficacy Period. At Visit 4 (Day 1), patients will be randomly 
assigned in a 2:1 ratio to K-877 0.2 mg twice daily or identical matching placebo tablets 
twice daily. During the 12-week Efficacy Period, patients will return to the site at Visit 5 
(Week 4), Visit 6 (Week 8), and Visit 7 (Week 12) for efficacy and safety evaluations. 
Patients who successfully complete the 12-week Efficacy Period are eligible to continue 
in a 40-week, double-blind, active-controlled Extension Period after completing the 
Visit 7 (Week 12) procedures. Patients randomized to receive K-877 0.2 mg twice daily 
in the 12-week Efficacy Period will continue to receive K-877 0.2 mg twice daily, as well 
as placebo matching fenofibrate 145 mg once daily, in the 40-week Extension Period. 
Patients randomized to receive placebo matching K-877 0.2 mg twice daily in the 
12-week Efficacy Period will receive fenofibrate 145 mg once daily and placebo 
matching K-877 0.2 mg twice daily in the 40-week Extension Period.  
From Visit 7 (Week 12), patients not on statins, ezetimibe, or PCSK9 inhibitors may 
initiate therapy, and patients receiving statins,  ezetimibe, or PCSK9 inhibitors may alter 
their dose, as indicated by guidelines or local standard of care. 
After Visit 8 (Week 16), patients are to return to the site every 12 weeks until the last 
visit (Visit 11 [Week 52]). 
Table 2 presents the clinical evaluation schedule performed during the study.  
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 9 of 77 
Table 2: 
Clinical Evaluation Schedule 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 
Lifestyle 
Stabilization/
Washout 
Period 
Triglyceride 
Qualifying Period [1] 
12-Week Efficacy Period 
40-Week Extension Period 
Time 
Week -8 or -6 
Week -2 
±3 days 
Week -1 
±3 days 
Day 1 
Week 4 
±3 days 
Week 8 
±3 days 
Week 12 
±3 days 
Week 16 
±3 days 
Week 28 
±7 days 
Week 40 
±7 days 
Week 52 
±7 days or ET 
Visit Number 
1 [2] 
2 
3 [1] 
4 
5 
6 
7 
8 
9 
10 
11 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, and family history, 
and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
Vital signs (heart rate, respiratory rate, 
and blood pressure) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height [3], weight, and waist 
circumference 
X 
 
 
X 
 
 
X 
 
 
 
X 
Register screening number with IRT 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug and blood alcohol screen 
[4] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase and lipase 
X 
 
 
X 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Insulin, glycated albumin, HOMA-IR, 
HOMA-β, and QUICKI 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Serum pregnancy test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test for WOCBP 
 
 
 
X 
 
 
X 
 
X 
 
X 
Chemistry, hematology, coagulation, 
and urinalysis 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Plasma Population PK sampling [7] 
PK/PD sampling [8] 
TG, TC, HDL-C, non-HDL-C, LDL-C, 
and remnant cholesterol [9] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*footnotes on following page 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol  
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 10 of 77 
Table 2: 
Clinical Evaluation Schedule (Continued) 
ASSESSMENTS PERFORMED 
STUDY PERIOD 
Screening Period 
Treatment Period 
Lifestyle 
Stabilization/
Washout 
Period
Triglyceride 
Qualifying Period [1] 
12-Week Efficacy Period 
40-Week Extension Period 
Time 
Week -8 or -6
Week -2 
±3 days
Week -1 
±3 days 
Day 1
Week 4 
±3 days
Week 8 
±3 days 
Week 12 
±3 days
Week 16 
±3 days
Week 28 
±7 days
Week 40 
±7 days
Week 52 
±7 days or ET
Visit Number 
1 [2]
2
3 [1] 
4
5
6 
7
8
9
10
11
Apo A1, Apo A2, Apo B, Apo B48, 
Apo B100, Apo C2, Apo C3, and 
Apo E 
 
 
 
X 
X 
 
X 
 
X 
 
X 
FFAs 
 
 
 
X 
 
 
X 
 
X 
 
X 
Ion mobility analysis and lipoprotein 
fraction (NMR) 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Withdraw lipid-altering medication(s) 
other than statins, ezetimibe, or PCSK9 
inhibitors, if applicable 
X 
 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
 
 
X 
 
 
X 
 
 
 
X 
Physical examination 
X 
 
 
X 
 
 
X 
 
 
 
X 
Assess and record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLC counseling [12] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Dispense study drug (efficacy period) 
 
 
 
X 
X 
X 
 
 
 
 
 
Dispense study drug (extension period) 
 
 
 
 
 
 
X 
X 
X 
X 
 
Collect study drug and record 
accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
1. 
Triglyceride levels are based on the mean of the Visit 2 (Week -2) and Visit 3 (Week -1) values. In cases in which a patient’s mean TG level from Visit 2 (Week -2) and Visit 3 (Week -1) falls outside the required range 
for entry into the study but is ≥450 mg/dL (5.09 mmol/L) and <500 mg/dL (5.65 mmol/L), an additional TG measurement can be collected 1 week (±3 days) later (Visit 3.1). If Visit 3.1 is required, the TG qualifying 
period will be extended, and Visit 4 will occur 1 week (±3 days) after Visit 3.1. If a third sample is collected, entry into the 12-week Efficacy Period is based on the mean of the values from Visit 2 (Week -2), Visit 3 
(Week -1), and Visit 3.1. 
2. 
Visit 1 for patients who require a washout is at Week -8. Visit 1 for patients who do not require a washout is at Week -6. 
3. 
Height is measured at Visit 1 (Week -8 or Week -6) only. 
 
 
 
 
 
 
*footnotes continued on following page 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol  
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 11 of 77 
Table 2: 
Clinical Evaluation Schedule (Continued) 
 
 
 
 
 
  
9. All lipid laboratory blood specimens must be obtained under fasting conditions (i.e., after the patient has fasted for at least 10 hours). 
 
12. TLC counseling can be provided by the Investigator or designee (see Section 8.5.1). 
AE = adverse event; Apo = apolipoprotein; ET = Early Termination; FFA = free fatty acid; 
; HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; 
HOMA-β = homeostasis model assessment for beta-cell function; HOMA-IR = homeostasis model assessment for insulin resistance; IRT = Interactive Response Technology; LDL-C = low-density lipoprotein cholesterol; 
NMR = nuclear magnetic resonance; PCSK9 = proprotein convertase subtilisin/kexin type 9; PD = pharmacodynamic; PK = pharmacokinetic; QUICKI = quantitative insulin sensitivity check index; T4 = thyroxine; TC = total 
cholesterol; TG = triglycerides; TLC = therapeutic lifestyle changes; Tmax = time to maximum plasma concentration; 
; WOCBP = women of childbearing potential. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 12 of 77 
 
PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA 
4.1 
INCLUSION CRITERIA 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Able to understand and willing to comply with all study requirements and 
procedures throughout the duration of the study and give written informed 
consent; 
2. Aged ≥18 years; 
3. Patients receiving statin therapy must meet one of the following criteria1 (see 
Appendix B for statin eligibility and monitoring): 
o 
Aged ≥21 years with clinical atherosclerotic cardiovascular disease 
(ASCVD) (history of acute coronary syndrome or myocardial infarction, 
stable or unstable angina, coronary revascularization, stroke, transient 
ischemic attack [TIA] presumed to be of atherosclerotic origin, or peripheral 
arterial disease or revascularization), on a high-intensity statin (or 
moderate-intensity statin if not a candidate for high-intensity statin due to 
safety concerns [see Appendix B]);  
o 
Aged ≥21 years with a history of LDL-C ≥190 mg/dL, which is not due to 
secondary 
modifiable 
causes, 
on 
a 
high-intensity 
statin 
(or 
moderate-intensity statin if not a candidate for high-intensity statin due to 
safety concerns [see Appendix B]);  
o 
Aged 40 to 75 years, inclusive, without clinical ASCVD but with diabetes 
and a history of LDL-C of 70 to 189 mg/dL, inclusive, on a moderate- or 
high-intensity statin; or  
o 
Aged 40 to 75 years, inclusive, without clinical ASCVD or diabetes, with a 
history of LDL-C of 70 to 189 mg/dL, inclusive, with estimated 10-year risk 
for ASCVD of ≥7.5% by the Pooled Cohort Equation (see Appendix C) on a 
moderate- or high-intensity statin; 
4. Patients not currently on statins, must not meet the criteria for statin therapy 
listed above (see inclusion criterion 3);  
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 13 of 77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 14 of 77 
 
 
4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from participation in the 
study: 
1. Patients who will require lipid-altering treatments other than study drugs (K-877 
or fenofibrate), statins, ezetimibe, or PCSK9 inhibitors during the course of the 
study. These include bile acid sequestrants, non-study fibrates, niacin 
(>100 mg/day), omega-3 fatty acids (>1000 mg/day), or any supplements used to 
alter lipid metabolism including, but not limited to, red rice yeast supplements, 
garlic supplements, soy isoflavone supplements, sterol/stanol products, or 
policosanols; 
2. Body mass index (BMI) >45 kg/m2 at Visit 1 (Week -8 or Week -6); 
3. Patients with type 1 diabetes mellitus; 
4. Patients with newly diagnosed (within 3 months prior to Visit 2 [Week -2]) or 
poorly controlled type 2 diabetes mellitus (T2DM), defined as hemoglobin A1c 
(HbA1c) >9.5% at Visit 1 (Week -8 or Week -6); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 15 of 77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 16 of 77 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3 
STUDY DRUG DISCONTINUATION CRITERIA 
It will be necessary to make a distinction between patients who prematurely discontinue 
study drug treatment and those who withdraw from the study for any reason.  
If the patient discontinues study drug, the reason should be captured and could include 
the following: 
1. The patient requests discontinuation of the study drug; 
2. The patient begins to take any medication(s) that is contraindicated by the 
protocol; 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 17 of 77 
3. The patient develops an AE that, in the opinion of the Investigator, would 
compromise the patient’s safety to continue the study drug; 
4. The patient meets any of the criteria specified in Section 4.6;  
5. A female patient becomes pregnant during the study; 
6. In the Investigator’s judgment, it is in the patient’s best interests; or 
7. The patient is unblinded. 
During the 12-week Efficacy Period, patients who discontinue study drug prematurely 
will remain in the study until Visit 7 (Week 12). However, patients who discontinue 
study drug during the 40-week Extension Period will be required to withdraw from the 
study and requested to complete the full panel of assessments scheduled for the Early 
Termination (ET) Visit (see Section 4.4). If a patient who has discontinued study drug 
fails to attend any follow-up appointments, reasonable efforts (telephone calls to family 
members or friends, e-mail contacts, etc.) will be made in order to encourage the patient 
to complete the study visits. 
Although a patient is not obligated to give his/her reason for discontinuing study drug, 
the Investigator will make a reasonable effort to obtain the reason while fully respecting 
the patient’s rights. The reason for discontinuation of study drug must be documented in 
the electronic case report form (eCRF). The Clinical Study Report (CSR) will include the 
reason(s) for discontinuation of study drug. 
Patients will not be allowed to restart the study drug in the event of discontinuation; 
however, study drug may be restarted in cases of study drug interruption due to 
temporary use of prohibited medication(s). 
4.4 
WITHDRAWAL CRITERIA 
The patient has the right to withdraw from the study at any time. Nevertheless, in this 
study, every attempt will be made to prevent missing data and to obtain complete 
follow-up of all patients during the 12-week Efficacy Period. Investigators will be trained 
to minimize full withdrawals from the 12-week Efficacy Period wherever possible. 
Patients who discontinue study drug during the first 12 weeks are not required to 
withdraw from the study. These patients will be encouraged to remain in the study and 
asked to conduct the remaining study visits as outlined in the protocol through Visit 7 
(Week 12). At a minimum, measurements of lipid parameters at key time points, 
particularly Visit 7 (Week 12), should be taken for all study patients, regardless of 
adherence to therapy or study protocol. If a patient fails to actively maintain contact with 
the Investigator, reasonable efforts (telephone calls to family members or friends, e-mail 
contacts, etc.) will be made in order to encourage the patient to complete the study visits. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 18 of 77 
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 of the study 
drug during the 40-week Extension Period; 
2. The patient begins to take any medication(s) during the 40-week Extension Period 
that is prohibited by the protocol; 
3. The patient develops an AE that, in the opinion of the Investigator, would 
compromise the patient’s safety by continuing in the study; 
4. The patient meets any of the criteria specified in Section 4.6 during the 40-week 
Extension Period; 
5. A female patient becomes pregnant during the study; 
6. 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; 
7. In the Investigator’s judgment, it is in the patient’s best interests; 
8. 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;  
9. The patient is unblinded during the 40-week Extension Period; or 
10. 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 CSR will include the reason(s) 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 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 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 19 of 77 
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, 
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 (INR) >1.5, confirmed on repeat;  
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 at or after Visit 7 (Week 12), confirmed on 
repeat. 
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 at Visit 7 (Week 12) or any subsequent visit, the study site 
will receive an alert from the central laboratory. 
For further details regarding study drug discontinuation for persistent abnormal clinical 
laboratory tests, see Section 5.2.2.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 20 of 77 
4.7 
SURVEILLANCE FOR POSSIBLE PANCREATITIS 
Investigators should be vigilant for potential cases of pancreatitis. If a patient experiences 
abdominal pain or unexplained gastrointestinal symptoms (e.g., nausea, vomiting, or 
diarrhea), they should return to the site for an unscheduled visit as soon as possible. A 
history including symptoms, concomitant medication and dietary and alcohol intake, a 
physical examination, and laboratory evaluation of TG, amylase and lipase, as well as 
any other evaluations deemed necessary by the Investigator should be performed and 
documented on the appropriate eCRF. Patients who are diagnosed with pancreatitis; who 
have elevations of amylase or lipase, with or without symptoms; or who have severe 
abdominal pain, or sustained (>7 days), unexplained abdominal pain, even without 
elevations of amylase or lipase should have their cases submitted for adjudication of 
pancreatitis. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 21 of 77 
 
PROCEDURES FOR EFFICACY, SAFETY, AND 
PHARMACOKINETIC EVALUATIONS 
5.1 
EFFICACY EVALUATIONS 
Blood samples for the determination of laboratory analytes for efficacy assessment will 
be collected as specified in Table 2. All visits with laboratory sampling are fasting visits 
and blood specimens must be obtained under fasting conditions (i.e., after the patient has 
fasted [nothing by mouth except water] for at least 10 hours). 
The following parameters will be measured or derived to assess efficacy in this study: 
• Lipid parameters including HDL-C, LDL-C, TC, TG, non-HDL-C, free fatty 
acids, remnant cholesterol (calculated as TC – LDL-C – HDL-C), Apo A1, 
Apo A2, Apo B, Apo B48, Apo B100, Apo C2, Apo C3, Apo E, TG:HDL-C ratio, 
TC:HDL-C ratio, non-HDL-C:HDL-C ratio, LDL-C:Apo B ratio, Apo B:Apo A1 
ratio, Apo C3:Apo C2 ratio, ion mobility analysis, and lipoprotein fraction 
(NMR); and 
• Biomarkers and exploratory parameters including FGF21, hsCRP, 
 
 
5.2 
SAFETY EVALUATIONS 
 Adverse Events 
The Investigator will determine at each study visit whether any AEs have occurred since 
the signing of informed consent. The patients will be questioned in a general way and no 
specific symptoms will be suggested. Section 9.0 presents further information with regard 
to AEs. 
 Clinical Laboratory Tests 
Blood and urine samples for the determination of laboratory analytes will be collected as 
specified in Table 2. 
 
All standard 
blood and urine tests will be performed by 
 All 
visits with laboratory sampling are fasting visits and blood specimens must be obtained 
under fasting conditions (i.e., after the patient has fasted [nothing by mouth except water] 
for at least 10 hours).  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 22 of 77 
The following parameters will be measured or derived at the time points indicated in 
Table 2: 
• Serum chemistry – sodium, chloride, potassium, bicarbonate, calcium, inorganic 
phosphorus, blood urea nitrogen, creatinine, eGFR, uric acid, ALT, AST, alkaline 
phosphatase, gamma-glutamyl transpeptidase, total and direct bilirubin, albumin, 
total protein, lipase, amylase, CK, lactate dehydrogenase, glucose, insulin, HbA1c, 
glycated albumin, homeostatic model assessment for insulin resistance 
(HOMA-IR), homeostatic model assessment for beta-cell function (HOMA-β), 
quantitative insulin sensitivity check index (QUICKI), homocysteine, and alcohol; 
• Hematology – hematocrit, hemoglobin, platelets, red blood cell count, and white 
blood cell count and differential; 
• Coagulation – fibrinogen, activated partial thromboplastin time, INR, and 
prothrombin time;  
 
 
• Urinalysis – bilirubin, blood, glucose, ketones, leukocyte esterase, microscopy (as 
needed based on dipstick results), nitrite, pH, protein, specific gravity, 
urobilinogen, urine albumin, urine creatinine, urine albumin:creatinine ratio, and 
 and  
 
 
See Appendix A for a complete list of clinical laboratory analytes to be measured.  
The Investigator or a delegated physician will evaluate all laboratory test results for their 
clinical significance and review, sign, and date all laboratory reports. 
For WOCBP, serum pregnancy tests will be analyzed by 
 at Visit 1 (Week -8 or 
Week -6). 
 will provide urine pregnancy test kits to the 
investigative sites so that sites may conduct urine pregnancy tests at Visit 4 (Day 1), 
Visit 7 (Week 12), Visit 9 (Week 28), and Visit 11 (Week 52) or the ET Visit. 
 
Liver Function Test Elevations 
With any of the following liver function test elevations, patients should undergo repeat 
laboratory measurements as soon as possible, preferably within 72 hours (unless 
otherwise specified), and no later than 1 week. Local laboratory measurements may be 
used to facilitate follow-up: 
• 
ALT or AST >8 × ULN; 
• 
ALT or AST >3 × ULN and bilirubin >2 × ULN or INR >1.5 × ULN; 
• 
ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%); and 
• 
ALT or AST >5 × ULN, regardless of symptoms should be followed up within 
1 week. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 23 of 77 
Repeat evaluation should include AST, ALT, prothrombin time/INR, total bilirubin, 
alkaline phosphatase, gamma-glutamyltransferase, creatinine, CK, and complete viral 
hepatitis screen. The patient should be questioned regarding symptoms, as well as 
potential causative factors. This information, including results and normal ranges of any 
laboratory parameters collected at a local laboratory, should be collected on the 
appropriate eCRF. Hepatobiliary ultrasonography and/or consultation with a hepatologist 
should be considered if clinically indicated. 
Abnormal laboratory parameters should be followed at least weekly (more frequently as 
clinically indicated) until they have returned to baseline or have stabilized. 
 
Creatine Kinase Elevations 
In the event of a CK elevation >5 × ULN, the patient should return to the site within 
1 week for evaluation.  
For a CK elevation >10 × ULN, study drug should be interrupted immediately while 
awaiting evaluation.  
Evaluation 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-MB, 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 D for a list of muscle AE definitions. 
Abnormalities should be followed until they have returned to baseline, or the Investigator 
considers them clinically stable. 
 
Triglyceride Elevations 
For alerts due to fasting TG levels >2000 mg/dL (22.60 mmol/L), the patient should 
return to the site within 1 week for clinical and laboratory assessments. Patients should be 
assessed for potential signs or symptoms of pancreatitis (including measurements of 
serum amylase and lipase), and a repeat assessment of fasting TG will be obtained. For 
patients with asymptomatic elevations of TG, compliance with study drug and lifestyle 
recommendations should be assessed and reinforced. Patients should be closely followed 
for the emergence of signs and symptoms of pancreatitis until TG levels are 
<2000 mg/dL (22.60 mmol/L). If 2 consecutive alerts for a patient are sent due to 
elevated TG levels >2000 mg/dL (22.60 mmol/L), the Investigator may contact the 
Medical Monitor to discuss study drug discontinuation and further monitoring. 
To maintain the integrity of the blind, TG values from post-randomization blood samples 
obtained prior to Visit 8 (Week 16), run by the central laboratory, will not be 
communicated to the sites (see Section 6.6). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 24 of 77 
 
Estimated Glomerular Filtration Rate Decrease 
For eGFR <30 mL/min/1.73 m2, the patient should return to the site within 1 week for 
repeat laboratory assessment. Abnormal laboratory parameters should be followed at 
least weekly (more frequently as clinically indicated) until they have returned to baseline 
or have stabilized. 
 Electrocardiogram and Vital Signs 
Twelve-lead ECGs will be performed at Visit 1 (Week -8 or Week -6), Visit 4 (Day 1), 
Visit 7 (Week 12), and Visit 11 (Week 52) or the ET Visit. Site personnel will make 
every attempt to perform a patient’s ECG using the same equipment at each visit. 
Vital signs (heart rate, respiratory rate, and blood pressure) will be assessed at all study 
visits. All blood pressure measurements will be obtained after a 5-minute rest in the 
sitting or supine position with a standard mercury sphygmomanometer or an automated 
oscillometric blood pressure monitor. Heart rate measurements will be made by counting 
events (heartbeats) for a period of 30 seconds and multiplying this value by 2 to obtain 
the rate per minute. Whenever possible, the same person will do all of the assessments for 
a given patient throughout the study. 
 Physical Examination 
A physical examination will be performed at Visit 1 (Week -8 or Week -6), Visit 4 
(Day 1), Visit 7 (Week 12), and Visit 11 (Week 52) or the ET Visit. The physical 
examination will consist of an examination of the following body systems: general 
appearance; eyes, ears, nose, and throat; head and neck; chest and lungs; cardiovascular; 
abdomen; musculoskeletal; lymphatic; dermatological; neurological; mental status; and 
extremities. 
 Demographics and Medical History 
Demographics and brief, relevant medical/social and surgical history, as well as alcohol 
consumption, cigarette smoking, hypertension, diabetes history, and family history of 
heart disease will be taken at Visit 1 (Week -8 or Week -6) and recorded in the eCRF.  
 Body Weight, Height, Body Mass Index, and Waist Circumference 
Body weight, height, and waist circumference will be measured at Visit 1 (Week -8 or 
Week -6). Body weight and height will be used to calculate the BMI. Body weight and 
waist circumference will also be measured at Visit 4 (Day 1), Visit 7 (Week 12), and 
Visit 11 (Week 52) or the ET Visit. Waist circumference will be measured with a tape 
measure. Starting at the top of the hip bone then bringing the tape measure all the way 
around, level with the navel. The tape measure should be snug around the waist, but 
without compressing the skin, and parallel with the floor. Patients should not hold their 
breath while measuring waist circumference. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 25 of 77 
5.3 
PHARMACOKINETIC EVALUATIONS 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 26 of 77 
 
5.4 
DATA MONITORING COMMITTEE 
A data monitoring committee is not planned for this study. 
5.5 
PANCREATITIS ADJUDICATION COMMITTEE 
An external expert Pancreatitis Adjudication Committee (PAC) will blindly adjudicate all 
suspected pancreatitis events reported by Investigators. A PAC Charter will describe the 
operations of the PAC and definitions to be utilized for adjudication. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 27 of 77 
 
CONDUCT OF THE STUDY 
6.1 
STUDY BLINDING AND RANDOMIZATION 
This is a multi-center, placebo-controlled, randomized, double-blind 12-week study with 
a 40-week, active-controlled, double-blind extension. Patients will be randomly assigned 
in a 2:1 ratio to treatment with either K-877 0.2 mg twice daily or a matching placebo 
twice daily. An Interactive Response Technology (IRT) system will be used to perform 
the randomization. At Visit 7 (Week 12), patients who were randomized to receive 
K-877 0.2 mg twice daily during the 12-week Efficacy Period will continue to receive 
K-877 0.2 mg twice daily and will also receive a placebo matching fenofibrate once daily. 
Patients who were randomized to receive placebo during the 12-week Efficacy Period 
will continue to receive placebo matching K-877 twice daily and will also receive 
fenofibrate 145 mg once daily. 
The Investigator or designee must contact the IRT system to register each patient. Patient 
numbers will consist of an 8-digit number and will be assigned based on the pre-printed 
value on the selected central laboratory requisition binder. Patient numbers will be 
composed of a 5-digit site identification (ID) plus a 3-digit patient ID, assigned 
sequentially starting at 001 for the first patient at each site. 
The patient number will be used to identify the patient throughout the study and will be 
entered on all documentation. 
A patient number will not be assigned to more than 1 patient. If a patient is not eligible to 
receive treatment, or should a patient discontinue from the study, the patient number 
cannot be reassigned to another patient. 
At Visit 4 (Day 1), qualified patients who meet all of the inclusion criteria and none of 
the exclusion criteria will receive the randomly assigned treatment. The Investigator or 
designee must contact the IRT system to randomize each patient. Randomization will be 
stratified by country and current statin therapy use (not on statin therapy versus currently 
receiving statin therapy). 
Investigators will be blinded to key results from lipid parameters, such as TG and LDL-C, 
obtained prior to Visit 8 (Week 16), in order to maintain the blind of the treatment 
assignments. Investigators are encouraged not to check lipid panels locally, especially 
during the 12-week Efficacy Period to avoid becoming unblinded. Beginning at Week 16, 
Investigators will receive unblinded lipid data. Investigators will receive an alert for 
TG levels >2000 mg/dL (22.60 mmol/L) at any time during the study. To ensure study 
blinding can be maintained, Investigators may receive a sham alert for TG elevation 
during the 12-week Efficacy Period (see Section 6.6). 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 28 of 77 
6.2 
PATIENT INFORMED CONSENT 
Written consent will be obtained from the patient prior to any study-specific procedure or 
investigation. 
Information about the study will be given to the patient both verbally and in writing. The 
written patient information will explain the objectives of the study, its potential risks, and 
benefits and the impact of early withdrawal on the scientific validity of the study. The 
patient must have adequate time to read the information and to ask the Investigator any 
questions. The Investigator must be satisfied that the patient has understood the 
information provided before written consent is obtained. If there is any doubt as to 
whether the patient has understood the written and verbal information, the patient should 
not enter the study. 
Participating patients will be asked to sign and date an ICF, the original copy of which 
will be kept by the Investigator. A copy of the signed ICF will be given to the patient. A 
record will be made in the source document that the patient voluntarily agreed to 
participate in the study.  
6.3 
STUDY VISITS 
The procedures and assessments to be performed at each visit are indicated in Table 2. 
All visits with laboratory sampling are fasting visits and blood specimens must be 
obtained under fasting conditions (i.e., after the patient has fasted [nothing by mouth 
except water] for at least 10 hours). 
A detailed list of procedures to be conducted at each study visit is also described below. 
Visit 1: Screening/Lifestyle Stabilization/Washout Period (Week -8 or Week -6) 
Screening procedures that will be performed at Visit 1 (Week -8 or Week -6) include: 
• Obtain written informed consent; 
• Evaluate inclusion and exclusion criteria; 
• Obtain medical history (including information on prior and concomitant 
medications), surgical history, family history, and demographic information; 
• Assess vital signs, height, weight, and waist circumference; 
• Perform physical examination; 
• Perform 12-lead ECG; 
• Obtain fasting blood sample for the following assessments: 
o 
Serum chemistry (see Appendix A for a complete list of analytes); 
o 
Hematology (see Appendix A for a complete list of analytes); 
o 
Coagulation (see Appendix A for a complete list of analytes); 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 29 of 77 
 
 
 
 
 
o 
Lipid parameters (see Appendix A for a complete list of analytes); 
 
 
 
 
 
o 
Serum pregnancy test for WOCBP; 
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes); 
 
 
 
 
• Instruct the patient to discontinue all lipid-altering medications other than statins, 
ezetimibe, or PCSK9 inhibitors, if applicable; 
• Provide Therapeutic Lifestyle Changes (TLC) counseling (see Section 8.5.1); 
• Contact the IRT system to register the patient’s screening number;  
• Assess and record AEs; and 
• Schedule Visit 2 (4 weeks or 6 weeks ±3 days from Visit 1). 
Visit 2: Triglyceride Qualifying Period (Week -2) 
Procedures that will be performed at Visit 2 (Week -2) include: 
• Evaluate inclusion and exclusion criteria; 
• Record concomitant medication(s); 
• Assess vital signs; 
• Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
• Provide TLC counseling (see Section 8.5.1); 
• Assess and record AEs; and 
• Schedule Visit 3 (1 week ±3 days from Visit 2). 
Visit 3: Triglyceride Qualifying Period (Week -1) 
Procedures that will be performed at Visit 3 (Week -1) include: 
• Evaluate inclusion and exclusion criteria; 
• Record concomitant medication(s); 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 30 of 77 
• Assess vital signs; 
• Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
• Provide TLC counseling (see Section 8.5.1); 
• Assess and record AEs; and 
• Schedule Visit 4 or Visit 3.1, if applicable (1 week ±3 days from Visit 3). 
Visit 3.1: Optional Triglyceride Qualifying Period (1 Week ±3 Days From Visit 3) 
Patients with a mean TG level ≥450 mg/dL (5.09 mmol/L) and <500 mg/dL 
(5.65 mmol/L) from Visit 2 (Week -2) and Visit 3 (Week -1) may have a third TG 
measurement collected 1 week later at Visit 3.1. Visit 4 (Day 1) will be scheduled for 
1 week (±3 days) after Visit 3.1. The following procedures will be performed at Visit 3.1: 
• Evaluate inclusion and exclusion criteria; 
• Record concomitant medication(s); 
• Assess vital signs; 
• Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
• Provide TLC counseling (see Section 8.5.1); 
• Assess and record AEs; and 
• Schedule Visit 4 (1 week ±3 days from Visit 3.1). 
Visit 4: Randomization (Day 1) 
Procedures that will be performed at Visit 4 (Day 1) include: 
• Evaluate inclusion and exclusion criteria; 
• Record concomitant medication(s); 
• Assess vital signs, weight, and waist circumference; 
• Perform 12-lead ECG; 
• Perform physical examination; 
• Obtain fasting blood sample for the following assessments: 
o 
Serum chemistry (see Appendix A for a complete list of analytes); 
o 
Hematology (see Appendix A for a complete list of analytes); 
o 
Coagulation (see Appendix A for a complete list of analytes);  
o 
Lipid parameters (see Appendix A for a complete list of analytes); 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 31 of 77 
 
 
 
 
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes) and urine pregnancy test (WOCBP only); 
• Provide TLC counseling (see Section 8.5.1); 
• Contact the IRT system to randomize the patient if all inclusion and exclusion 
criteria are met and the laboratory results and physical examination findings are 
acceptable; 
• Dispense study drug via the IRT system and provide instructions for proper use; 
• Assess and record AEs; and 
• Schedule Visit 5 (4 weeks ±3 days from Visit 4). 
Visit 5: Efficacy Period (Week 4) 
Procedures that will be performed at Visit 5 (Week 4) include: 
• Record concomitant medication(s); 
• Assess vital signs; 
• Obtain fasting blood sample for the following assessments: 
o 
Serum chemistry (see Appendix A for a complete list of analytes); 
o 
Hematology (see Appendix A for a complete list of analytes); 
o 
Coagulation (see Appendix A for a complete list of analytes);  
o 
Lipid parameters (see Appendix A for a complete list of analytes); and 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 32 of 77 
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes); 
• Provide TLC counseling (see Section 8.5.1); 
• Dispense study drug via the IRT system and provide instructions for proper use; 
• Collect study drug and assess study drug accountability; 
• Assess and record AEs; and 
• Schedule Visit 6 (8 weeks ±3 days from Visit 4). 
Visit 6: Efficacy Period (Week 8) 
Procedures that will be performed at Visit 6 (Week 8) include: 
• Record concomitant medication(s); 
• Assess vital signs; 
• Obtain fasting blood sample for lipid parameters (see Appendix A for a complete 
list of analytes); 
 
 
 
 
 
 
• Provide TLC counseling (see Section 8.5.1); 
• Dispense study drug via the IRT system and provide instructions for proper use; 
• Collect study drug and assess study drug accountability; 
• Assess and record AEs; and 
• Schedule Visit 7 (12 weeks ±3 days from Visit 4). 
Visit 7: Efficacy Period (Week 12) 
Procedures that will be performed at Visit 7 (Week 12) include: 
• Record concomitant medication(s); 
• Assess vital signs, weight, and waist circumference; 
• Perform 12-lead ECG; 
• Perform physical examination; 
• Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes);  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 33 of 77 
o Lipid parameters (see Appendix A for a complete list of analytes); 
 
 
 
 
  
 
  
 
 
 
 
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes) and urine pregnancy test (WOCBP only); 
• Provide TLC counseling (see Section 8.5.1); 
• Dispense study drug via the IRT system and provide instructions for proper use; 
• Collect study drug and assess study drug accountability; 
• Assess and record AEs; and 
• Schedule Visit 8 (16 weeks ±3 days from Visit 4). 
Visit 8: Extension Period (Week 16) 
Procedures that will be performed at Visit 8 (Week 16) include: 
• Record concomitant medication(s); 
• Assess vital signs; 
• Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes); and 
o Lipid parameters (see Appendix A for a complete list of analytes);  
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes); 
• Provide TLC counseling (see Section 8.5.1); 
• Dispense study drug via the IRT system and provide instructions for proper use; 
• Collect study drug and assess study drug accountability; 
• Assess and record AEs; and 
• Schedule Visit 9 (28 weeks ±7 days from Visit 4). 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 34 of 77 
Visit 9: Extension Period (Week 28) 
Procedures that will be performed at Visit 9 (Week 28) include: 
• Record concomitant medication(s); 
• Assess vital signs; 
• Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes); and 
o Lipid parameters (see Appendix A for a complete list of analytes);  
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes) and urine pregnancy test (WOCBP only); 
• Provide TLC counseling (see Section 8.5.1); 
• Dispense study drug via the IRT system and provide instructions for proper use; 
• Collect study drug and assess study drug accountability; 
• Assess and record AEs; and 
• Schedule Visit 10 (40 weeks ±7 days from Visit 4). 
Visit 10: Extension Period (Week 40) 
Procedures that will be performed at Visit 10 (Week 40) include: 
• Record concomitant medication(s); 
• Assess vital signs; 
• Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes); and 
o Lipid parameters (see Appendix A for a complete list of analytes);  
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes); 
• Provide TLC counseling (see Section 8.5.1); 
• Dispense study drug via the IRT system and provide instructions for proper use; 
• Collect study drug and assess study drug accountability; 
• Assess and record AEs; and 
• Schedule Visit 11 (52 weeks ±7 days from Visit 4). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 35 of 77 
Visit 11: Extension Period (Week 52) or Early Termination Visit 
Procedures that will be performed at Visit 11 (Week 52) include: 
• Record concomitant medication(s); 
• Assess vital signs, weight, and waist circumference; 
• Perform 12-lead ECG; 
• Perform physical examination; 
• Obtain fasting blood sample for the following assessments: 
o Serum chemistry (see Appendix A for a complete list of analytes); 
o Hematology (see Appendix A for a complete list of analytes); 
o Coagulation (see Appendix A for a complete list of analytes);  
o Lipid parameters (see Appendix A for a complete list of analytes);  
 
 
 
 
 
 
 
• Obtain urine sample for urinalysis (see Appendix A for a complete list of 
analytes) and urine pregnancy test (WOCBP only); 
• Provide TLC counseling (see Section 8.5.1); 
• Collect study drug and assess study drug accountability; and 
• Assess and record AEs. 
6.4 
COMPLIANCE WITH THE PROTOCOL 
The Investigator must agree to implement the study protocol as written and adhere to the 
guidelines given in the “Investigator’s Statement,” which will be signed by the 
Investigator prior to the start of the study. The study will be performed in accordance 
with Declaration of Helsinki, International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines, local laws, and other applicable guidance documents. 
Sites in the United States will also comply with the Health Insurance Portability and 
Accountability Act (HIPAA) and Food and Drug Administration (FDA) GCP regulations 
(21 Code of Federal Regulations [CFR] Parts 11, 50, 54, 56, and 312).  
Protocol noncompliance must be reported to 
 and Kowa Research Institute, Inc. 
(KRI). Each deviation and the reason for its occurrence must be documented. Kowa 
Research Institute, Inc. retains the right to require the withdrawal of any patient who 
violates the protocol. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 36 of 77 
6.5 
TERMINATION OF THE STUDY 
 Site Termination 
If it becomes apparent that patient enrollment is unsatisfactory with respect to quality or 
quantity, or data recording is inaccurate or incomplete on a chronic basis, KRI has the 
right to terminate the study at an investigational site and remove all study materials from 
the investigational site. A written statement will be provided to the Investigator, the 
Institutional Review Board (IRB)/Ethics Committee (EC), and regulatory authorities, if 
required. In the event of any serious or non-serious AE(s) having occurred at a site, all 
documentation relating to the event(s) must be obtained. 
 Study Termination 
If, in the opinion of KRI, the clinical observations in the study suggest that it may be 
unwise to continue, the study may be terminated. In addition, KRI may terminate the 
study at any time. 
6.6 
LABORATORY ALERT RELATED TO HIGH TRIGLYCERIDES 
Sites will receive an alert for any reported TG level >2000 mg/dL (22.60 mmol/L) during 
the study. In order to maintain the study blind during the placebo-controlled 12-week 
Efficacy Period, sites may receive a sham alert. A sham alert is an alert which will be 
sent to a site for randomly selected patients who do not actually meet the alert criteria for 
TG levels >2000 mg/dL (22.60 mmol/L). These alerts will be programmed to occur in 
patients assigned to K-877, at the expected (low) frequency that they would occur in the 
placebo population, and will be indistinguishable from “true” alerts. Investigators are 
expected to respond to every alert (see Section 5.2.2.3).  
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 37 of 77 
 
INVESTIGATIONAL DRUG 
7.1 
DESCRIPTION OF STUDY DRUGS 
Kowa Research Institute, Inc. will supply sufficient K-877 0.2 mg film-coated tablets and 
matching placebo to allow for completion of the study. The lot numbers of the study drug 
will be recorded in the final study report.  
All K-877 and matching placebo tablets are 
 To 
ensure study blinding can be maintained, each tablet is indistinguishable by size, 
markings, or weight. Each K-877 tablet contains 0.2 mg of K-877; each K-877 and 
placebo tablet also contains the following excipients: 
 
 
 
 
 
 
Fenofibrate is supplied as a white to off-white bi-convex oblong tablet containing 145 mg 
fenofibrate, as well as the following excipients: anhydrous lactose, croscarmellose 
sodium, hypromellose, magnesium stearate, purified water, simethicone emulsion, 
sodium lauryl sulfate, polyvinyl alcohol, titanium dioxide, talc, soybean lecithin, and 
xanthan gum. To ensure study blinding can be maintained, each tablet will be 
over-encapsulated and backfilled with anhydrous lactose, and matching placebo capsules 
containing anhydrous lactose as a backfill will be manufactured by 
  
7.2 
DRUG PACKAGING 
Drug packaging will be completed by 
 
  
Study drugs will be packaged in clear polyvinyl chloride/aluminum foil blisters within a 
child-resistant sleeve. Patients will have approximately a 1-month supply of study drug in 
each blister card. Study drug will be labeled in accordance with Section 7.3. Patients will 
receive an adequate supply of study drug at each visit to ensure proper dosing can occur 
until the next scheduled study visit.  
7.3 
DRUG LABELING 
Study drugs will be labeled according to country/state/province specific requirements. 
For example, the label will include the following information: 
• Name and address of Sponsor (i.e., KRI); 
• A study reference code (e.g., protocol number) allowing ID of the investigational 
site and Investigator; 
• Blank space for patient ID; 
• Blank space for site/Investigator ID; 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 38 of 77 
• Route of administration, quantity of dosage units, and pharmacological form as 
appropriate;  
• A code number that will allow appropriate blinded assignment of the correct 
clinical trial material kit via the randomization code; 
• Lot number (as required);  
• Directions for use;  
• The statement “Caution - New Drug - Limited by Federal (United States) Law to 
Investigational Use”; 
• The statement “Keep out of reach of children”;  
• The storage conditions; and 
• Expiration date (as required). 
7.4 
DRUG STORAGE 
K-877 0.2 mg tablets, fenofibrate 145 mg capsules, and matching placebos will be stored 
at controlled room temperatures of 20°C to 25°C (68°F to 77°F) in a secured area with 
access limited to the Investigator and the site staff. The permitted excursion temperature 
range is 15°C to 30°C (59°F to 86°F).  
7.5 
DISPENSING AND ADMINISTRATION OF TREATMENT 
Study drugs will be dispensed to eligible patients beginning at Visit 4 (Day 1) after 
randomization via the IRT system and at Visit 5 (Week 4), Visit 6 (Week 8), Visit 7 
(Week 12), Visit 8 (Week 16), Visit 9 (Week 28), and Visit 10 (Week 40). From Visit 4 
(Day 1) to Visit 6 (Week 8), an approximately 1-month supply of blinded study drug will 
be dispensed to patients at each visit. Each patient will receive 1 blister card of 
K-877 0.2  mg or matching placebo. At Visit 7 (Week 12), an approximately 1-month 
supply of blinded study drug will be dispensed. Each patient will receive 1 blister card of 
K-877 0.2 mg or matching placebo, and 1 blister card of fenofibrate 145 mg or matching 
placebo. From Visit 8 (Week 16) to Visit 10 (Week 40), an approximately 3-month 
supply of blinded study drug will be dispensed at each visit. Each patient will receive 
3 blister cards of K-877 0.2 mg or matching placebo, and 3 blister cards of fenofibrate 
145 mg or matching placebo. 
 Drug Administration 
Patients will receive an oral dose of K-877 0.2 mg or matching placebo twice daily 
starting at Visit 4 (Day 1) until Visit 7 (Week 12). Starting at Visit 7 (Week 12), patients 
will receive an oral dose of K-877 0.2 mg twice daily and placebo matching fenofibrate 
once daily, or fenofibrate 145 mg once daily and placebo matching K-877 twice daily. 
Patients may take study drug in a fed or fasted state (before or after meals); however, 
patients should be instructed that fed/fasted state and dosing time should remain 
consistent for all doses throughout the study. Study drug will be dispensed at Visit 4 
(Day 1) through Visit 10 (Week 40). Patients will be instructed by the site to follow 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 39 of 77 
dosing instructions on the drug packaging and to return the remaining study drug at the 
next visit. 
7.6 
COMPLIANCE 
WITH 
PRESCRIBED 
STUDY 
DRUG 
DOSING 
REGIMEN 
Study drug or placebo will be dispensed in excess of the amount required between study 
visits. Patients will be instructed to return all unused study drug at the next visit. The 
patient will be asked whether there have been any problems with taking the medication, 
and the Investigator will record any significant departure from the dosing instructions 
(e.g., misuse or overdose) as a protocol deviation. A record of the number of 
tablets/capsules dispensed, taken, and returned for each patient must be documented on 
the Drug Accountability Log and eCRF. Compliance will be assessed from information 
recorded in the eCRF, including study drug count and the start and end date of therapy. 
Patients will be considered compliant if they have taken between 80% and 120% of the 
intended regimen. 
During the treatment period, if compliance is not between 80% and 120%, inclusive, the 
patient will be counseled about the importance of compliance with the regimen. See 
Section 7.5.1 for study drug administration. 
7.7 
DRUG ACCOUNTABILITY 
Sites will be instructed to maintain drug accountability and retain all used, partially used, 
and unused study drug materials until the end of the study. 
7.8 
PROCEDURE FOR UNBLINDING 
As needed, the randomization code may be broken by the Investigator to manage an 
urgent medical event. If possible, the Medical Monitor will be contacted to discuss the 
case and ET assessments will be completed before the code is broken. 
For each patient, the treatment group can be unblinded using the IRT system and the 
site’s Emergency Unblinding IRT Code, provided with the site’s study start-up materials. 
Using the Emergency Unblinding IRT Code, the Investigator or designee will be able to 
unblind a patient by following the instructions on 
 
 When the unblinding is completed, the study’s Medical Monitor, the Clinical Trial 
Manager, and designated KRI personnel will be notified that the unblinding has taken 
place. 
If it becomes necessary to unblind treatment information during the study, the reason for 
unblinding must be documented in the eCRF. The Investigator must contact the Medical 
Monitor within one business day and explain the reason for the premature unblinding 
(e.g., unblinding due to a serious AE [SAE]). Patients whose treatment assignment is 
unblinded are no longer eligible to receive treatment. Patients unblinded during the 
12-week Efficacy Period should complete the 12-week Efficacy Period. Patients who are 
unblinded in the 40-week Extension Period must be discontinued from the study after ET 
assessments are completed (see Section 6.3). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 40 of 77 
 
CONCOMITANT MEDICATION 
All concomitant medications, both prescribed and over-the-counter, as well as dietary 
supplements, must be recorded in the eCRF. This includes drugs used on a chronic and 
as-needed basis. 
8.1 
GENERAL CONSIDERATIONS 
Patients shall be advised not to start any new medication, either prescribed or 
over-the-counter, without consulting the Investigator, unless the new medication is 
required for emergency use. 
 
 
 
 
 
 
 
 
 
 
8.3 
PROHIBITED MEDICATION 
The following medications and products (prescription and over-the-counter) must not be 
taken by the patient during the course of the study, except as noted: 
• Insulin or insulin analogues, except for basal insulin therapy with a single insulin 
that has been stable for ≥4 weeks prior to Visit 1 (Week -8 or Week -6); 
• All systemic corticosteroids, except for local, topical, inhaled, or nasal 
corticosteroids; 
• Prescription or over-the-counter agents taken for the purpose of weight reduction; 
• Any non-study lipid-lowering treatments except for statins, ezetimibe, and 
PCSK9 inhibitors including bile acid sequestrants, fibrates, niacin (>100 mg/day), 
omega-3 fatty acids (>1000 mg/day), or any supplements used to alter lipid 
metabolism including but not limited to red rice yeast supplements, garlic 
supplements, soy isoflavone supplements, sterol/stanol products, or policosanols; 
• During the 12-week Efficacy Period, dietary fiber supplements cannot be 
increased or started; or 
• Cyclosporine, rifampin, or other strong inhibitors of OATP1B1 or OATP1B3. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 41 of 77 
8.4 
PERMITTED MEDICATION 
The following frequently prescribed medications are permitted by the protocol, if the 
patient has been on a stable dose for ≥4 weeks prior to Visit 1 (Week -8 or Week -6) 
unless otherwise noted, and doses should remain stable throughout the duration of the 
study: 
• Basal insulin therapy with a single insulin; 
• Oral contraceptives and hormone replacement therapy; 
• Statins, ezetimibe, or PCSK9 inhibitors that have been at a stable dose for 
≥6 weeks prior to Visit 1 (Week -8 or Week -6); 
o After Week 16, patients not on statins, ezetimibe, or PCSK9 inhibitors may 
initiate therapy, and patients receiving statins, ezetimibe, or PCSK9 
inhibitors may alter their dose; and  
o Simvastatin 80 mg or Vytorin (ezetimibe/simvastatin) 10/80 mg are 
permitted if tolerated for ≥6 weeks prior to Visit 1 (Week -8 or Week -6). 
However, simvastatin 80 mg or Vytorin 10/80 mg cannot be started at any 
point during the study; 
• Dietary fiber supplements that are taken as part of the TLC diet during the 
lifestyle stabilization period may be used at a stable dose for the duration of the 
study. Dietary fiber supplements cannot be increased or started during the 
12-week Efficacy Period; 
• Chronic prescription pharmacotherapy for metabolic or CVD management or risk 
factor modification; 
o During the 40-week Extension Period, patients not on chronic prescription 
pharmacotherapy for metabolic or CVD management (other than statins, 
ezetimibe, or PCSK9 inhibitors) or risk factor modification may initiate 
therapy, and patients receiving therapy may alter their dose, as indicated by 
guidelines or local standard of care; 
• Tamoxifen, estrogens, or progestins that have been at a stable dose for ≥4 weeks 
prior to the first TG qualifying visit (Visit 2 [Week -2]); 
• Thyroid replacement therapy that has been at a stable dose for ≥4 weeks prior to 
the first TG qualifying visit (Visit 2 [Week -2]); and 
• Local, topical, inhaled, or nasal corticosteroids. 
Note: Other than the prohibited medications (see Section 8.3), medications needed for 
chronic conditions and AEs are permitted. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 42 of 77 
8.5 
PATIENT RESTRICTIONS 
 Therapeutic Lifestyle Changes 
The Investigator or designee will provide TLC instructions based on the NCEP 
recommendations (see Appendix E) with implementation beginning at Visit 1 (Week -8 
or Week -6). From Visit 4 (Day 1), the Investigator or designee will instruct patients to 
stably maintain these lifestyle changes. Goals and recommendations on diet,18 weight loss, 
physical activity, and abstaining from alcohol will be reviewed at all study visits.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 43 of 77 
 
ADVERSE EVENTS 
9.1 
ADVERSE EVENT DEFINITION 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the 
pharmaceutical product. An AE can, therefore, be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not related to the medicinal product. Any worsening of the patient’s disease under 
study or other medical conditions will also be considered to be an AE, unless it is within 
the normal range of disease fluctuation for that patient. 
Clinically meaningful (for a given patient) changes in physical examination findings and 
abnormal objective test findings (e.g., clinical laboratory tests, ECGs) will also be 
recorded as AEs. The criteria for determining whether an abnormal objective test finding 
will be reported as an AE are as follows: 
1. Test result is associated with accompanying symptoms, and/or; 
2. Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or; 
3. Test result leads to a change in study drug dosing or discontinuation from the 
study, significant additional concomitant drug treatment or other therapy, and/or; 
4. Test result leads to any of the outcomes included in the definition of an SAE.  
Merely repeating a test, in the absence of any of the above conditions, does not meet 
condition number 2 above for reporting as an AE. 
Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
A treatment-emergent AE (TEAE) is defined as an AE that begins after the start of study 
drug or an event that begins before the start of the study drug and worsens in intensity 
after starting treatment with the study drug. 
9.2 
ADVERSE DRUG REACTIONS 
All noxious and unintended responses to a medicinal product related to any dose will be 
considered adverse drug reactions. The phrase “responses to a medicinal product” means 
that a causal relationship between a medicinal product and the AE is at least a reasonable 
possibility (see Section 9.3). 
9.3 
REPORTING ADVERSE EVENTS 
At each evaluation, the Investigator will determine whether any AEs have occurred. The 
patient will be questioned in a general way and no specific symptoms will be suggested. 
If any AEs have occurred, they will be recorded on the AE pages of the eCRF and in the 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 44 of 77 
patient’s medical record. If known, the diagnosis should be recorded, in preference to the 
listing of individual signs and symptoms. 
Adverse event assessment and reporting begins with the signing of informed consent, and 
occurs at every scheduled study visit through Visit 11 (Week 52), unless an unresolved 
AE is still being followed (see Section 9.4). 
The severity (intensity) of AEs will be classified as follows: 
• 
Mild: An AE that is easily tolerated by the patient, causes minimal discomfort, 
and does not interfere with everyday activities;  
• 
Moderate: An AE that causes enough discomfort to interfere with normal 
everyday activities and may require intervention; and 
• 
Severe: An AE that prevents normal everyday activities;  
o Note: Treatment or intervention will usually be required.  
The Investigator will make a judgment regarding whether or not the AE was related to 
the study drug. The following factors should be considered: 
• 
The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time 
from study drug exposure to event should be evaluated in the clinical 
context of the event. 
• 
Underlying, concomitant, intercurrent diseases- 
o 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 drugs- 
o 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- 
o Clinical and/or preclinical data may indicate whether a particular response is 
likely to be a class effect. 
• 
Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the patient and 
provide a logical and better explanation for the event. 
• 
The pharmacology and PK of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, 
and excretion) of the study drug should be considered. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 45 of 77 
The relationship of an AE to the administration of the study drug is to be assessed 
according to the following definitions: 
• 
Definite: An AE which is consistent with the suspected type of reaction known 
for the drug, in line with the reasonable temporal order after treatment, and is 
alleviated or disappears upon discontinuation of the study drug; 
• 
Probable: An AE which is consistent with the suspected type of reaction known 
for the drug, in line with the reasonable temporal order after treatment, alleviates 
or disappears upon discontinuation of the study drug, but could also be caused by 
the clinical conditions of the study patient or other factors;  
• 
Possible: An AE which is consistent with the suspected type of reaction known 
for the drug, not in line with the reasonable temporal order after treatment, and 
could also be caused by the clinical conditions of the study patient or other 
factors;  
• 
Improbable: An AE which is inconsistent with the suspected type of reaction 
known for the drug, not in line with the reasonable temporal order after treatment, 
and could also be caused by the clinical conditions of the study patient or other 
factors; and 
• 
Not related: An AE which is inconsistent with the suspected type of reaction 
known for the drug, not in line with the reasonable temporal order from 
administration of the study drug, or that can be easily explained by other factors, 
such as underlying diseases, complication, concomitant drugs, and concurrent 
treatment.  
If the causality assessment for an individual event is “Definite,” “Probable,” or “Possible,” 
the event will be considered a suspected adverse drug reaction.  
The Investigator will evaluate any changes in laboratory values, make a determination as 
to whether or not the change is clinically important, and whether or not the changes were 
related to the study drug. However, even if the Investigator feels there is no relationship 
to the study drug, the AE or laboratory abnormality MUST be recorded in the eCRF. 
The Investigator will record the action taken to treat the AE, if any, the action taken with 
study treatment, and the outcome for each AE in the eCRF according to the following: 
Action taken to treat the AE 
• 
None, 
• 
Treatment required, 
• 
Hospitalization, 
• 
Patient withdrawn, or 
• 
Other (specify). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 46 of 77 
Action taken with study treatment 
• 
Dose not changed, 
• 
Drug interrupted, 
• 
Drug withdrawn, 
• 
Not applicable, or 
• 
Unknown. 
Outcome 
• 
Resolved: The event has recovered;  
o Note: An SAE/AE stop date should be provided.  
• 
Resolved with sequelae: The study patient has recovered as much as may be 
expected but is left with sequelae of the event that are not expected to recover 
further;  
o Note: If the sequelae are severe enough to represent a significant disability 
or incapacity then the event should be reported as an SAE. 
• 
Resolving: Can be used in cases where study patient is known to be clearly 
recovering from the event at the end of a study, although the event is not yet 
resolved, and the Investigator and Medical Monitor agree that further follow-up is 
not necessary; 
• 
Death: The study patient died as a result of the AE;  
o Note: Death is considered an outcome of an AE rather than an AE in its own 
right, and the cause of death should be recorded as the AE. There may be 
rare circumstances where the cause of death is unknown and the death may 
have to be recorded as the event (e.g., “sudden cardiac death”). Adverse 
events resulting in death are SAEs. 
• 
Not resolved: The patient has an AE that has not improved or recuperated at the 
time of the report; or 
o Note: The decision not to continue follow-up should be discussed between 
the Investigator and Medical Monitor and recorded in the source documents. 
• 
Unknown: The outcome of the event is genuinely unknown in spite of efforts to 
contact the patient. 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 47 of 77 
9.4 
FOLLOW-UP OF ADVERSE EVENTS 
If any AEs are present when a patient completes the study, or if a patient is withdrawn 
from the study, the patient will be re-evaluated. At the Investigator’s discretion, clinically 
minor AEs can be re-evaluated via telephone and documented. If the AE is still not 
resolved, additional follow-up will be performed as appropriate. Every effort will be 
made by the Investigator or delegate to contact the patient until the AE is resolved or 
stabilized, or until the Medical Monitor and Investigator agree that further follow-up is 
not necessary. The follow-up of AEs will be documented in the patient’s study records. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 48 of 77 
 SERIOUS ADVERSE EVENTS 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires patient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability/incapacity,  
• 
Is a congenital anomaly/birth defect, or 
• 
Is an important medical event. 
Medical and scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  
10.1 LIFE-THREATENING ADVERSE EVENT 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it were more severe. 
10.2 HOSPITALIZATION 
OR 
PROLONGATION 
OF 
EXISTING 
HOSPITALIZATION 
Hospitalization is defined as the patient being hospitalized overnight, or the patient’s 
hospital stay being prolonged for at least an additional overnight stay. An emergency 
room visit without hospital admission will not be recorded as an SAE under this criterion, 
nor will hospitalization for a procedure scheduled or planned before the signing of 
informed consent. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed 
for seriousness. Admission to the hospital for social or situational reasons (i.e., no place 
to stay, live too far away to come for hospital visits) will not be considered inpatient 
hospitalizations. Twenty-three hour hospitalizations for observation should be discussed 
with the Medical Monitor to determine whether they are appropriate for SAE reporting. 
10.3 PREGNANCY 
If a patient becomes pregnant during the study or within 30 days of discontinuing study 
drug, the Investigator will report the pregnancy to 
 within 
24 hours of being notified (see Section 10.6.1 for contact information). 
 
 will then forward the Exposure In Utero form to the Investigator for completion.  
A patient who becomes pregnant while on study drug will immediately be withdrawn 
from the study and ET study procedures will be performed. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 49 of 77 
The patient will be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator will notify 
 At the completion of the pregnancy, the Investigator will 
document the outcome of the pregnancy. 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 
will follow the procedures for reporting an SAE (see Section 10.6). 
10.4 
PATIENT WITHDRAWAL 
If a patient experiences an AE that leads to discontinuation of study drug treatment and/or 
withdrawal from the study, the eCRF will identify the AE as the reason for study drug 
discontinuation or withdrawal. 
10.5 
SERIOUS UNEXPECTED SUSPECTED ADVERSE REACTIONS 
According to FDA CFR 312.32(a), FDA Guidance “Safety Reporting Requirements for 
Investigational New Drugs (INDs) and Bioavailability/Bioequivalence (BA/BE) Studies” 
finalized December 2012, European Directives 2001/20/EC and CT-3 Guideline, 
suspected adverse reaction means any AE for which there is a reasonable possibility that 
the medicinal product caused the AE. The phrase “reasonable possibility” means there is 
evidence to suggest a causal relationship between the AE and the medicinal product 
(see Section 9.3). 
The following are examples of types of evidence that would suggest a causal relationship 
between the drug and the AE: 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome); or 
• One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug 
(e.g., tendon rupture).  
A suspected adverse reaction is considered “unexpected” if it is not listed in the 
Reference Safety Information in Section 6 of the K-877 Investigator’s Brochure or is not 
listed at the specificity or severity that has been described in the K-877 Investigator’s 
Brochure or the approved package insert of fenofibrate. Study sites will be provided with 
the current version of the fenofibrate package insert. 
The Sponsor will report suspected unexpected serious adverse reactions (SUSARs) to 
Investigators, Competent Authorities, and IRB/ECs in an expedited manner according to 
national requirements. Fatal and life-threatening SUSARs will be reported within 
7 calendar days of Day 0, where Day 0 is defined as the day on which the information 
containing the minimum reporting criteria is received by the Sponsor. All other SUSARs 
will be reported within 15 calendar days of Day 0. All cases will be unblinded for 
reporting purposes, as required.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 50 of 77 
10.6 REPORTING SERIOUS ADVERSE EVENTS, URGENT SAFETY ISSUES, 
AND SERIOUS BREACHES 
 Serious Adverse Events 
 Initial Reports  
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to 
 within 
24 hours of the knowledge of the occurrence (this refers to any AE that meets any of the 
aforementioned serious criteria). All SAEs that the Investigator considers related to study 
drug occurring after the 30 day follow-up period must be reported to the Sponsor. 
To report the SAE, complete the SAE form electronically in the electronic data capture 
(EDC) system for the study. When the form is completed, 
 will 
be notified electronically 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 
 
 or call 
 
 and fax the completed paper SAE form to 
 
) within 24 hours of awareness. When the EDC system becomes available, 
the SAE information must be entered within 24 hours. 
Safety Contact Information: 
 
 
 
 
 
 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. Written confirmation that these 
serious, unexpected, and related AEs have been submitted to the IRB/EC must be 
forwarded to KRI and kept in the Investigator files. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 51 of 77 
 Urgent Safety Issues and Serious Breaches of Clinical Trial Regulation 
If 
 or any Investigator become aware of an actual 
or potential urgent safety issue or a serious breach of clinical trial regulations, the 
Medical Monitor and the Sponsor must be immediately contacted so that agreement can 
be made on appropriate urgent safety measures. An urgent safety issue is defined as: 
• 
An immediate hazard to the health or safety of study patients participating in a 
clinical trial, or 
• 
A serious risk to human health or potentially a serious risk to human health. 
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, intercurrent illness (including pandemic infections), concomitant 
medications, concurrent medical conditions, or any other issues related to the safe 
conduct of the study or that pose a risk to study patients. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, 
 may take urgent safety measures before informing the 
Sponsor, but the Sponsor must be informed immediately after the hazard has been 
resolved. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 52 of 77 
 STATISTICAL METHODS AND DATA ANALYSIS 
11.1 
SAMPLE SIZE JUSTIFICATION 
Approximately 630 patients with fasting TG levels ≥500 mg/dL (5.65 mmol/L) and 
<2000 mg/dL (22.60 mmol/L) will be randomized in a 2:1 ratio into one of the following 
treatment groups: K-877 0.2 mg twice daily or identical matching placebo twice daily. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2 
ANALYSIS POPULATIONS 
The study population will consist of male and female patients ≥18 years of age with 
fasting TG levels ≥500 mg/dL (5.65 mmol/L) and <2000 mg/dL (22.60 mmol/L) after 
washout from background lipid-altering therapy other than statins, ezetimibe, or PCSK9 
inhibitors and with normal renal function. The active-controlled study population will 
consist of patients who complete the 12-week portion of the efficacy study and who 
continue the study. 
 Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized patients who take at least 
1 dose of double-blind study drug and have a baseline TG measurement. The FAS 
Population is the primary analysis population. All efficacy analyses will be performed on 
the FAS Population. 
 Per-Protocol Set 
The Per-Protocol Set will include all FAS patients for the 12-week Efficacy Period who 
complete the 12-week, placebo-controlled Efficacy Period without any major protocol 
deviations and have valid baseline and Week 12 fasting serum TG measurements. Major 
protocol deviations will be pre-specified prior to unblinding the study. The Per-Protocol 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 53 of 77 
Set will be used to assess robustness of the primary analysis results during the 12-week 
Efficacy Period. 
 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. 
 Pharmacokinetic Analysis Set 
The PK Analysis Set will include all patients from the Safety Analysis Set who have at 
least 1 PK sample.  
11.3 
DEMOGRAPHIC/BASELINE INFORMATION 
Summary statistics will be provided by treatment group for demographics (e.g., age, 
gender, race, and ethnicity).  
Baseline for TG, TC, HDL-C, non-HDL-C, LDL-C, and remnant cholesterol will be 
defined as the mean of Visit 4 (Day 1) and the preceding TG qualifying visit (either 
Visit 3 [Week -1] or Visit 3.1, if required) measurements. Baseline for all other efficacy 
and safety variables will be defined as Visit 4 (Day 1). If the measurement at this visit is 
missing, the last measurement prior to the first dose of randomized study drug will be 
used. 
 
 
11.4 
STUDY DRUG EXPOSURE, COMPLIANCE, AND CONCOMITANT 
THERAPIES 
Days of exposure to randomized study drug and study drug for the 12-week Efficacy 
Period and the 40-week Extension Period will be summarized with descriptive statistics 
by treatment for the Safety Analysis Set. Exposure in days is defined as the date of last 
dose of study drug minus the date of first dose of study drug plus 1. 
Patient compliance with the study drug will be summarized by treatment group in each 
period. 
Prior/concomitant medications will be coded with Anatomical Therapeutic Chemical 
(ATC) class and preferred term (defined by the most recent version of the World Health 
Organization Drug Dictionary) and summarized by ATC class and preferred term for 
each treatment group for the Safety Analysis Set. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 54 of 77 
11.5 
ANALYSIS OF EFFICACY  
 Hypothesis Testing Procedure 
In order to control the family-wise Type I error at a 0.05 level, a fixed sequential testing 
procedure will be implemented. In a hierarchical step-down manner, the primary endpoint 
will be tested first, followed by secondary endpoints, tested in the following hierarchical 
manner: percent change from baseline to Week 12 in a fixed sequence of (1) remnant 
cholesterol (calculated as TC − LDL-C − HDL-C), (2) HDL-C, (3) Apo A1, and 
(4) non-HDL-C. Each test is planned to be performed at a 0.05 significance level. 
Inferential conclusions about these efficacy endpoints will require statistical significance 
of the previous one. 
For other efficacy endpoints, nominal p-values and 95% confidence intervals (CIs) will 
be presented, but should not be considered as confirmatory. 
 Analysis of Primary Efficacy Parameters 
The primary efficacy analysis will be based on Hodges-Lehmann estimator with 
pattern-mixture model imputation based on the FAS. The pattern-mixture model will be 
used as the primary imputation method as part of the primary analysis for the percent 
change in fasting TGs from baseline to Week 12. This imputation model will include 
factors such as patient demographics, disease status, and baseline TG, as well as 
adherence to therapy. The imputation model will impute missing Week 12 TG values as 
follows: 
• For patients who do not adhere to therapy and who do not have a Week 12 
measurement, the missing data imputation method will use patients in the same 
treatment arm who do not adhere to therapy and have a Week 12 measurement; 
and 
• If there are no patients in the same treatment arm who do not adhere to therapy 
and have a Week 12 measurement, missing Week 12 TG values will be imputed 
as follows: 
o For the K-877 arm, the treatment effect is considered washed out and 
baseline TG values will be used to impute the Week 12 TG values; and 
o For the placebo arm, missing Week 12 TG values will be imputed 
assuming missing at random, including patient demographics, disease 
status, and baseline and post-baseline efficacy data from the placebo arm.  
After the multiple imputation step, each imputed dataset will be analyzed by the 
nonparametric Hodges-Lehmann method and the Hodges-Lehmann estimator and 
standard error will be combined to produce treatment difference estimate and 95% CI and 
p-value. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 55 of 77 
 
 
 
 
 
 
 
The primary efficacy analysis will be repeated on the Per-Protocol Set. 
Summary statistics (number of patients, mean, standard deviation, median, minimum, 
maximum, 25th percentile, and 75th percentile) at baseline, each scheduled visit, and 
change and percent change in fasting TG from baseline to each scheduled visit will be 
provided. 
 Analysis of Secondary and Exploratory Efficacy Parameters 
Secondary efficacy endpoints included in the hierarchical step-down testing procedure 
include percent change from baseline to Week 12 in a fixed sequence of (1) remnant 
cholesterol, (2) HDL-C, (3) Apo A1, and (4) non-HDL-C. 
The secondary and exploratory efficacy endpoints during the 12-week Efficacy Period 
will be analyzed using an ANCOVA model with the same imputation method used for 
the primary analysis. The ANCOVA model will include country, current statin therapy 
use (not on statin therapy versus currently receiving statin therapy), and treatment as 
factors; baseline value as a covariate. If the normality assumption is not met, the 
Hodges-Lehmann estimator with the same imputation method used for the primary 
analysis will be used. 
The secondary efficacy endpoint of percent change in fasting TG from baseline to 
Week 52 will be summarized descriptively.
 
 
 Other efficacy endpoints during the 40-week Extension Period will be summarized 
descriptively. No hypothesis testing will be performed. 
 
 
 
 
11.6 
ANALYSIS OF SAFETY DATA 
The safety endpoint data will be summarized for the Safety Analysis Set for the 12-week 
Efficacy Period, 40-week Extension Period, and overall. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 56 of 77 
The AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities. A general summary of the AEs and SAEs will be summarized by overall 
number of AEs, severity, and relationship to study drug per treatment group. The number 
of AEs leading to withdrawal and SAEs leading to death will also be summarized. The 
incidence of AEs will be summarized by body system and treatment group. The incidence 
of TEAEs will also be summarized by system organ class and preferred term. 
The safety laboratory data will be summarized by visit and by treatment group, along 
with changes from the baseline. The values that are below the lower limit or above the 
upper limit of the reference range will be flagged. Those values or changes in values that 
are identified as being clinically significant will be flagged. Laboratory abnormalities of 
special interest, such as liver function tests and pancreatitis events, will be summarized. 
Vital signs and 12-lead ECGs will also be summarized by visit and by treatment group, 
along with the changes from baseline. 
11.7 
ANALYSIS OF PHARMACOKINETIC DATA 
Population PK and PK/PD data will be analyzed and reported separately. 
 
 
 
 
 
 
 
 
 
11.8 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 57 of 77 
 STUDY MANAGEMENT AND DATA COLLECTION 
12.1 
ETHICAL CONDUCT OF THE TRIAL 
This study will be conducted according to the protocol; FDA GCP, as described in 
21 CFR Parts 11, 50, 54, 56, and 312 and HIPAA (in the United States) or Directive 
2001/20/EC; the World Medical Association Declaration of Helsinki; ICH GCP (E6/R1), 
and the laws and regulations of the country where the study is to be conducted. Each 
Investigator will also conduct the study according to applicable local or regional 
regulatory requirements. 
12.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
The IRB/EC must be constituted according to the applicable state, federal, and local 
requirements of each participating location, and those of the ICH GCP guidance and, in 
the United States, FDA GCP regulations. 
It is the responsibility of each investigational site to submit the protocol, Investigator’s 
Brochure, patient informed consent, patient recruitment materials (if applicable), and 
other required documentation to the IRB/EC for review and approval. Copies of the 
written approvals must be provided to 
 The documentation should clearly 
mention the approval/favorable opinion of the protocol, the patient ICF, and patient 
recruitment materials (if applicable). The respective version dates are to be included. The 
written approvals and a list of the voting members, their titles or occupations, and their 
institutional affiliations must be obtained from the IRB/EC and provided to 
 
prior to the release of clinical study supplies to the investigational site and 
commencement of the study. If any member of the IRB/EC has direct participation in the 
study, written notification regarding his or her abstinence from voting must also be 
obtained. 
Sites must adhere to all requirements stipulated by the IRB/EC. This includes notification 
to the IRB/EC regarding protocol amendments; updates to the patient informed consent 
and recruitment materials intended for viewing by patients; IND safety reports; serious 
and unexpected AEs; updates regarding the ongoing review of the study at intervals 
specified by the IRB/EC; and final study reports or summaries. 
It is the responsibility of each investigational site to submit information to the appropriate 
IRB/EC for annual review and annual re-approval. 
12.3 
PATIENT INFORMED CONSENT 
Prior to the implementation of study procedures, patients and persons conducting the 
consent discussion will be required to sign and date the IRB/EC-approved ICF, and each 
patient will be given a copy. In addition, this information will be recorded in the patient’s 
medical record (i.e., source document). 
The written consent document will embody the elements of informed consent as 
described in HIPAA, World Medical Association Declaration of Helsinki, FDA 21 CFR 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 58 of 77 
Part 50.25, ICH GCP, and in accordance with any local regulations. The Investigator is 
responsible for the preparation, content, and IRB/EC approval of the ICF. The ICF must 
be approved by the site-designated IRB/EC and be acceptable to KRI and 
. 
The ICF must be written in a language fully comprehensible to the prospective patient. 
The Investigator or designee will give the patient adequate opportunity to read it before it 
is signed and dated. Information provided will be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the IRB/EC. Patients must 
be given ample opportunity to inquire about study details. 
12.4 
AMENDMENTS TO THE PROTOCOL 
An amendment must be agreed to in writing by KRI and 
, submitted as an IND 
application amendment in the United States, and submitted to and approved by the 
respective IRB/EC for each investigational site, and an applicable regulatory authority 
before it is implemented. Written approval of a protocol amendment is not required prior 
to implementation for changes to the protocol that eliminate immediate hazard to the 
patient; however, approval must be obtained as soon as possible thereafter. Approved 
amendments must also be signed by the Investigator. 
12.5 
STUDY INITIATION 
The Investigator must not enroll any patients prior to the completion of a formal meeting 
conducted by a representative of 
 or KRI. This meeting will include a detailed 
review of the study protocol and eCRFs. Study drug will not be supplied to an 
Investigator until all the necessary pre-study requirements have been completed and 
essential signed documents are received by 
 and KRI. 
12.6 
STUDY MONITORING 
It is the responsibility of the Investigator to ensure that the study is conducted in 
accordance with the protocol, ICH/FDA GCPs, other applicable regional or local 
regulatory requirements, HIPAA, and the current Declaration of Helsinki. Valid data are 
to be entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same 
time, 
 and KRI in the maintenance of accurate, complete, legible, well-organized, 
and easily retrievable data. The monitor will review the protocol with the Investigator. In 
addition, the monitor will explain the Investigator’s reporting responsibilities and all 
applicable regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of KRI and 
to monitor the study 
as frequently as 
 or KRI deems is necessary to determine that data recording and 
protocol adherence are acceptable. The eCRFs and related source documents will be 
reviewed in detail by the monitor at each visit, in accordance with relevant Standard 
Operating Procedures (SOPs), ICH GCP guidance, and FDA GCP regulations. This 
includes results of tests performed as a requirement for participation in this study and any 
other medical records required to confirm information contained in the eCRFs, such as 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 59 of 77 
medical history and secondary diagnoses. The Investigator and staff will be expected to 
cooperate with the monitor and provide any missing information, whenever possible. 
All monitoring activities will be summarized in a report, which will be filed in the Trial 
Master File. In addition, performance of monitoring visits will be acknowledged at the 
investigational site by the monitor’s signature and date on the study-specific monitoring 
log. 
12.7 
CASE REPORT FORM 
All patient data generated during the study will be recorded on the eCRF. Data will be 
reviewed by the KRI or 
 Clinical Research Associate (CRA) during monitoring 
visits. The CRA will verify the accuracy of data recorded on the eCRF using source 
documents.  
The Investigator will ensure that all data are entered promptly, legibly, and completely, in 
accordance with specific instructions accompanying the eCRFs, which will be designed 
for this study and supplied by 
 for each patient. The Investigator will also ensure 
that all applicable entries agree with the source data. 
 will only consider the eCRFs to be complete after they are reviewed and signed 
by the Investigator, indicating his/her assurance of the accuracy of all recorded data. It is 
expected that the Investigator and staff will cooperate with the monitoring team and 
provide missing data in a timely manner. 
12.8 
VERIFICATION PROCEDURES 
In fulfillment of their obligations to KRI and to verify compliance with this protocol, 
ICH GCP guidance, FDA GCP regulations (in the United States), local regulations, and 
regulations in the countries in which the study is conducted, the Investigator will permit 
, the IRB/EC, the monitor, the auditors, and regulatory authorities to have direct 
access to the patient’s medical records. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the 
patient’s medical record. The patient’s medical record will be considered the source 
document and must include the following information: medical history/concomitant 
disease, patient ID number, confirmation of informed consent and the date of study 
enrollment, visit dates, administration of study drugs, AEs (start and stop dates), and all 
concomitant medications (start and stop dates). This information may not be recorded 
directly into the eCRF. 
The Investigator will maintain a Patient ID Code List to enable unambiguous ID of the 
patients (patient names and corresponding patient numbers).  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 60 of 77 
12.9 
RETENTION OF RECORDS 
All documentation pertaining to the study will be retained by KRI in accordance with 
regulatory requirements and the ICH GCP guidance document. 
 will provide each Investigator with a study file, which will be used to file the 
Investigator’s Brochure; protocol; drug accountability records; correspondence with the 
IRB/EC, KRI, and 
; and other study-related documents. 
The Investigator agrees to keep records and those documents that include (but are not 
limited to) the ID of all participating patients, medical records, study-specific source 
documents, source worksheets, all original signed and dated ICFs, copies of all eCRFs, 
query responses, and detailed records of drug disposition, to enable evaluations or audits 
from regulatory authorities and KRI or its designees. 
The Investigator will retain records required to be maintained under federal regulations 
for a period of 2 years following the date a marketing application is approved for the drug 
for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. However, these documents will be retained for a 
longer period if required by the applicable regulatory requirement(s) or if needed by KRI. 
In addition, the Investigator must make provision for the patient’s medical records to be 
kept for the same period of time. 
Patients’ medical records and other original data will be archived in accordance with 
applicable regulations and requirements established by the investigational sites. 
12.10 INSURANCE AND INDEMNITY 
Kowa Research Institute, Inc.’s obligations regarding insurance and indemnification are 
described in other documents or agreements. 
12.11 AUDIT 
It is the responsibility of 
 and KRI to perform audits (if applicable), as part of 
implementing quality assurance. The purpose of an audit, which is independent of and 
separate from routine monitoring or quality control functions, is to evaluate trial conduct 
and compliance with the protocol, SOPs, ICH/FDA GCPs, HIPAA, and other applicable 
regulatory requirements. The auditor and regulatory authorities will require direct access 
to the patients’ medical records. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 61 of 77 
 USE OF INFORMATION 
13.1 
GENERAL ASPECTS 
All information concerning 
 and KRI, such as patent applications, formula, 
manufacturing processes, basic scientific data or formulation information supplied by 
KRI and not previously published, are considered confidential and will remain the sole 
property of KRI. The Investigator agrees to use this information only in accomplishing 
this study and will not use it for other purposes without the written consent of KRI, 
except for official representatives, such as regulatory authorities. 
It is understood by the Investigator that the information developed in this clinical study, 
in connection with the development of K-877 will be used by KRI and, therefore, may be 
disclosed by KRI as required to other clinical Investigators, other pharmaceutical 
companies, and to other government agencies. In order to allow for the use of the 
information derived from clinical studies, it is understood that there is an obligation to 
provide to KRI complete test results and all data compiled in this study. 
13.2 
PATIENT CONFIDENTIALITY AND DATA PROTECTION 
Kowa Research Institute, Inc. and its designees affirm and uphold the principle of the 
patient’s right to protection against invasion of privacy. Throughout this study, all data 
will be linked to the eCRF via a unique ID number. The data will be blinded 
correspondingly in all data analyses. 
However, in compliance with the guidelines and regulations of the United States FDA 
concerning the acceptance of clinical studies in support of IND applications and the ICH 
GCP (whether performed in the United States or elsewhere), and in fulfillment of its 
obligations to KRI to verify compliance with this protocol, KRI’s designee requires that 
the Investigator permit its monitor, representatives from the FDA, KRI’s designated 
auditors, IRBs/ECs, and other governmental regulatory authorities to review the patient’s 
primary medical records (source data or documents) including, but not limited to 
laboratory test result reports, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a patient’s study participation, and autopsy reports 
related to deaths occurring during the study. 
Should access to such medical records require a waiver or authorization separate from the 
statement of informed consent, the Investigator will obtain such permission in writing 
from the patient before the patient is entered into the study. 
13.3 
FINAL REPORT AND PUBLICATION POLICY 
All information regarding this study will be kept strictly confidential. All data derived 
from the study will be the property of KRI. The Investigator must undertake not to submit 
any part of the data from this study for publication without prior consent of KRI. Kowa 
Research Institute, Inc. may disclose data derived from the study to other Investigators 
and drug regulatory authorities. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 62 of 77 
After completion of the study, and as agreed by the Investigator and KRI, the Investigator 
may send a draft manuscript to KRI to be reviewed in order to reach an agreement 
regarding publication. The Investigator must receive written approval from KRI before 
the final version of the manuscript is submitted for publication. 
At the conclusion of the study, after the data are analyzed, KRI or its designee will 
prepare a final CSR. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 63 of 77 
 REFERENCES
 
1  Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the 
Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in 
Adults; A Report of the American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines. Circulation. 2014;129:S1-S45. 
2  Miller M, Stone NJ, Ballantyne C, et al. American Heart Association Clinical 
Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, 
Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and 
Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in 
Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific 
statement from the American Heart Association. Circulation. 
2011;123(20):2292-2333. 
3  Scherer J, Singh VP, Pitchumoni CS, Yadav D. Issues in hypertriglyceridemic 
pancreatitis: an update. J Clin Gastroenterol. 2014;48(3):195-203. 
4  Anderson F, Thomson SR, Clarke DL, Buccimazza I. Dyslipidaemic pancreatitis 
clinical assessment and analysis of disease severity and outcomes. Pancreatology. 
2009;9(3):252-257. 
5  Deng LH, Xue P, Xia Q, Yang NX, Wan MH. Effect of admission 
hypertriglyceridemia on the episodes of severe acute pancreatitis. World J 
Gastroenterol. 2008;14(28):4558-4561. 
6  Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. 
Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 
1998;98:2088-2093. 
7  National Institutes of Health, National Heart, Lung, and Blood Institute. 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. 2002;pII-1-61;September 2002. 
8  Pirillo A, Catapano AL. Update on the management of severe hypertriglyceridemia – 
focus on free fatty acid forms of omega-3. Drug Des Devel Ther. 2015;9:2128-2137. 
9  Task Force for the management of dyslipidaemias of the European Society of 
Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS 
Guidelines for the management of dyslipidaemias. Eur Heart J. 2011;32:1769-1818. 
10  Package insert for Lipidil® Tablets, revised in May 2012 (2nd edition). 
11  Package insert for Bezatol® SR Tablets, revised in June 2009 (12th edition). 
12  Package insert for Clofibrate Capsules, revised in July 2009 (6th edition). 
13  Ciprofibrate 100 mg tablets, Summary of Product Characteristics at eMedicines 
Compendium. 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 64 of 77 
 
14  Lopid 300 mg capsules and 600 mg tablets, Summary of Product Characteristics at 
eMedicines Compendium. 
15  Package insert for Tricor® tablets, revised in September 2011. 
16  Package insert for Trilipix® capsule, revised in September 2012. 
17  Package insert for Lopid® tablets, revised in September 2010. 
18  US Department of Health and Human Services; National Institutes of Health; and 
National Heart, Lung and Blood Institute. Your Guide to Lowering Your Cholesterol 
With Therapeutic Lifestyle Changes. NIH Publication. December 2005; No. 06-5235.  


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
 
K-877 
 
 
13 Sep 2016 v1.0 
Page 65 of 77 
 APPENDICES 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 66 of 77 
APPENDIX A: CLINICAL LABORATORY PARAMETERS 
 
Chemistry 
Sodium  
Chloride 
Potassium 
Bicarbonate 
Calcium 
Inorganic phosphorus 
 
Blood urea nitrogen 
Creatinine 
Estimated glomerular filtration rate 
Uric acid 
 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase 
Gamma-glutamyl transpeptidase (GGT) 
Total bilirubin 
Direct bilirubin 
Albumin 
Total protein 
 
Lipase (Visits 1 and 4 only) 
Amylase (Visits 1 and 4 only) 
 
Creatine kinase (CK) 
Lactate dehydrogenase 
 
 
Glucose 
 
Insulin (Visits 4, 7, 9, 10, and 11 only) 
Glycosylated hemoglobin (HbA1c) (Visits 1, 4, 7, 9, 10, and 11 only) 
Glycated albumin (Visits 4, 7, 9, 10, and 11 only) 
Homeostasis model assessment for insulin resistance (Visits 4, 7, 9, 10, and 11 only)
Homeostasis model assessment for beta-cell function (Visits 4, 7, 9, 10, and 11 only)
Quantitative insulin sensitivity check index (Visits 4, 7, 9, 10, and 11 only) 
Homocysteine 
 
 
 
 
 
Hematology 
Hematocrit 
 
Hemoglobin 
 
Platelets 
 
Red blood cell count 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 67 of 77 
White blood cell count and differential [1] 
Mean corpuscular hemoglobin 
Mean corpuscular volume 
Mean corpuscular hemoglobin concentration 
 
1. Manual microscopic review is performed only if white blood cell count and/or 
differential values are out of reference range. 
 
Coagulation 
Fibrinogen 
Activated partial thromboplastin time 
 
International Normalized Ratio (INR) 
 
Prothrombin time 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
Bilirubin 
 
Blood 
 
Glucose 
 
Ketones 
 
Leukocyte esterase 
 
Microscopy [1] 
 
Nitrite 
 
pH 
 
Protein 
 
Specific gravity 
 
Urobilinogen 
 
Urine albumin [2] 
 
Urine creatinine [2] 
 
1. Microscopy is performed only as needed based on positive dipstick test 
results. 
2. Urine albumin:creatinine ratio will be derived based on laboratory values 
obtained at that particular visit. 
 
  
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 68 of 77 
 
 
 
Pregnancy Test 
Serum (× 1; Visit 1) and urine (× 4; Visits 4, 7, 9, and 11) pregnancy tests will be 
administered to all female patients of childbearing potential. 
 
Lipid Parameters 
The following laboratory tests will be performed to assess efficacy in this study: 
High-density lipoprotein cholesterol (HDL-C) 
Low-density lipoprotein cholesterol (LDL-C) 
Total cholesterol (TC) 
Triglycerides (TG) 
Non-HDL-C 
Free fatty acids (Visits 4, 7, 9, and 11 only) 
Lipoprotein fraction (via nuclear magnetic resonance) (Visits 4, 7, and 11 only) 
Ion mobility analysis (Visits 4, 7, and 11 only) 
Apolipoprotein (Apo) A1 (Visits 4, 5, 7, 9, and 11 only) 
Apo A2 (Visits 4, 5, 7, 9, and 11 only) 
Apo B (Visits 4, 5, 7, 9, and 11 only) 
Apo B48 (Visits 4, 5, 7, 9, and 11 only) 
Apo B100 (Visits 4, 5, 7, 9, and 11 only) 
Apo C2 (Visits 4, 5, 7, 9, and 11 only) 
Apo C3 (Visits 4, 5, 7, 9, and 11 only) 
Apo E (Visits 4, 5, 7, 9, and 11 only) 
The following values will be derived based on laboratory values obtained at that 
particular visit:  
Remnant cholesterol (calculated as TC – LDL-C – HDL-C) 
TG:HDL-C ratio 
TC:HDL-C ratio 
Non-HDL-C:HDL-C ratio 
LDL-C:Apo B ratio 
Apo B:Apo A1 ratio 
Apo C3:Apo C2 ratio 
 
Biomarkers and Exploratory Parameters 
The following laboratory tests will be performed to assess efficacy in this study: 
Fibroblast growth factor 21 (Visits 4, 7, and 11 only) 
High-sensitivity C-reactive protein (Visits 4, 7, and 11 only) 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 69 of 77 
APPENDIX B: ASSESSING STATIN ELIGIBILITY CRITERIA AND 
MONITORING STATIN USE DURING THE STUDY  
 
Table B1: Recommendations for Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults - Statin Treatment 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
Secondary Prevention 
 
1. High-intensity statin therapy should be initiated or continued as first-line 
therapy in women and men ≤75 years of age who have clinical 
ASCVD*, unless contraindicated. 
A (Strong) 
I 
A 
2. Individuals with clinical ASCVD* in whom high-intensity statin therapy 
would otherwise be used, when high-intensity statin therapy is 
contraindicated† or when characteristics predisposing to 
statin-associated adverse effects are present, moderate-intensity statin 
should be used as the second option if tolerated. 
A (Strong) 
I 
A 
3. In individuals with clinical ASCVD* >75 years of age, it is reasonable 
to evaluate the potential for ASCVD risk-reduction benefits and for 
adverse effects and drug-drug interactions and to consider patient 
preferences when initiating a moderate- or high-intensity statin. It is 
reasonable to continue statin therapy in those who are tolerating it. 
E (Expert Opinion) 
IIa 
B 
Primary Prevention in Individuals ≥21 Years of Age with LDL-C ≥190 mg/dL 
1. Individuals with LDL-C ≥190 mg/dL or TG ≥500 mg/dL should be 
evaluated for secondary causes of hyperlipidemia. 
B (Moderate) 
I‡ 
B 
2. Adults ≥21 years of age with primary LDL-C ≥190 mg/dL should be 
treated with statin therapy (10-year ASCVD risk estimation is not 
required): 
• Use high-intensity statin therapy unless contraindicated; and  
• For individuals unable to tolerate high-intensity statin therapy, use 
the maximum tolerated statin intensity. 
B (Moderate) 
I§ 
B 
3. For individuals ≥21 years of age with an untreated primary LDL-C 
≥190 mg/dL, it is reasonable to intensify statin therapy to achieve at 
least a 50% LDL-C reduction. 
E (Expert Opinion) 
IIa 
B 
4. For individuals ≥21 years of age with an untreated primary LDL-C of 
≥190 mg/dL, after the maximum intensity of statin therapy has been 
achieved, addition of a non-statin drug may be considered to further 
lower LDL-C. Evaluate the potential for ASCVD risk-reduction 
benefits, adverse effects, and drug-drug interactions, and consider 
patient preferences. 
E (Expert Opinion) 
IIb 
C 
Primary Prevention in Individuals With Diabetes and LDL-C 70-189 mg/dL
1. Moderate-intensity statin therapy should be initiated or continued for 
adults 40-75 years of age with diabetes. 
 A (Strong) 
I 
A 
2. High-intensity statin therapy is reasonable for adults 40-75 years of age 
with diabetes with a ≥7.5% estimated 10-year ASCVDǁ risk unless 
contraindicated. 
E (Expert Opinion) 
IIa 
B 
Footnotes are located at the end of the table on a later page. 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 70 of 77 
Table B1: Recommendations for Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults - Statin Treatment (Continued) 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
Primary Prevention in Individuals With Diabetes and LDL-C 70-189 mg/dL
3. In adults with diabetes, who are <40 years of age or >75 years of age, 
or with LDL <70 mg/dL it is reasonable to evaluate the potential for 
ASCVD benefits and for adverse effects and drug-drug interactions 
and to consider patient preferences when deciding to initiate, continue, 
or intensify statin therapy.  
E (Expert Opinion) 
IIa 
C 
Primary Prevention in Individuals Without Diabetes and LDL-C 70-189 mg/dL
 
1. The Pooled Cohort Equations should be used to estimate 10-year 
ASCVDǁ risk for individuals with LDL-C 70-189 mg/dL without 
clinical ASCVD* to guide initiation of statin therapy for the primary 
prevention of ASCVD. 
E (Expert Opinion) 
I 
B 
2. Adults 40-75 year of age with LDL-C 70-189 mg/dL, without clinical 
ASCVD* or diabetes and with an estimated 10-year ASCVDǁ risk of 
≥7.5% should be treated with moderate- to high-intensity statin 
therapy. 
A (Strong) 
I 
A 
3. It is reasonable to offer treatment with a moderate-intensity statin to 
adults 40-75 years of age, with LDL-C 70-189 mg/dL, without clinical 
ASCVD* or diabetes, and with an estimated 10-year ASCVDǁ risk of 5 
to <7.5%.  
C (Weak) 
IIa 
B 
4. Before initiation of statin therapy for the primary prevention of 
ASCVD in adults with LDL-C 70-189 mg/dL without clinical 
ASCVD* or diabetes, it is reasonable for clinicians and patients to 
engage in a discussion that considers the potential for ASCVD 
risk-reduction benefits and for adverse effects and drug-drug 
interactions, as well as patient preferences for treatment. 
E (Expert Opinion) 
IIa 
C 
5. In adults with LDL-C <190 mg/dL who are not otherwise identified in 
a statin benefit group, or for whom after quantitative risk assessment a 
risk-based treatment decision is uncertain, additional factors¶ may be 
considered to inform treatment decision making. In these individuals, 
statin therapy for primary prevention may be considered after 
evaluation of the potential for ASCVD risk-reduction benefits, adverse 
effects, and drug-drug interactions and consider patient preferences.  
E (Expert Opinion) 
IIb 
C 
Footnotes are located at the end of the table on the following page. 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 71 of 77 
Table B1: Recommendations for Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults - Statin Treatment (Continued) 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
*Clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial 
revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin. 
†Contraindications, warnings, and precautions are defined for each statin according to the manufacturer’s prescribing information. 
‡Individuals with secondary causes of hyperlipidemia were excluded from RCTs reviewed. A TG level ≥500 mg/dL was an 
exclusion criterion for almost all RCTs. Therefore, ruling out secondary causes is necessary to avoid inappropriate statin therapy.  
§No RCTs included only individuals with LDL-C ≥190 mg/dL. However, many trials did include individuals with 
LDL-C ≥190 mg/dL, and all of these trials consistently demonstrated a reduction in ASCVD events. In addition, the Cholesterol 
Treatment Trialists meta-analyses have shown that each 39-mg/dL reduction in LDL-C with statin therapy reduced ASCVD 
events by 22%, and the relative reductions in ASCVD events were consistent across the range of LDL-C levels. Therefore, 
individuals with primary LDL-C ≥190 mg/dL should be treated with stain therapy. 
ǁEstimated 10-year or “hard” ASCVD risk includes first occurrence of nonfatal MI, coronary heart disease death, and nonfatal and 
fatal stroke as used by the Risk Assessment Work Group in developing the Pooled Cohort Equations. 
¶These factors may include primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature 
ASCVD with onset <55 years of age in a first degree male relative or <65 years of age in a first degree female relative; 
high-sensitivity C-reactive protein ≥2 mg/L; CAC score ≥300 Agatston units, or ≥75th percentile for age, sex, and ethnicity; 
ABI <0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the 
future.  
ABI = ankle-brachial index; ACC = American College of Cardiology; AHA = American Heart Association; 
ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcium; COR = Class of Recommendation; 
LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LOE = Level of Evidence; MI = myocardial 
infarction; NA = not applicable; NHLBI = National Heart, Lung, and Blood Institute; RCT = randomized controlled trials; 
TG = triglyceride; TIA = transient ischemic attack. 
Source: American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults; Table 4 (2013) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 72 of 77 
Table B2: High-, Moderate-, and Low-Intensity Statin Therapy (Used in the RCTs 
Reviewed by the Expert Panel)* 
High-Intensity Statin Therapy 
Moderate-Intensity Statin Therapy 
Low-Intensity Statin Therapy 
Daily dose lowers LDL-C, on average, by 
approximately ≥50% 
Daily dose lowers LDL-C, on average, by 
approximately 30% to <50% 
Daily dose lowers LDL-C, on average, 
by approximately <30%  
Atorvastatin (40†)-80 mg 
Atorvastatin 10 (20) mg
Simvastatin 10 mg 
Rosuvastatin 20 (40) mg 
Rosuvastatin (5) 10 mg
Pravastatin 10-20 mg 
 
Simvastatin 20-40 mg‡
Lovastatin 20 mg 
 
Pravastatin 40 (80) mg
Fluvastatin 20-40 mg 
 
Lovastatin 40 mg 
Pitavastatin 1 mg 
 
Fluvastatin XL 80 mg 
 
 
Fluvastatin 40 mg BID 
 
 
Pitavastatin 2-4 mg 
 
Boldface type indicates specific statins and doses that were evaluated in RCTs included in CQ1, CQ2, and the Cholesterol Treatment 
Trialists 2010 meta-analysis included in CQ3. All of these RCTs demonstrated a reduction in major cardiovascular events.  
Italic type indicates statins and doses that have been approved by the FDA but were not tested in the RCTs reviewed.  
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a 
biological basis for a less-than-average response. 
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the Incremental Decrease through Aggressive 
Lipid Lowering study. 
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the 
FDA because of the increased risk of myopathy, including rhabdomyolysis.  
BID = twice daily; FDA = Food and Drug Administration; LDL-C = low-density lipoprotein cholesterol; CQ = critical question; 
RCT = randomized controlled trials. 
Source: American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults; Table 5 (2013)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 73 of 77 
Table B3: Characteristics Predisposing Individuals to Statin Adverse Effects 
Recommendations 
NHLBI Grade 
ACC/AHA 
COR 
ACC/AHA 
LOE 
Safety 
1. To maximize the safety of statins, selection of the appropriate statin 
and dose in men and nonpregnant/nonnursing women should be based 
on patient characteristics, level of ASCVD* risk, and potential for 
adverse effects. Moderate-intensity statin therapy should be used in 
individuals in whom high-intensity statin therapy would otherwise be 
recommended when characteristics predisposing them to statin-
associated adverse effects are present. 
Characteristics predisposing individuals to statin adverse effects 
include but are not limited to: 
• Multiple or serious comorbidities, including impaired renal or 
hepatic function; 
• History of previous statin intolerance or muscle disorders; 
• Unexplained ALT elevations ≥3 times ULN; 
• Patient characteristics or concomitant use of drugs affecting statin 
metabolism; 
• Age >75 years; and 
• Additional characteristics that could modify the decision to use 
higher statin intensities might include but are not limited to: 
o 
History of hemorrhagic stroke, and  
o 
Asian ancestry. 
A (Strong) 
I 
B 
*Based on the presence of clinical ASCVD, diabetes, LDL-C ≥190 mg/dL, or level of estimated 10-year ASCVD risk. 
ACC = American College of Cardiology; AHA = American Heart Association; ALT = alanine aminotransferase; 
ASCVD = atherosclerotic cardiovascular disease; COR = Class of Recommendation; NHLBI = National Heart, Lung, and Blood 
Institute; LDL-C = low-density lipoprotein cholesterol; LOE = Level of Evidence; ULN = upper limit of normal. 
Source: American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults; Table 8 (2013)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 74 of 77 
Statin Intolerance 
Statin intolerance occurs when a patient is unable to continue statin therapy due to a 
negative side effect or because creatine kinase (elevations >10 × upper limit of normal 
[ULN]) and/or hepatic transaminases (alanine aminotransferase and aspartate 
aminotransferase; elevations >3 × ULN) are sufficiently abnormal to cause concern for 
muscle and liver function, respectively. Intolerance can be partial (statin-specific and/or 
specific doses) or complete (all statins at any dose).  
Myalgia is the most common presentation of statin intolerance, which can occur in up to 
15% of treated patients. Other common presentations of statin intolerance include 
myopathy and rhabdomyolysis (see Appendix D for muscle event definitions). Table B4 
contains a complete list of potential adverse effects due to statin therapy.  
Table B4: Potential Adverse Effects of Statins 
Adverse Effects for Which There is Good 
Supportive Evidence 
Adverse Effects for Which There is Little or No 
Supportive Evidence 
Myopathy (muscle aches/cramps, myositis, 
rhabdomyolysis) 
Cancer 
Increase in liver function enzymes 
Intracerebral hemorrhage (bleeding stroke) 
New-onset diabetes mellitus 
Cognitive decline (Alzheimer disease) 
 
Lung disease 
 
Erectile dysfunction 
 
Fatigue, headaches, or dizziness 
 
Psychiatric illness 
 
Cataracts 
 
Rheumatoid arthritis 
 
Gastrointestinal upset, abdominal cramping 
 
Permanent liver or kidney damage 
Source: Cardiology Patient Page. Statin Intolerance. Circulation. 2015;131(13)e389-391; Table 2 
 
Statin intolerance will be managed by reducing the dose of statin to the maximum 
tolerated statin intensity per Table B1 and in accordance with the study design 
(see Section 8.4). 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 75 of 77 
APPENDIX C: POOLED COHORT EQUATION 
 
The Pooled Cohort Equation for estimating atherosclerotic cardiovascular disease 
(ASCVD) risk in qualified patients will be entered using the ASVCD risk estimator and 
recorded in the electronic data capture system (see Figure C1).  
Figure C1: ASCVD Risk Estimator 
 
Source: American College of Cardiology Atherosclerotic Cardiovascular Disease Risk Estimator: 
http://tools.acc.org/ASCVD-Risk-Estimator/#page_calc  
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 76 of 77 
APPENDIX D: MUSCLE ADVERSE EVENT DEFINITIONS 
 
 
Spectrum of Muscle Adverse Events 
• 
Myalgia 
Unexplained muscle discomfort often described as “flu-like” symptoms with normal 
creatine kinase (CK) level. The spectrum of myalgia complaints includes: 
Muscle aches, 
Muscle soreness, 
Muscle stiffness, 
Muscle tenderness, and 
Muscle cramps with or shortly after exercise (not nocturnal cramping). 
• 
Myopathy 
Muscle weakness (not attributed to pain and not necessarily associated with elevated 
CK). 
• 
Myositis 
Muscle inflammation. 
• 
Myonecrosis 
Muscle enzyme elevations or hyperCKemia. 
o 
Mild = >3-fold upper limit of normal. 
o 
Moderate = ≥10-fold upper limit of normal. 
o 
Severe = ≥50-fold upper limit of normal. 
• 
Myonecrosis with myoglobinuria or acute renal failure (increase in serum creatinine ≥0.5 mg/dL 
(clinical rhabdomyolysis). 
Source: Adapted from the National Lipid Association Task Force on Statin Safety – 2014 Update 
 
 


CONFIDENTIAL 
 
Kowa Research Institute, Inc.  
K-877-301, Study Protocol 
K-877 
 
 
13 Sep 2016 v1.0 
Page 77 of 77 
APPENDIX E: THERAPEUTIC LIFESTYLE CHANGES (TLC) 
 
Table E1: Summary of Lifestyle Management 
Lifestyle  
Recommended Management [1,2] 
Diet 
Maintenance of the diet outlined in Table E2 
Physical activity 
Encourage 30 minutes of moderate exercise on most, if not all, days  
Smoking  
Support cessation from using tobacco products or e-cigarettes 
Alcohol consumption 
Support abstinence from use of alcohol 
Weight management 
Provide support to patients to maintain or attain a healthy weight 
1. At each study visit, patients will be counseled on the importance of maintaining the lifestyle management guidelines 
(see Section 8.5.1). 
2. From Visit 4 (Day 1), the Investigator or designee will instruct patients to stably maintain these lifestyle changes. 
 
Source: National Institutes of Health, National Heart, Lung, and Blood Institute (2002)7 
 
 
Table E2: Summary of the TLC Diet for High Cholesterol 
TLC Diet for High Cholesterol 
Total fat 
25% - 35% total calories [1] 
Saturated fat 
<7% total calories 
Polyunsaturated fat 
up to 10% total calories 
Monounsaturated fat 
up to 20% total calories 
Carbohydrates 
50% - 60% total calories 
Protein 
~15% total calories 
Cholesterol 
<200 mg/dL 
Plant sterols 
2 g 
Soluble fiber such as psyllium 
10 g - 25 g 
1. For subjects with triglycerides >1000 mg/dL, it is recommended that <15% of total 
calories come from total fat. 
Source: National Heart, Lung, and Blood Institute (2005)18