Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT)
Phase: PHASE3
Conditions: Type2 Diabetes, Dyslipidemia
Sponsor: Kowa Research Institute, Inc.

NCT03071692 

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INVESTIGATOR’S AGREEMENT 
 
I, the Investigator, understand that all information concerning the product supplied to me in connection 
with this study and not previously published is confidential information.   
I understand that any changes to the protocol must be approved in writing by the Sponsor and the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/Research Ethics Committee 
(REC) 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); 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(ies) in which the study is 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 the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 

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administered at a dose of 0.2 mg twice daily will delay the time to first occurrence of any 
component of the clinical composite endpoint of:  
• 
nonfatal MI; 
• 
nonfatal ischemic stroke; 
• 
hospitalization for unstable angina requiring unplanned coronary revascularization; or  
• 
CV death. 
At the time of the Screening/Enrollment Visit (Visit 1), participants must be either: 
1. Receiving treatment with a stable dose (ie, for at least 12 weeks) of a qualifying 
moderate-to high-intensity statin (atorvastatin ≥ 40 mg/day, rosuvastatin ≥ 20 mg/day, 
simvastatin ≥ 40 mg/daya, or pitavastatin 4 mg/day), or  
2. Have evidence of LDL-C ≤ 70 mg/dL (1.81 mmol/L) by local laboratory determination 
within the previous 12 monthsb, or 
3. Statin intolerantc and have evidence of LDL-C ≤ 100 mg/dL (2.59 mmol/L) by local 
laboratory determination within the previous 12 months. 
a Participants enrolled on simvastatin > 40 mg/day must have been taking and tolerating that 
dose for at least 12 months. 
b If untreated or on stable dosing (ie, for at least 12 weeks) of another lipid-lowering regimen 
that may include a statin with or without ezetimibe and/or a proprotein convertase 
subtilisin/kexin type 9 (PCSK9) inhibitor 
c Statin intolerance is defined as: the inability to tolerate at least 2 statins: 1 statin at the lowest 
daily starting dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, 
lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg or pitavastatin 2 mg), AND another 
statin at any dose, due to skeletal muscle-related symptoms, other than those due to strain or 
trauma, such as pain, aches, weakness, or cramping, that begins or increases during statin 
therapy and stops when statin therapy is discontinued. Participants not receiving a daily 
regimen of a statin (e.g., 1-3 times weekly) could also be considered “statin intolerant” if they 
cannot tolerate a cumulative weekly statin dose of 7 times the lowest approved tablet size, and 
the criteria outlined above are also met. 
Methodology:  
The PROMINENT study is a randomized, double-blind, placebo-controlled, international 
study evaluating the ability of pemafibrate to prevent CV events among 10,000 male and 
female adults with T2D and moderate hypertriglyceridemia with low HDL-C, and on 
background moderate- to high-intensity statin therapy (atorvastatin ≥ 40 mg/day, rosuvastatin 
≥ 20 mg/day, simvastatin ≥ 40 mg/day, or pitavastatin 4 mg/day) unless meeting LDL-C 
criteria with or without statin intolerance. Fasting TG levels must be ≥ 200 mg/dL 
(2.26 mmol/L) and < 500 mg/dL (5.65 mmol/L) and HDL-C must be ≤ 40 mg/dL 
(1.03 mmol/L). Two-thirds of the enrolled study population will have prior evidence of 
systemic atherosclerosis (secondary prevention cohort) while one-third will not (primary 
prevention cohort, age ≥ 50 years [male] or ≥ 55 years [female]). PROMINENT will be 
conducted in 20-25 countries to ensure generalizability and allow for the enrollment and 

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follow-up period to complete in 5 years. 
The primary endpoint will be the first occurrence of nonfatal MI, nonfatal ischemic stroke, 
hospitalization for unstable angina requiring unplanned coronary revascularization, or CV 
death. The study is event-driven such that after 1,092 events have been confirmed, with a 
minimum of 200 events accrued in women, and assuming a conservative 1% annual loss to 
follow-up, there will be 90% power to detect clinically meaningful relative reductions in the 
primary endpoint of at least 18% in the pemafibrate group. In addition to spontaneous adverse 
event (AE) reporting, systematic surveillance for liver disease and muscle AEs will occur.  
This study will include the following: a Pre-Screening Visit (Visit 0), a Screening/Enrollment 
Visit (Visit 1), a 21-day (maximum 35 day) Placebo Run-In Period, a Randomization Visit 
(Visit 2), a Treatment Period consisting of approximately 30 visits (post-randomization Visits 
3 through 33, as applicable), a Common Study End Date (CSED) Visit, and a Post-Study 
Safety Call.  
During the Pre-Screening Visit (Visit 0; Week -6), participants will provide informed consent 
to participate in the study and follow-up. After consent, the site will be asked to submit 
medical records for a qualifying cardiovascular disease (CVD) event if applicable and entry 
criteria including: documentation of diabetes; documentation of statin intolerance, if 
applicable; and prior TG, HDL-C, and LDL-C levels, if available, within the last 12 months. 
Screening lab values may be used if prior local laboratory documentation is unavailable. At 
the Screening/Enrollment Visit (Visit 1; Week -3), participants will be queried regarding their 
medical histories (including clinical and lifestyle CV risk factors and alcohol use) and 
concomitant medication use, and will be screened against the inclusion/exclusion criteria. A 
physical examination comprising a general review of body systems will be performed. 
Additionally, fasting blood samples will be collected from all participants for eligibility 
assessment, including a serum pregnancy test in women of child-bearing potential (WOCP). 
Where local regulations permit, study participants may be asked to arrive fasting at the Pre-
Screening Visit (Visit 0) such that activities of the Screening/Enrollment Visit (Visit 1) can be 
performed concurrently with the Pre-Screening Visit. For expediency, participants meeting all 
applicable inclusion and exclusion criteria at the end of the Screening/Enrollment Visit 
(Visit 1), other than screening TG, HDL-C, and other exclusionary lab testing, can be enrolled 
into the Placebo Run-In Period while awaiting results of qualifying laboratory testing. Placebo 
tablets will be dispensed to participants at Visit 1 along with administration instructions for the 
Placebo Run-In Period, which is designed to select compliant individuals for long-term 
follow-up and adherence. The placebo dosing card will contain sufficient placebo tablets for a 
maximum duration of 35 days. 
On a one-time basis, at the optional Retesting Visit (Visit 1.1), participants may undergo 
retesting for borderline lipid values, specifically TG 175-199 mg/dL (1.98-2.25 mmol/L) or 
500-650 mg/dL (5.65-7.34 mmol/L) and/or HDL-C 41-45 mg/dL (1.06-1.16 mmol/L).  
Rescreening of participants for failure to meet other eligibility criteria (eg, hemoglobin A1c 
[HbA1c] >9.5%, severe hypertension, or medical instability of concurrent clinical condition) 
may occur once only. Prior to Randomization, serious adverse events (SAEs) and primary 
endpoints will be recorded and adjudicated, respectively. Thereafter, all AEs and endpoints 

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will be assessed. 
Participants who continue to be eligible, are compliant with medication during the Placebo 
Run-In Period, and have completed submission of relevant medical records will return for the 
Randomization Visit (Visit 2; Week 0) to be randomly allocated in a 1:1 ratio to receive either 
pemafibrate at a dose of 0.2 mg twice daily or a matching placebo tablet to be taken twice 
daily. A non-fasting sample for lipid testing will be collected, and the participant will complete 
a quality of life questionnaire. Importantly, in addition to other eligibility criteria, randomized 
participants must have the following: 
• 
Medical record documentation of diabetes longer than 12 weeks duration 
• 
Medical record documentation of a qualifying CV event (if secondary prevention 
cohort) 
• 
TG levels ≥ 200 mg/dL (2.26 mmol/L) and < 500 mg/dL (5.65 mmol/L) 
• 
HDL-C ≤ 40 mg/dL (1.03 mmol/L)  
• 
LDL-C ≤ 70 mg/dL (1.81 mmol/L) if not on qualifying statin regimen or ≤ 100 mg/dL 
(2.59 mmol/L) if documented statin intolerant 
At 2-weeks post randomization (Visit 3), sites will perform a well-being telephone visit to 
provide general support and to reinforce dosing instructions. Adverse events and endpoints 
will also be collected. If a participant reports or is reported to have an efficacy endpoint, then 
additional data about the nature and date of the event, and the treatment and care provided 
during and after the event will be collected by the investigator. 
Throughout the treatment period, beginning with Month 2 (Visit 4), telephone visits will 
alternate with in-person visits occurring approximately every 2 months after Month 10. During 
each telephone call and in-person visit, concomitant medication use will be reviewed, and the 
participant will be queried for AEs and efficacy events. During the in-person visits, in 
addition, physical examinations will be performed and vital signs will be measured, change in 
risk factors will be documented, and study drug compliance will be determined by tablet 
count.  
At the Months 4 and 12 visits, at annual visits thereafter (ie, Months 24, 36, 48, and 60, as 
applicable) and at the CSED Visit, fasting blood samples and urine samples will be collected 
for safety and efficacy assessments. After Month 12, blood samples will also be collected for 
safety assessment (chemistry panel only) at each intervening in-person visit (eg, Months 16, 
20, 28, 32, etc.) throughout the study. Frequency of these additional blood safety 
measurements may be reduced to once annually after DSMB review of blood safety data. In 
addition, WOCP will undergo serum pregnancy testing. At the Month 6 visit an on-treatment, 
non-fasting sample will be collected. Participants will complete a quality of life questionnaire 
annually, at the first in-person visit after a study endpoint occurs, and at the CSED Visit. 
Lipid parameters will be measured in all participants, including testing for TG, HDL-C, 
LDL-C (direct and calculated), very low-density lipoprotein cholesterol (VLDL-C) and 
non-HDL-C (both calculated), total cholesterol (TC), apolipoprotein B (ApoB), ApoE, directly 
measured remnant cholesterol, ApoA1, ApoC3, LDL-C by beta-quantification (preparative 

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ultracentrifugation [PUC]), lipoprotein particles (nuclear magnetic resonance size, 
concentrations, and subfractions), HDL-TG and LDL-TG by PUC, and directly measured 
small dense LDL-C (sdLDL-C) and low-density lipoprotein associated triglycerides (LDL-
TG). Inflammatory and glycemic parameters will be measured in all participants and include 
high-sensitivity C-reactive protein (hsCRP), fasting glucose, hemoglobin A1c (HbA1c), and 
fibroblast growth factor-21 (FGF-21). A subcohort of participants in the United States (US) 
and Canada will have additional blood testing for ApoA5, ApoB48, angiopoietin-like 3 
(ANGPTL3), ANGPTL4, PSCK9 mass, cytokeratin-18 (CK-18), and type IV collagen. 
At Screening/Enrollment, Randomization, and Month 4 Visits, a blood sample will be 
collected for archiving in countries and sites approved by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Research Ethics Committee (REC) and regulatory 
authorities, as applicable. 
Throughout the course of the study, several steps will be taken to minimize changes in LDL-C 
lowering therapies including frequent monitoring of ApoB with guided institution of 
additional lipid lowering therapy for evidence of persistent ApoB elevation when evident. 
The CSED Visit will be scheduled within a 60-day window after the study termination is 
announced, irrespective of the date that the participants were randomized. At the CSED Visit, 
participants will undergo physical examinations, risk factors will be documented, and study 
drug compliance will be determined by unused tablet count. Additionally, WOCP will undergo 
a serum pregnancy test. Finally, fasting blood and urine samples will be collected from all 
participants for safety and efficacy assessments. A Post Study Safety Call will follow 30 days 
later to collect post study efficacy events and SAEs.  
Participants will be followed for an average period of approximately 4 years after 
randomization; estimated study duration is 5 years. The study will be completed when the 
required number of adjudicated and confirmed primary endpoints have accrued. The aim is to 
collect a complete set of data from all participants from the time of randomization to the end 
of the study. Participants should be encouraged to continue taking their assigned study 
medication during the entire treatment period, with as little change of background medication 
as possible, even if they experience an AE or event which constitutes a study endpoint. 
Participants who discontinue their medication for any reason and are not able to recommence 
therapy should still continue to be followed for the collection of data and samples. 
PROMINENT will be conducted to fulfill all international standards of Good Clinical Practice 
(GCP) to ensure that a positive finding will lead to changes in the care of at-risk participants 
globally and to a labeling indication for CV event reduction for pemafibrate by worldwide 
regulatory authorities.  
Number of Participants (planned):  
Approximately 10,000 participants will be randomized in a 1:1 ratio to receive either 
pemafibrate or matching placebo. 

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Diagnosis and Inclusion Criteria: 
Participants must meet all of the following criteria for enrollment into the study: 
1. Fasting TG ≥ 200 mg/dL (2.26 mmol/L) and < 500 mg/dL (5.65 mmol/L) at Visit 1 
(Screening/Enrollment Visit) or Visit 1.1 (Retest) 
2. HDL-C ≤ 40 mg/dL (1.03 mmol/L) at Visit 1 (Screening/Enrollment Visit) or Visit 1.1 
(Retest) 
3. Type 2 diabetes of longer than 12 weeks duration documented in medical records, for 
example: local laboratory evidence through medical record review of elevated HbA1c 
(≥ 6.5% [48 mmol/mol]), elevated plasma glucose (fasting ≥ 126 mg/dL [7.0 mmol/L], 
2-hour ≥ 200 mg/dL [11.1 mmol/L] during oral glucose tolerance testing, or random 
value ≥ 200 mg/dL with classic symptoms, or currently taking medication for treatment 
of diabetes; AND either 
a) Age ≥ 50 years if male or ≥ 55 years if female (primary prevention cohort); OR 
b) Age ≥ 18 years and established systemic atherosclerosis (secondary prevention 
cohort), defined as any 1 of the following: 
i. Prior MI or ischemic (non-hemorrhagic) stroke 
ii. Coronary angiographic lesion of ≥ 60% stenosis in a major epicardial 
vessel or ≥ 50% left main stenosis 
iii. Asymptomatic carotid disease with ≥ 70% carotid artery stenosis  
iv. Symptomatic carotid disease with ≥ 50% carotid artery stenosis 
v. Symptomatic lower extremity peripheral artery disease (PAD) 
(ie, intermittent claudication, rest pain, lower extremity ischemic 
ulceration, or major amputation with either ankle-brachial index ≤ 0.9 or 
other diagnostic testing [eg, toe-brachial index, angiogram, or other 
imaging study]) 
vi. Prior arterial revascularization procedure (including coronary, carotid, 
or peripheral angioplasty/stenting, bypass, or 
atherectomy/endarterectomy) 
4. In addition, by Visit 1 (Screening/Enrollment Visit), participants must be either:  
a) Receiving treatment with a stable dose (ie, for at least 12 weeks) of a qualifying 
moderate- to high-intensity statin (atorvastatin ≥ 40 mg/day, rosuvastatin 
≥ 20 mg/day, simvastatin ≥ 40 mg/day*, or pitavastatin 4 mg/day); or  
b) Have evidence of LDL-C ≤ 70 mg/dL (1.81 mmol/L) by local laboratory 

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determination within the previous 12 months#, or 
c) Statin intolerant+ and have evidence of LDL-C ≤ 100 mg/dL (2.59 mmol/L) by local 
laboratory determination within the previous 12 months. 
* Participants enrolled on simvastatin > 40 mg/day must have been taking and tolerating 
that dose for at least 12 months.  
# If untreated or on stable dosing (ie, for at least 12 weeks) of another lipid-lowering 
regimen that may include a statin with or without ezetimibe and/or a PCSK9 inhibitor 
+ Statin intolerance is defined as: the inability to tolerate at least 2 statins: 1 statin at the 
lowest daily starting dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 
10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg or pitavastatin 2 mg), 
AND another statin at any dose, due to skeletal muscle-related symptoms, other than 
those due to strain or trauma, such as pain, aches, weakness, or cramping, that begins or 
increases during statin therapy and stops when statin therapy is discontinued. Participants 
not receiving a daily regimen of a statin (e.g., 1-3 times weekly) could also be considered 
“statin intolerant” if they cannot tolerate a cumulative weekly statin dose of 7 times the 
lowest approved tablet size, and the criteria outlined above are also met. 
5. Ability to understand and comply with study procedures and give written informed 
consent. 
Exclusion Criteria: 
Presence of exclusionary criteria will be assessed at the Screening/Enrollment Visit (Visit 1), 
which is then followed by a 21-day Placebo Run-In Period preceding randomization into the 
study. Participants are excluded from participation if any of the following criteria apply: 
1. Current or planned use of fibrates or agents with potent peroxisome proliferator 
activated receptor (PPAR)-α agonist activity (eg, saroglitazar) within 6 weeks 
(42 days) of Visit 1 (Screening/Enrollment Visit). Note: PPAR-γ agonists (eg, 
glizatones such as pioglitazone and rosiglitazone) are allowed 
2. Known sensitivity to PPAR-α agonists or tablet excipients 
3. Initiation of, or change in, current TG-lowering therapy within 12 weeks of Visit 1 (if 
applicable). Note: TG-lowering therapy is defined as niacin > 100 mg/day or dietary 
supplements or prescription omega-3 fatty acids > 1 g/day 
4. Type 1 diabetes mellitus 
5. Uncontrolled diabetes mellitus as defined by a HbA1c > 9.5% [80 mmol/mol] at 
Visit 1 (Screening/Enrollment Visit) 
6. Untreated or inadequately treated hypothyroidism [thyroid stimulating hormone (TSH) 
> 2.0 X the upper limit of normal (ULN) or free thyroxine (T4) ≤ ULN] or 
hyperthyroidism; controlled thyroid disease (permitted) requires normal TSH and 

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stable therapy for at least 4 weeks 
7. Recent CVD event (eg, MI or stroke) within 8 weeks of Visit 2 (Randomization Visit) 
8. Recent or planned vascular intervention within 8 weeks of Visit 2 (Randomization 
Visit) 
9. New York Heart Association Class IV heart failure (HF) 
10. Known homozygous familial hypercholesterolemia (heterozygous is permitted) or 
familial hypoalphalipoproteinemia 
11. Documented previous occurrence of myositis/myopathy  
12. Unexplained creatine kinase (CK) > 5 X ULN  
13. Liver disease defined as cirrhosis or Child-Pugh class B and C, or alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 X ULN 
14. Biliary obstruction or hyperbilirubinemia (ie, total bilirubin > 2 X ULN, except with a 
documented diagnosis of Gilbert’s disease) 
15. Chronic renal insufficiency, defined by an estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) formula or kidney transplant, regardless of renal function 
16. Unexplained anemia (hematocrit ≤ 30%) 
17. Uncontrolled hypertension (seated systolic blood pressure > 160 mmHg and/or 
diastolic blood pressure > 100 mmHg) at Visit 2 (Randomization Visit). 
18. History of chronic active hepatitis B or hepatitis C, or known infection with human 
immunodeficiency virus (HIV); participants with documented hepatitis C resolution 
after treatment are permitted 
19. Active malignancy, except non-melanoma skin cancer or carcinoma in situ of the 
cervix, within the last 2 years. 
20. Prior organ transplant or any condition likely to lead to organ transplantation in the 
next 5 years 
21. Current or anticipated chronic use of cyclosporine, rifampicin, or other inhibitors of 
organic anion transporting polypeptides (OATP)1B1, or OATP1B3 
22. History of alcoholism or unwillingness to limit alcohol intake to < 15 alcoholic 
beverages (or units) per week or < 5 alcoholic beverages (or units) during a single 
occasion for men and < 8 alcoholic beverages (or units) per week or < 4 alcoholic 
beverages (or units) during a single occasion for women during the study period. Note: 

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One alcoholic beverage (unit) is defined as 12 oz. (350 mL) of beer, 5 oz. (150 mL) of 
wine, or 1.5 oz. (45 mL) of liquor 
23. History of hereditary problems of galactose intolerance, Lapp lactase deficiency, or 
glucose-galactose malabsorption 
24. Women who are pregnant, lactating, planning to be pregnant or lactating during the 
study period, or WOCP who are not using an acceptable method of contraception 
WOCP are adult females who are sexually active with a non-sterilized male 
partner unless she meets 1 of the following criteria as documented by the investigator:  
• history of hysterectomy or tubal ligation prior to signing the informed consent form 
(ICF); or  
• menopause, defined as either a) age > 50 years old and ≥ 1 year since last 
menstrual period or documented follicle-stimulating hormone (FSH) level in the 
post-menopausal range or b) for women ≤ 50 years old, ≥ 2 years since her last 
menstrual period without an alternative medical cause, and documented FSH level 
in the post-menopausal range 
To be eligible, WOCP must have a negative pregnancy test at Visit 1 
(Screening/Enrollment Visit) and agree to use an adequate method of contraception 
during the study and for 1 additional menstrual cycle following the final study visit. 
Adequate methods of contraception for WOCP include: oral, implanted or injectable 
contraceptive hormones; mechanical products (eg, intrauterine device [IUD]); or 
barrier methods (eg, diaphragm, condoms, cervical cap) with spermicide. Local 
regulatory authorities or IRB/IEC/REC may impose additional restrictions on 
acceptable contraceptive methods which must be applied by relevant sites and be 
documented in the investigator study documents. The participant’s understanding of 
the contraceptive requirements must be documented by the investigator. 
25. A medical condition, other than vascular disease, with life expectancy < 3 years, which 
might prevent the participant from completing the study 
26. Any factors likely to limit adherence to the study medications and procedures, such as 
substance abuse, dementia, plans to move within the next 2 years, and/or history of 
noncompliance with medication or scheduled appointments, and 
27. Participation in another clinical study at the time of informed consent, or has received 
an investigational drug within 90 days before signing the informed consent for this 
study. 
Participants with uncontrolled diabetes, uncontrolled hypertension, uncontrolled thyroid 
disease, recent CVD event or revascularization procedure, or other medical instability due to 
an intervening medical condition may be re-evaluated for re-screening at the investigator’s 
discretion once remedies have been instituted and the participant is stable for at least 4 weeks 
(28 days) at the time of the repeat Pre-Screening Visit (Visit 0). Re-screening may occur on a 

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one-time basis only and should occur after a discussion with the 
 Medical Monitor. 
Investigational product, dosage and mode of administration:  
Test Product: 
K-877 (pemafibrate) 0.2 mg 
Dose:  
1 tablet twice daily  
Mode of Administration:  Oral 
Duration of treatment:  
The total expected treatment duration is up to 5 years, with an expected average follow-up 
period of approximately 4 years.  
Reference product, dosage and mode of administration:  
Reference Product: 
Matching placebo tablet (placebo)  
Dose:  
1 tablet twice daily  
Mode of Administration:  Oral 
Criteria for evaluation: 
Efficacy: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the time from randomization to the first occurrence of any 
component of the clinical composite endpoint of:  
• Nonfatal MI 
• Nonfatal ischemic stroke 
• Hospitalization for unstable angina requiring unplanned coronary revascularization 
• Cardiovascular death 
Secondary Clinical Efficacy Endpoints:  
The group A (clinical) endpoints are time to first occurrence of: 
1. Any component of the 3-component composite endpoint of non-fatal MI, non-fatal 
stroke, or cardiovascular death 

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2. Any component of the primary endpoint or hospitalization for HF 
3. Any component of the primary endpoint or all-cause mortality 
4. Any component of the primary endpoint, any coronary revascularization, or 
hospitalization for HF 
5. Any new or worsening PAD, defined as incidence of lower extremity 
revascularization, intermittent claudication, rest pain, lower extremity ischemic 
ulceration, or major amputation with either ankle-brachial index ≤ 0.9 or other 
diagnostic testing (eg, toe-brachial index, angiogram, or other imaging study) 
The group B (lipid) endpoints are: 
• The change from Screening/Enrollment Visit (Visit 1) to Month 4 Visit (Visit 5) for the 
following lipid biomarkers: TC, TG, HDL-C, non-HDL-C (calculated), VLDL-C 
(calculated), ApoA1, ApoC3, and ApoE; and 
• The change from Randomization Visit (Visit 2) to Month 6 Visit (Visit 6) for non-
fasting remnant cholesterol 
* VLDL-C will be calculated as TC minus HDL-C minus LDL-C, where LDL-C is 
measured by a direct homogenous method. 
Tertiary Efficacy Endpoints: 
Tertiary endpoints include microvascular endpoints (ie, diabetic retinopathy and diabetic 
nephropathy as defined below) as well as exploratory mechanistic studies evaluating 
differences in average achieved levels and change from baseline between pemafibrate and 
placebo arms in: 
• Core lipid parameters (total cohort): TG, HDL-C, calculated and directly measured 
LDL-C, calculated VLDL-C and non-HDL-C, TC, ApoB, ApoE, and directly 
measured remnant cholesterol 
• Advanced lipid parameters (total cohort): ApoA1, ApoC3, LDL-C by 
beta-quantification (PUC), lipoprotein particles (nuclear magnetic resonance [NMR] 
size, concentrations, and subfractions), HDL-TG and LDL-TG by PUC, and directly 
measured sdLDL-C and LDL-TG 
• Inflammatory and glycemic parameters (total cohort): hsCRP, fasting glucose, 
HbA1c, and FGF-21 
• Expanded exploratory lipid and non-lipid parameters (US/Canada subcohort): 
ApoA5, ApoB48, ANGPTL3, ANGPTL4, PCSK9 mass, CK-18, and type IV collagen 
Microvascular endpoints will also be examined. These will include diabetic retinopathy, 

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defined as use of retinal laser treatment, anti-vascular endothelial growth factor therapy, or 
vitrectomy due to development of and/or deterioration in diabetic retinopathy and blindness; 
and diabetic nephropathy, defined as an increase in microalbumin/creatinine ratio to 
> 30 mg/g among those without microalbuminuria at baseline, or categorical change from 
baseline albuminuria (normo-, micro-, or macroalbuminuria), doubling of creatinine from 
baseline, creatinine level > 6.0 mg/dL, eGFR < 15 mL/min/1.73 m2, or initiation of renal 
replacement therapy (dialysis or transplant) among all participants. 
Safety: 
Safety will be evaluated through a comprehensive assessment of the extent of exposure to 
study drug, the occurrence of AEs, clinical laboratory tests (chemistry, hematology, and 
urinalysis), vital signs (blood pressure, heart rate, height, body weight, waist circumference, 
body mass index [BMI]), and physical examinations comprising of a general review of body 
systems. 
Statistical methods: 
Sample Size Justification: 
Sample size and power have been estimated using an event-driven approach where all 
participants are followed until a sufficient number of events have accrued. All estimates are 
based on a 2-sided log-rank test comparing the time to occurrence between the 2 treatment 
groups at the 0.05 significance level, incorporating interim analyses. These estimates use the 
approach of Lachin and Foulkes under the assumption of a uniform hazard and allow for a 1% 
annual attrition rate due to drop-outs.  
In order to achieve 90% power to detect the anticipated 18% reduction in the rate of the 
primary endpoint in the pemafibrate arm compared to placebo, at least 1,092 participants who 
meet a component of the primary endpoint are required, with a minimum of 200 events 
accrued in women. Given the study sample size of 10,000 participants, an expected enrollment 
period of 30 months, and an anticipated annual event rate of 3.5 to 4.5 per 100 person-years in 
the placebo group, the expected study duration is 5 years (with a 3.75-year average follow-up 
with approximately uniform enrollment). 
Primary Analyses: 
The primary analysis of the study will use a likelihood ratio test based on a proportional 
hazards model stratified sex, prior history of CVD (primary vs. secondary prevention cohorts), 
and statin use at baseline (defined as those who are taking no statin at baseline or are statin 
intolerant compared to all others) to test the null hypothesis of no association between 
assignment to pemafibrate and the rate of the primary endpoint. The Intent-To-Treat (ITT) 
population will serve as the primary analysis population and will include all randomized 
participants who received at least 1 dose of study treatment. Participants will be analyzed 
according to their randomized treatment group, regardless of whether they adhere to their 
assigned treatment. Statistical significance will be based on a 2-sided test with level 0.05. The 
estimated relative hazard in the pemafibrate group compared to the placebo group with an 

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accompanying 95% confidence interval (CI) will quantify the treatment effect. If this relative 
hazard is less than 1, then 100*(1-estimated relative hazard) will be defined as the percent 
reduction in hazard associated with pemafibrate treatment. Rates of occurrence of the primary 
endpoint will be defined as the total number of participants who have this event in a treatment 
group per 100 person-years of follow-up, counting all time from randomization until the event, 
death, end of trial, or withdrawal of consent, whichever comes first. Estimates of the 
probability of the primary endpoint by time after randomization within treatment groups will 
be based on the method of Kaplan and Meier. We will also use the proportional hazards model 
to control for baseline factors that might influence the rate of the primary endpoint (eg, age, 
race, sex, baseline comorbidities, and concomitant medications), as control for these variables 
may yield more efficient estimates of relative treatment effects. If Kaplan-Meier plots of 
event-free survival by study time, or related plots of log (-log) (survival), indicate violations of 
the proportional hazards assumption, or a formal test of trend in the scaled Schoenfeld 
residuals indicates such a violation, then weighted log-rank tests will be used according to 
strategies described by Pecková and Fleming. However, even in the presence of an apparent 
violation of the proportional hazards assumption, the primary analysis described above gives a 
valid (although perhaps not optimal) test of the main study hypothesis and will remain the 
primary analytic strategy, with these weighted log-rank tests serving as sensitivity analyses.  
Secondary Analyses: 
Secondary clinical endpoint analyses will follow the same outline as the primary analysis for 
time to event data. Secondary lipid efficacy endpoints will use analysis of covariance with 
adjustment for baseline measurements and imputation of missing values. 
Safety Analyses: 
The safety population includes all participants who received at least 1 dose of study treatment. 
Participants will be analyzed according to their randomized treatment group, unless a 
participant inadvertently receives the incorrect drug during the entire study, in which case, the 
participant will be grouped according to the treatment actually received. Safety analyses will 
include comparisons of post-randomization laboratory values by treatment group and rates of 
SAEs and AEs by treatment group, both overall and within system organ class (SOC). 
Planned Interim Analyses: 
To preserve alpha and to minimize the likelihood of an inflated effect estimate associated with 
early stopping, preplanned efficacy analyses will occur only upon accrual of approximately 
50% and 75% of the planned study primary endpoints. The design of the study, including 
evaluation of the implications of interim monitoring on study power, considered that stopping 
boundaries will be based on the Haybittle-Peto method. Inefficacy will be assessed at 30%, 
50%, and 75% of endpoints, based upon the Linear 10% Inefficacy Boundary approach 
described by Freidlin, Korn, and Gray. 
 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
Investigator’s Agreement ............................................................................................................. 2 
PROTOCOL SIGNATURE PAGE ............................................................................................. 3 
1. 
Synopsis .............................................................................................................................. 4 
2. 
Table of Contents, List of Tables, and List of Figures ................................................ 17 
3. 
List of Abbreviations and Definitions of Terms ........................................................... 25 
4. 
Introduction ..................................................................................................................... 29 
4.1. 
Evolving Role of Hypertriglyceridemia in Cardiovascular Disease 
Prevention ............................................................................................................ 29 
4.2. 
Triglyceride Elevation, Remnant Cholesterol, and ApoC3 in 
Atherogenesis: Targets for PPAR-α Modulation ............................................. 29 
4.3. 
Epidemiologic and Mendelian Randomization Data Support a 
Causal Link.......................................................................................................... 31 
4.4. 
Fibrates, Triglyceride Reduction, and Cardiovascular Events: 
Evidence from Prior Randomized Clinical Studies ......................................... 32 
4.5. 
Current Guidelines for the Classification and Treatment of 
Hypertriglyceridemia ......................................................................................... 33 
4.6. 
Prevention of CVD Among Diabetic Patients: Targeting of PPAR-
α Agonism in the Right Patient Population ...................................................... 34 
4.7. 
Drug Profile from Nonclinical and Clinical Studies ........................................ 38 
4.7.1. 
Nonclinical Studies ................................................................................. 38 
4.7.2. 
Clinical Studies ....................................................................................... 38 
4.8. 
Benefit-Risk Assessment ..................................................................................... 40 
5. 
Trial Objectives and Endpoints ..................................................................................... 42 
5.1. 
Primary Objective ............................................................................................... 42 
5.1.1. 
Primary Endpoint .................................................................................... 43 

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5.2. 
Secondary Objective ........................................................................................... 43 
5.2.1. 
Group A: Clinical Endpoints .................................................................. 43 
5.2.2. 
Group B: Lipid Endpoints ...................................................................... 44 
5.3. 
Tertiary Objective ............................................................................................... 44 
5.3.1. 
Tertiary Endpoints .................................................................................. 44 
6. 
Investigational Plan ........................................................................................................ 46 
6.1. 
Overall Study Design .......................................................................................... 46 
6.2. 
Number of Participants ...................................................................................... 54 
6.3. 
Treatment Assignment ....................................................................................... 54 
6.4. 
Study Drug Dose Adjustment Criteria ............................................................. 54 
6.5. 
Study Withdrawal ............................................................................................... 54 
6.5.1. 
Overall Study Termination ..................................................................... 54 
6.5.2. 
Study Termination at Investigational Sites ............................................. 54 
7. 
Selection and Withdrawal of Participants .................................................................... 55 
7.1. 
Participant Inclusion Criteria ............................................................................ 55 
7.2. 
Participant Exclusion Criteria ........................................................................... 56 
7.3. 
Study Drug Discontinuation .............................................................................. 59 
7.3.1. 
Study Drug Discontinuation Criteria for Persistent Abnormal 
Clinical Laboratory Values ..................................................................... 59 
7.4. 
Follow-up after Early Study Drug Discontinuation or Withdrawal .............. 61 
7.4.1. 
Lost-to-Follow-up ................................................................................... 61 
8. 
Treatment of Participants .............................................................................................. 62 
8.1. 
Description of Study Drug ................................................................................. 62 
8.2. 
Concomitant Medications .................................................................................. 62 
8.2.1. 
Contraindicated Medications .................................................................. 63 
8.2.2. 
Statins and Other LDL-Lowering Therapies .......................................... 63 

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8.2.3. 
Rescue Therapy for Persistently Elevated TG During the 
Study ....................................................................................................... 65 
8.2.4. 
Other Study Restrictions ......................................................................... 66 
8.3. 
Treatment Compliance ....................................................................................... 66 
8.4. 
Randomization and Blinding ............................................................................. 66 
9. 
Study Drug Materials and Management ...................................................................... 68 
9.1. 
Study Drug ........................................................................................................... 68 
9.2. 
Study Drug Packaging and Labeling ................................................................ 68 
9.3. 
Study Drug Storage............................................................................................. 69 
9.4. 
Study Drug Preparation ..................................................................................... 69 
9.5. 
Study Drug Administration ............................................................................... 69 
9.6. 
Study Drug Accountability................................................................................. 70 
9.7. 
Study Drug Handling and Disposal ................................................................... 70 
10. 
Study Procedures ............................................................................................................ 71 
10.1. Pre-Screening Visit (Visit 0) ............................................................................... 71 
10.2. Screening/Enrollment Visit (Visit 1) ................................................................. 73 
10.2.1. Re-screening (if applicable) ................................................................... 74 
10.3. Retesting Visit (Visit 1.1) (if applicable) ........................................................... 74 
10.4. Randomization Procedures and the Randomization Visit (Visit 2) ............... 74 
10.5. Treatment Period Telephone Visits: Week 2 and at 4-Month 
Intervals ............................................................................................................... 76 
10.6. Treatment Period In-Person Visits: 4-Month Intervals Starting at 
Month 4 ................................................................................................................ 76 
10.7. Common Study End Date (CSED) Visit ........................................................... 78 
11. 
Assessment of Efficacy .................................................................................................... 80 
11.1. Monitoring for the Occurrence of Cardiovascular Events ............................. 80 

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11.2. Monitoring for the Occurrence of Diabetes-Related Events and 
Parameters ........................................................................................................... 89 
11.3. Monitoring of Tertiary Efficacy Endpoints (Biomarkers) .............................. 89 
11.4. Future Genetic Testing ....................................................................................... 90 
11.5. Archival of Blood Samples ................................................................................. 90 
12. 
Assessment of Safety ....................................................................................................... 91 
12.1. Safety Parameters ............................................................................................... 91 
12.1.1. Vital Signs and Physical Examination ................................................... 91 
12.1.2. Laboratory Assessments ......................................................................... 91 
12.1.2.1. Safety Laboratory Tests ........................................................ 91 
12.1.2.2. Reporting of Critical Laboratory Values .............................. 92 
12.1.3. Pregnancy Screen ................................................................................... 93 
12.2. Adverse and Serious Adverse Events ................................................................ 93 
12.2.1. Definition of Adverse Events ................................................................. 93 
12.2.1.1. Adverse Events ..................................................................... 93 
12.2.1.2. Serious Adverse Events ........................................................ 93 
12.2.2. Adverse Event Severity .......................................................................... 94 
12.2.3. Relationship to Study Drug .................................................................... 94 
12.2.4. Action Taken Due to AE ........................................................................ 95 
12.2.5. Adverse Event Outcomes ....................................................................... 96 
12.2.6. Adverse Event Collection Period ........................................................... 96 
12.2.7. Adverse Events of Special Interest ......................................................... 96 
12.2.8. Pregnancy 97 
12.3. Recording Adverse Events ................................................................................. 97 
12.3.1. Detection and Initial Report of Adverse Events ..................................... 97 
12.3.2. Trial Endpoints and Adverse Events ...................................................... 97 

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12.3.3. Reporting Adverse Events ...................................................................... 97 
12.3.3.1. Investigator Responsibilities ................................................ 97 
12.3.3.2. Sponsor Responsibilities ...................................................... 98 
12.4. Data Safety Monitoring Board (DSMB) ........................................................... 99 
13. 
Patient Reported Outcomes ......................................................................................... 100 
13.1. Quality of Life Assessment ............................................................................... 100 
14. 
Statistics ......................................................................................................................... 101 
14.1. Stratification and Randomization ................................................................... 101 
14.2. Sample Size and Power ..................................................................................... 101 
14.3. Demographics and Baseline Characteristics .................................................. 103 
14.4. Primary Analyses .............................................................................................. 103 
14.5. Secondary and Tertiary Analyses.................................................................... 104 
14.6. Subgroup Analyses............................................................................................ 105 
14.7. Planned Interim Analyses ................................................................................ 105 
15. 
Direct Access to Source Data/Documents ................................................................... 107 
15.1. Study Monitoring .............................................................................................. 107 
15.1.1. Committees ........................................................................................... 107 
15.1.2. Data Coordinating Center and Treatment Masking .............................. 108 
15.1.3. Data and Safety Monitoring Board (DSMB) ........................................ 108 
15.2. Audits and Inspections ..................................................................................... 108 
16. 
Quality Control and Quality Assurance ..................................................................... 110 
17. 
Ethics .............................................................................................................................. 111 
17.1. Ethics Review .................................................................................................... 111 
17.2. Ethical Conduct of the Study ........................................................................... 111 
17.3. Written Informed Consent ............................................................................... 112 
18. 
Data Handling and Recordkeeping ............................................................................. 113 

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18.1. Electronic Data Capture ................................................................................... 113 
18.2. Source documents ............................................................................................. 114 
18.3. Inspection of Records ....................................................................................... 115 
18.4. Retention of Records......................................................................................... 115 
19. 
Publication Policy.......................................................................................................... 116 
20. 
List of References .......................................................................................................... 117 
21. 
Appendices ..................................................................................................................... 123 
21.1. Appendix A: Schedule of Laboratory Testing................................................ 124 
21.2. Appendix B: Serious Adverse Event Endpoints Exempted from 
Regulatory Reporting ....................................................................................... 126 
 

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LIST OF TABLES 
Table 1: 
Mendelian Randomization Studies of Genetic Variants, Associations with 
TG Elevation, and CVD Events ..................................................................................31 
Table 2: 
Guideline-Specified Categories of Hypertriglyceridemia ..........................................34 
Table 3: 
Placebo Event Rate and Risk Reduction in Major Cardiovascular Disease 
Prevention Trials in Patients with Diabetes With/Without Baseline CVD and 
With/Without Baseline Elevated TG ..........................................................................36 
Table 4: 
Study Design and Schedule of Assessments ..............................................................50 
Table 5: 
Investigational Product ...............................................................................................62 
Table 6: 
Number of Events and Estimated Study Duration in Years to Achieve 90% 
Power with 10,000 Randomized Participants ...........................................................102 
 

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LIST OF FIGURES 
Figure 1: 
Hypotheses to Explain Why Hypertriglyceridemia is Pro-Atherogenic .....................30 
Figure 2: 
Relative Risk Reduction Compared with Placebo ......................................................33 
Figure 3: 
Approaches to Minimize Changes in Statins and Other LDL-Lowering 
Therapies During the Study ........................................................................................65 
Figure 4: 
Screening Approach - Ascertainment of Qualifying TG and HDL-C ........................72 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Explanation 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANGPTL 
Angiopoietin-like 
Apo 
Apolipoprotein 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BCRP 
Breast cancer resistance protein 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass grafting 
CAD 
Coronary artery disease 
CBC 
Complete blood count 
CCS 
Canadian Cardiovascular Society 
CCVDP 
Center for Cardiovascular Disease Prevention 
CEC 
Clinical Endpoint Committee 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CK 
Creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CK-18 
Cytokeratin-18 
Cmax 
Maximum plasma concentration 
CrCl 
Creatinine clearance 
CRO 
Contract Research Organization 
CSED 
Common Study End Date 
CSR 
Clinical Study Report 
CT 
Computed tomography 

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Abbreviation  
Explanation 
cTn 
Cardiac troponin 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
EC 
Executive Committee 
EC50 
Effective concentration in 50% of participants 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EQ-5D-5L 
European Quality of Life–5 Dimensions 5 Level Questionnaire 
ESRD 
End-stage renal disease 
FDA 
Food and Drug Administration 
FGF-21 
Fibroblast growth factor -21 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
HbA1c 
Hemoglobin A1c 
HDL-C 
High-density lipoprotein cholesterol 
HF 
Heart failure 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
hsCRP 
High-sensitivity C-reactive protein 
HTG 
Hypertriglyceridemia 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 

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Abbreviation  
Explanation 
IDL 
Intermediate-density lipoprotein 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
KOL 
Key Opinion Leader 
LBBB 
Left bundle branch block 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDL-TG 
Low-density lipoprotein associated triglycerides 
LPL 
Lipoprotein lipase 
MACE 
Major adverse cardiovascular events  
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MRI 
Magnetic Resonance Imaging 
NMR 
Nuclear magnetic resonance 
NTCP 
Na+ taurocholate cotransporting polypeptides 
OATP 
Organic anion transporting polypeptides 
OC 
Operations Committee 
OCT 
Organic cation transporter 
OR 
Odds ratio 
PAD 
Peripheral artery disease 
PCI 
Percutaneous Coronary Intervention 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PE 
Pulmonary embolism 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 

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Abbreviation  
Explanation 
PPAR 
Peroxisome proliferator activated receptor 
PROMINENT 
Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides 
IN patiENts with diabeTes  
PUC 
Preparative ultracentrifugation 
RBC 
Red blood cell 
REC 
Research Ethics Committee 
RLP 
Remnant lipoprotein 
RRR 
Relative risk reduction 
SAC 
Scientific Advisory Committee 
SAE 
Serious adverse event 
SC 
Steering Committee 
sdLDL-C 
Small dense low-density lipoprotein cholesterol 
SLC 
Several solute carrier 
SOC 
System organ class 
SPPARM-α 
Selective peroxisome proliferator activated receptor modulator alpha  
TC 
Total cholesterol 
T2D 
Type 2 diabetes 
T4 
Thyroxine 
TG 
Triglyceride(s) 
TQT 
Thorough QT/QTc  
TRL 
Triglyceride-rich lipoprotein 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
URL 
Upper reference limit 
US 
United States 
VLDL-C 
Very low-density lipoprotein cholesterol 
WHO DD 
World Health Organization Drug Dictionary 
WOCP 
Women of childbearing potential 

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4. 
INTRODUCTION 
4.1. 
Evolving Role of Hypertriglyceridemia in Cardiovascular Disease 
Prevention 
Treatment of dyslipidemia for cardiovascular disease (CVD) prevention has traditionally focused 
on mitigating the atherogenic potential of elevated low-density lipoprotein cholesterol (LDL-C), 
which today is the chief lipid target in clinical practice. While statins are the mainstay of therapy 
for lowering LDL-C in the majority of patients, many individuals retain a high CVD risk despite 
achieving LDL-C goals.1, 2 Specifically, the 5-year incidence of major vascular events among 
patients with established coronary disease remains above 20% while on aggressive statin 
therapy.3  
In efforts to ameliorate this residual CVD risk, the last decade in lipid research has been 
dominated by investigations into the potential added vascular benefits of raising high-density 
lipoprotein cholesterol (HDL-C). However, despite seemingly concordant in vitro and in vivo 
experimental data, consistent evidentiary support for the pharmacologic strategy of raising 
plasma HDL-C levels is currently lacking. Indeed, results from several recent interventional 
trials with a cholesteryl ester transfer protein inhibitor or with nicotinic acid to increase HDL-C 
levels have failed to show a reduction in cardiovascular (CV) events.4-7 Yet, importantly, low 
HDL-C remains a potent marker of increased vascular risk after statin therapy8 and improving 
HDL functionality may ultimately prove to be a promising therapeutic strategy. 
As described below, the recognition that hypertriglyceridemia (HTG) commonly accompanies 
low HDL-C, a plausible pathobiology, associative prospective epidemiologic data, showing 
consistent benefits in subgroup analyses of completed triglyceride (TG) reduction trials, and 
more recent Mendelian randomization and other genetic studies supporting a causal link have all 
fueled renewed interest in HTG as a secondary lipid target, especially in the context of type 2 
diabetes (T2D).9 Yet, no clinical trial has examined the effect of TG reduction on hard CVD 
outcomes among patients most likely to benefit, that is, those with established dyslipidemia 
(elevated TG and low HDL-C). This knowledge gap is especially disconcerting, given that mean 
TG levels have risen in the United States (US), as elsewhere, along with the growing global 
pandemic of obesity and T2D.10-12 
4.2. 
Triglyceride Elevation, Remnant Cholesterol, and ApoC3 in 
Atherogenesis: Targets for PPAR-α Modulation 
In humans, cholesterol accumulation, not TG accumulation, is the classic pathological feature in 
atherosclerotic lesions. Indeed, TGs per se are not traditionally implicated in the atherogenic 
process; rather TG-rich lipoprotein (TRL) metabolism and subsequent release of downstream 
atherogenic mediators is the probable pathogenic link. Two alternative mechanisms have been 
described to explain why hypertriglyceridemia is pro-atherogenic: the remnant infiltration 
hypothesis and the lipolytic toxin hypothesis (Figure 1).13, 14 
Remnant Infiltration Hypothesis 

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Triglyceride-rich lipoproteins in plasma consist of chylomicrons, chylomicron remnants, very 
low-density lipoprotein (VLDL), and intermediate-density lipoproteins (IDL). Conversion of 
TRLs to remnant lipoproteins (RLPs) by arterial lipoprotein lipase (LPL) yields TG-depleted but 
cholesterol-rich particles, which due to their size, contain up to 20 times more cholesterol than 
LDL-C and can cross the endothelial barrier. Importantly, unlike native LDL, RLPs may undergo 
direct uptake by resident macrophages in the subendothelial space in an unregulated fashion via 
scavenger receptors, leading to foam-cell formation and ensuing atherosclerosis.15 Thus, high 
plasma concentrations of TG-rich particles result in accelerated lipid deposition in the arterial 
intima. 
Lipolytic Toxin Hypothesis 
Perhaps the major toxicity of TRLs is not from intact particles, but from their lipolysis along the 
arterial wall. Byproducts of TRL lipolysis act at the arterial wall to unfavorably alter endothelial 
cell biology. Lipolysis of TRLs, especially VLDL, releases oxidized fatty acids, which have a 
number of adverse effects, including promotion of inflammation, macrophage cytotoxicity, 
expression of adhesion molecules, and enhanced coagulation.16-19 
Figure 1: 
Hypotheses to Explain Why Hypertriglyceridemia is Pro-Atherogenic 
 
Source: Reproduced from Watts GF, et al. Nature Rev Card. 2013;10:648-661. 
In this framework, it is important to note that hypertriglyceridemia results not only from 
overproduction of VLDL, but delayed clearance. The key enzyme involved in the 
VLDL-IDL-LDL delipidation cascade is LPL. Among inhibitors of LPL, apolipoprotein 
(Apo)C3, a resident surface protein on ApoA- and ApoB-containing lipoproteins, has emerged as 
a key modulator of lipid metabolism via a number of recently elucidated pathways, which 
specifically alter plasma TRLs. These include increase in their hepatic production through 
promotion of VLDL assembly and secretion,20 impaired intravascular processing by direct 
noncompetitive inhibition of LPL (and hepatic lipase),21, 22 and delayed removal by interference 
with ApoB10023 or ApoE24 binding to hepatic receptors.  

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The great promise of peroxisome proliferator activated receptor (PPAR)-α agonists, particularly 
in high-risk patients with overt hypertriglyceridemia, lies with the potential of these agents to 
remedy each of these lipid abnormalities. PPAR-α agonism increases acyl-coenzyme A synthase 
and fatty acid transporter protein, with the end result being decreased availability of fatty acids 
for TG synthesis and hepatic VLDL-ApoB secretion.25 In vitro, these agents can induce the 
expression of genes encoding LPL,26 ApoA1,27 ApoA3,28 and ABCAI,29 a transporter that 
controls ApoA1-mediated cholesterol efflux from macrophages. Reduction in the expression of 
ApoC3 is perhaps the most consistent effect of PPAR-α agonists,30 with a 36% reduction in 
plasma ApoC3 levels observed among patients with metabolic syndrome treated with fenofibrate 
over a 5-week period.31 
4.3. 
Epidemiologic and Mendelian Randomization Data Support a 
Causal Link 
Several meta-analyses, aggregating data from over 29 observational studies conducted through 
the mid-2000s, showed that elevated TG levels are associated with increased risk of coronary 
heart disease.32, 33 
The major difficulty in assessing CV risk attributable to HTG in observational studies has been 
the association of high TG with other CVD risk factors such as obesity, dysglycemia, and low 
HDL-C. Thus, residual confounding factors cannot be excluded on the basis of these studies. 
Mendelian randomization studies utilize a different approach to assess causality. In these studies, 
the effect of common genetic variants on TG level and CV risk are evaluated. If the effect of a 
variant on CVD risk is similar in direction and magnitude to that which would be predicted based 
on the variant’s effects on TG concentrations, the Mendelian randomization study supports a 
causal role for TG in the development of CVD.  
With regard to hypertriglyceridemia, several Mendelian randomization studies support a causal 
role for TG (Table 1). In a case-control study of 20,842 patients with coronary heart disease and 
35,206 controls, the -1131T>C (rs662799) variant in APOA5 was associated with a 16% (95% 
confidence interval [CI]: 12.9-18.7%) increase in TG, and an increase in the odds ratio (OR) of 
coronary heart disease (OR 1.18, 95% CI: 1.11-1.26), which was consistent with predicted 
hazard ratio [HR] of 1.10 (95% CI: 1.08-1.12) predicted based on the change in TG.34 In another 
study, investigators identified the -1131T>C variant, as well as 2 other variants in APOA5, that 
led to an average increase of 68% in non-fasting TG.35 These variants were then associated with 
a near doubling in the risk of myocardial infarction (MI) (OR 1.94, 95% CI: 1.40-2.85), which 
was not statistically different than the expected effect based on the variants’ effects on TG 
concentrations. 
Table 1: 
Mendelian Randomization Studies of Genetic Variants, Associations with TG 
Elevation, and CVD Events 
Publication 
Difference in TG 
Total Sample  
(n) 
Total Events (n) 
Hazard Ratio 
(95% CI) 
Jorgensen, Eur Heart J 
201335 
2-fold increase 
60,113 
5705 
1.9 (1.4-2.7) 

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Publication 
Difference in TG 
Total Sample  
(n) 
Total Events (n) 
Hazard Ratio 
(95% CI) 
Thomsen, Clin Chem 
201436 
1 mmol/L 
(88.5 mg/dL) increase 
10,208 
4005 
2.0 (1.2-3.3) 
TG and HDL WG, 
NEJM 201437 
38.5% increase 
110,970 
34,002 
1.7 (1.3-2.1) 
Jorgensen, NEJM 201438 
4.0 vs 1.0 mmol/L 
(350 vs 90 mg/dL) 
75,725 
7557 
2.3 (1.9-2.9) 
Variants that lead to reductions in TG may also be causally linked to lower CVD risk, and 2 
studies have demonstrated this. These studies assessed the effects of rare variants in ApoC3 on 
TG concentrations, and found evidence that decreased TG is causally related to CVD risk.37, 38 In 
a study of 75,725 Danish men and women, carriers of at least 1 copy of 4 different variants in 
ApoC3 had TG concentrations that were 44% lower than non-carriers. Carriers of any of the 
variants were at 41% lower risk of CVD (HR 0.59, 95% CI: 0.41-0.86), which was similar to the 
predicted risk reduction of 0.77 (0.73-0.81) based on the observed TG reduction.38 In a 
sequencing study of more than 18,000 genes in 3734 individuals, investigators identified the 
same variants in ApoC3 and also found they were associated with a 39% lower TG 
concentration. Compared to more than 110,000 non-carriers, they found that the 498 carriers of 
any of the rare ApoC3 mutations were at 40% lower risk for CVD (OR: 0.60, 95% 
CI: 0.47-0.95). 37 
4.4. 
Fibrates, Triglyceride Reduction, and Cardiovascular Events: 
Evidence from Prior Randomized Clinical Studies 
Fibrates, 1 class of compounds with PPAR-α agonist activity, have demonstrated efficacy in 
lowering TG and raising HDL-C concentrations. In addition to their lipid-modifying properties, 
PPAR-α agonists exhibit anti-inflammatory activity, may increase plaque stability, and modulate 
atherothrombosis subsequent to plaque rupture, which may also confer vascular benefit.39 A 
2010 meta-analyses40 of randomized clinical study data from 18 studies including over 
45,000 participants, showed that fibrate therapy produced a modest 10% relative risk reduction 
(RRR) [RR 0.90; 95% CI: 0.82-1.00; p = 0.048] for major CV events and a 13% RRR (RR 0.87; 
95% CI: 0.81-0.93; p < 0.001) for coronary events. However, none of the randomized studies 
included in the meta-analysis utilized high TGs as an entry criterion. Importantly, the authors 
note a significant relationship between higher baseline TG level (p = 0.03) and the observed 
benefit in risk reduction for coronary events, whereas there was no apparent difference in benefit 
according to baseline HDL-C (p = 0.47). 
The efficacy of fibrates in subpopulations marked by hypertriglyceridemia at study entry in the 5 
large fibrate trials (HHS, VA-HIT, BIP, FIELD, and ACCORD-Lipid) was formally assessed in 
2 subsequent meta-analyses,41, 42 both yielding similar results. The greatest benefit was seen 
among patients with elevated TGs relative to the entire cohort in each study (Figure 2). 
Furthermore, the pooled relative risk reduction associated with fibrate therapy was 25% (95% 
CI: 14%-45%) for subgroups with elevated TGs compared to 16% (95% CI: 9%-13%) for low 
HDL-C. When combining lipid parameters, the subpopulation with the greatest benefit was that 

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marked by both elevated TG and low HDL-C (relative risk reduction [RRR] 29%; 18%-38%). 
Despite these promising findings, to date, no randomized clinical study has been conducted with 
enrollment based on hypertriglyceridemia. 
A direct test of the TG hypothesis of atherogenesis with pemafibrate in the PROMINENT study 
is well timed. This newer generation selective PPAR-α modulator (SPPARM-α) has greater 
potency and PPAR-α selectivity, and hence, greater TG-lowering efficacy and an improved 
safety and tolerability profile compared to fenofibrate.  
Figure 2: 
Relative Risk Reduction Compared with Placebo 
 
Source: Adapted from Bruckert E, et al. J Cardiovasc Pharmacol. 2011;57:267-272.  
4.5. 
Current Guidelines for the Classification and Treatment of 
Hypertriglyceridemia 
Although prospective cohort and case-control studies have identified high plasma TG levels as 
an independent risk factor for CVD,32, 33 and post hoc analyses of interventional studies have 
characterized subgroups most likely to benefit (with most studies using a cut-off point of 
~200 mg/dL (2.26 mmol/L), mild-to-moderate hypertriglyceridemia is often viewed as simply a 
marker of CV risk that does not mandate treatment in most current guidelines. Table 2 
summarizes the major international guidelines for classification of hypertriglyceridemia as they 
have evolved over the past 15 years. In the US, mild-to-moderate hypertriglyceridemia is 
diagnosed at a level of 200 mg/dL (2.26 mmol/L) whereas current European guidelines use a 
lower threshold of 175 mg/dL (1.98 mmol/L).  

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Table 2: 
Guideline-Specified Categories of Hypertriglyceridemia 
International Guideline 
Categories 
TG Concentration  
Fasting 
Status 
(mg/dL) 
(mmol/L) 
2002 NCEP-ATP III43 
Normal 
Borderline 
High 
Very High 
< 150 
150-199 
200-499 
≥ 500 
< 1.7 
1.7-2.3 
2.3-5.6 
≥ 5.6 
Fasting 
2011 ESC/EAS44, 45 
Normal 
Hypertriglyceridemia 
Severe  
< 150  
150-884 
≥ 885 
< 1.7 
1.7-9.9 
≥ 10 
Fasting 
2012 Endocrine Society46 
Normal 
Mild 
Moderate 
Severe 
Very Severe 
< 150  
150-199 
200-999 
1000-1999 
≥ 2000 
< 1.7 
1.7-2.3 
2.3-11.2 
11.2-22.4 
≥ 22.4 
Fasting 
2013 Japanese Expert 
Guidelines47-49 
Desirable 
Elevated 
Very High 
Extremely High 
< 150 
150-400 
400-2000 
> 2000 
< 1.7 
1.7-4.5 
4.5-22.5 
> 22.5 
Fasting 
2014 EAS Consensus Panel50 
Normal 
Mild-Moderate 
Severe 
< 175  
175-885 
> 885 
< 2.0 
2.0-10.0 
> 10.0 
Not 
Specified 
 
4.6. 
Prevention of CVD Among Diabetic Patients: Targeting of PPAR-α 
Agonism in the Right Patient Population 
It is well known that T2D is a complex metabolic disorder characterized by elevated blood 
glucose and a marked increase in CVD risk. Progressive insulin resistance, the core metabolic 
defect in T2D, is strongly associated with disordered lipid metabolism, which manifests as HTG 
and low levels of HDL-C. The prevalence of hypertriglyceridemia in this patient population is 
quite high. A recent analysis51 conducted in an adult US population (National Health and 
Examination Surveys 2003-2006; NHANES) estimates that 70.6%, 72.1%, and 74.9% of diabetic 
patients are at intermediate risk (Framingham CVD Risk Score 10%-20%), high risk 
(FRS > 20%), or with diagnosed CVD, respectively, fail to achieve optimal TG levels of 
< 150 mg/dL (1.70 mmol/L). 
Contemporary data also demonstrate that despite advances in CV care, diabetes remains 
associated with a 2-fold increase in CVD risk52, 53, and this risk increase compared to nondiabetic 
patients is greatest among diabetic women.53 Unfortunately, results of large randomized studies 
evaluating a strategy of intensive glucose control for CVD prevention (ACCORD, ADVANCE, 
and VADT) have failed to show consistent and substantive reductions in macrovascular events. 

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Thus, reducing the rate of diabetes-related complications requires more than just adequate 
glycemic control, and to ameliorate residual macrovascular risk, lipid management may require 
more than statins alone. 
Table 3 summarizes the placebo event rates in major contemporary CVD prevention studies 
conducted in diabetic populations. None of these studies have shown treatment-related 
reductions in the prespecified primary CV endpoints, which varied across studies. The placebo 
rate of major adverse cardiovascular events (MACE) and MACE+ (inclusive of unstable angina 
requiring unplanned coronary revascularization) with endpoint definitions most closely aligned 
to those planned for use in the current study are indicated in the table when available from the 
primary publications. These data demonstrate the high event rates and residual CV risk in this 
patient population for whom PPAR-α agonism may have the greatest benefit. 

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Table 3: 
Placebo Event Rate and Risk Reduction in Major Cardiovascular Disease Prevention Trials in Patients with 
Diabetes With/Without Baseline CVD and With/Without Baseline Elevated TG 
Trial 
Year of 
Publication 
Characteristics 
CER 
(%) 
Averag
e F/U 
Est. 
Annualized 
MACE 
Rate 
(% per 
year) 
Est. 
Annualized 
MACE+ 
Rate 
(% per 
year) 
RRR 
(%) 
MACE Definition 
PROACTIVE54 
(pioglitazone) 
2005 
DM with CVD 
43% baseline 
statin 
13.6% 
2.8 
years 
4.9% per 
year 
NR 
NR 
MI, stroke, all cause death 
ADVANCE55 
(intensive glycemic 
control) 
2008 
DM with 
CVD/Micro or 1+ 
RF; 32% prior 
CVD 
28% baseline 
statin 
10.6% 
5.0 
years 
2.1% per 
year 
NR 
NR 
MI, stroke, CVD death 
VADT56 (intensive 
glycemic control) 
2009 
DM;  
40% prior CVD  
% baseline statin 
NR 
29.4% 
5.6 
years 
5.2% per 
year 
NR 
NR 
MI, stroke, CVD death, 
CHF, surgical intervention 
for CVD, inoperable CAD, 
amputation 
SAVOR-TIMI 50, 57 
(saxagliptin) 
2013 
DM with CVD or 
age +1 RF; 79% 
prior CVD 
78% baseline 
statin 
7.2% 
2.1 
years 
3.4% per 
year 
5.9%* 
NR 
MI, stroke, CVD death 
FIELD58, DM (All 
Patients) 
2007 
DM no baseline 
statin, 
22% prior CVD 
13.9% 
5.0 
years 
2.8% per 
year 
already 
included 
10.1
% 
MI, stroke, CVD death, 
coronary/carotid 
revascularization 
DM+TG ≥ 200 
mg/dL (2.26 
mmol/L) 
2005 
DM no baseline 
statin 
+ baseline TG 
≥ 200 
17.2% 
5.0 
years 
3.4% per 
year 
already 
included 
22.1
% 
" 

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Trial 
Year of 
Publication 
Characteristics 
CER 
(%) 
Averag
e F/U 
Est. 
Annualized 
MACE 
Rate 
(% per 
year) 
Est. 
Annualized 
MACE+ 
Rate 
(% per 
year) 
RRR 
(%) 
MACE Definition 
DM+CVD 
2005 
DM no baseline 
statin 
+ baseline CVD 
25.1% 
5.0 
years 
5.0% per 
year 
already 
included 
+1.0
% 
" 
ACCORD-Lipid59, 
DM All Patients 
2010 
DM + Simva 
36.5% prior CVD 
11.3% 
4.7 
years 
2.4% per 
year 
5.6%* 
6.6% 
MI, stroke, CVD death 
DM+TG 
≥ 200 mg/dL 
(2.26 mmol/L) 
2010 
DM + Simva + 
baseline TG ≥ 200 
mg/dL 
12.8% 
4.7 
years 
2.7% per 
year 
NR 
13.3
% 
" 
DM+CVD 
2010 
DM + Simva + 
baseline CVD 
18.1% 
4.7 
years 
3.9% per 
year 
NR 
10.5
% 
" 
ACCORD: Action to Control Cardiovascular Risk in Diabetes; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled 
Evaluation; CAD: coronary artery disease; CER: cumulative event rate; Estimated Annualized Event Rate = CER/Average Duration of F/U; CHF: congestive heart failure; CVD: 
cardiovascular disease; DM: diabetes mellitus; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes; F/U: follow-up (mean or median); MACE: major adverse 
cardiovascular events; MACE+: MACE + unstable angina requiring unplanned coronary revascularization; MI: myocardial infarction; NR: not reported; PROACTIVE: 
Prospective Pioglitazone Clinic Trial In Macrovascular Events; RRR: relative risk reduction; SAVOR-TIMI 53: Saxagliptin Assessment of Vascular Outcomes Recorded in 
Patients with Diabetes Mellitus; Simva: simvastatin; VADT: Veterans Affairs Diabetes Trial. 
* Includes hospitalization for CHF and any coronary revascularization 
Note: Fibrate trials are shown below the line. 

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4.7. 
Drug Profile from Nonclinical and Clinical Studies 
4.7.1. 
Nonclinical Studies 
Pemafibrate, a SPPARM-α, is approximately 2,500 times more potent than fenofibric acid, in 
terms of the concentration producing 50% effectiveness (ie, effective concentration in 50% of 
participants [EC50]) of the PPAR-α-activating effect. Pemafibrate is approximately 5,000 times 
more potent for PPAR-α than PPAR-γ and 11,000 times more potent for PPAR-α than for PPAR-
δ. It is also more effective than fenofibrate in decreasing TG, increasing HDL-C, and 
ameliorating atherosclerosis in disease-model animals.  
Pemafibrate is metabolized by oxidation and glucuronidation. Cytochrome P450 (CYP)2C8, 
CYP2C9, CYP3A4, and CYP3A7 are involved in oxidation, and UGT1A1, UGT1A3, and 
UGT1A8 are involved in glucuronidation. Pemafibrate is a substrate for P-glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP), as well as for several solute carrier (SLC) 
transporter proteins (organic cation transporter [OCT] 2, Na+ taurocholate cotransporting 
polypeptide [NTCP], and organic anion transporting polypeptides [OATP] OATP1A2, 
OATP1B1, and OATP1B3). Pemafibrate has minimal inhibitory effects on major drug-
metabolizing enzymes and transporters.  
The liver appears to be the primary target organ of pemafibrate toxicity in nonclinical studies. In 
2-year carcinogenicity studies in mice and rats, increased incidences of hepatocellular 
adenomas/carcinomas, pancreatic acinar cell adenomas/carcinomas, testicular Leydig cell 
adenomas, and thyroid follicular cell adenomas were observed. Additional data from studies in 
rats and monkeys to assess the mode of action of these tumors suggests that the carcinogenicity 
profile of pemafibrate in rodents is consistent with the generally accepted greater sensitivity of 
rodents to effects elicited by PPAR-α activation, relative to nonhuman primates and, by 
extension, humans. Pemafibrate was not genotoxic in bacterial reverse mutation, chromosomal 
aberration, or micronucleus tests. 
No teratogenic effects have been observed in rats or rabbits. Decreases in the number of corpora 
lutea and live embryos were observed at 50 mg/kg/day in a fertility and early embryonic 
development study in rats, but there were no effects on pre- or post-implantation loss. Deaths and 
poor nursing occurred in dams, and delayed physical development of subsequent generations was 
observed at ≥ 3 mg/kg/day in a prenatal and postnatal development study in rats. 
4.7.2. 
Clinical Studies 
The clinical pharmacology of pemafibrate has been studied in 18 Phase 1 studies. Doses of 
0.05-1.6 mg administered as a single daily dose or divided twice per day, were assessed in 
multiple-dose studies, for up to 7 days. Increases in maximum plasma concentration (Cmax) and 
area under the concentration-time curve (AUC) were dose-dependent. The oral bioavailability of 
pemafibrate was approximately 62%. Pemafibrate is extensively metabolized and exists in 
plasma predominantly as 1 of 2 metabolites (K-23605 and K-23467) or as pemafibrate. 
Pemafibrate is excreted mostly as metabolites, predominantly through the feces (73% of dosed 
radioactivity), with some excretion through the urine (15% of dosed radioactivity).  

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Clinically important drug interactions were observed with cyclosporine and rifampicin. Based on 
these findings, inhibitors of OATP1B1 or OATP1B3 should not be used with K-877. Other drug 
interaction studies demonstrated clarithromycin and clopidogrel increased the blood level of 
pemafibrate by approximately 2-fold and fluconazole increased K-877 levels by approximately 
1.7-fold, while no meaningful effect was seen on the pharmacokinetics (PK) of digoxin. Drug 
interaction studies were also conducted with multiple statins (pitavastatin, atorvastatin, 
rosuvastatin, pravastatin, simvastatin, and fluvastatin) with no interactions observed. Refer to 
Sections 7.2, 7.3, and 8.2 for information on the use/restrictions of these drugs in this study. 
In patients with hepatic dysfunction dosed with pemafibrate, Cmax and AUC were increased 
approximately 2- and 4-fold for Child-Pugh A and B cirrhosis patients, respectively. A minor 
increase of 20% was observed in both Cmax and AUC among patients with hepatic steatosis. 
In patients with renal dysfunction, ranging from mild impairment (creatinine clearance [CrCl]: 
50 to < 80 mL/min) to end-stage renal disease (ESRD; treated with hemodialysis), the increases 
in AUC ranged from approximately 15%-63%, and the increases in Cmax ranged from 
approximately 9%-64%. There was no apparent correlation between degree of renal dysfunction 
and effect on maximum or total exposure, and the largest changes for both AUC and Cmax were 
observed in patients with mild renal dysfunction. 
A thorough QT/QTc (TQT) study was conducted, which demonstrated that neither clinical 
(0.4 mg) nor supratherapeutic (1.6 mg) single doses of pemafibrate caused prolongation of the 
corrected QT (QTc) interval.  
The efficacy and safety of pemafibrate was evaluated in 6 clinical studies of up to 12 weeks 
duration at daily doses ranging from 0.05-0.4 mg taken once daily or divided twice daily in 
participants with dyslipidemia and: (1) HTG; (2) HTG with low HDL-C; (3) HTG with elevated 
non-HDL-C. Pemafibrate was used as monotherapy and in combination with statins in both 
diabetic and non-diabetic participants. Major efficacy and safety findings are summarized 
below.60 
Efficacy 
Treatment with pemafibrate produced statistically significant and clinically relevant reductions in 
fasting plasma TGs, and also reduced postprandial HTG. Other effects on lipids and lipoproteins, 
included reductions in non-HDL-C, total cholesterol (TC), VLDL-C, remnant-like lipoprotein 
particle cholesterol (RLP-C), ApoB, ApoB48, ApoC2, ApoC3, and increases in ApoA1, ApoA2, 
and HDL-C were also observed. 
Increases in LDL-C were observed in some studies; however, the absence of corresponding 
increases in ApoB suggests that this change is not associated with an increase in LDL particles. 
Safety 
The adverse events (AEs) in the pemafibrate group tended to occur at rates similar to those in the 
placebo or active comparator (fenofibrate at 100 or 200 mg/day) groups. No AE pattern 
indicative of organ system toxicity or pathophysiology was observed. The occurrence of AEs 
related to transaminase elevation (eg, liver function test abnormal, alanine aminotransferase 

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[ALT] increased, or aspartate aminotransferase [AST] increased) in the pemafibrate group 
occurred at frequencies higher than those in the placebo group, but lower than those in the 
fenofibrate group. In general, transaminase and γ-glutamyl transpeptidase (GGT) levels 
decreased from baseline and increases in AST or ALT ≥ 5 × upper limit of normal (ULN) were 
infrequent. Mean creatinine levels increased with pemafibrate, but at a lower magnitude and 
incidence than those with fenofibrate; these increases were not clinically significant, and very 
few AEs were reported. Statistically significant decreases in mean fibrinogen levels were noted 
in multiple studies; however, these changes did not occur in the setting of AEs, so the clinical 
relevance of this decrease is unknown. 
4.8. 
Benefit-Risk Assessment 
The overall drug profile outlined in Section 4.7 is favorable for human studies at chronic doses 
up to 0.4 mg/day. The maximum dose administered in a single-dose study was 1.6 mg and the 
maximum dose for 1-week of treatment was 1.6 mg/day; both regimens were well tolerated. In 
patients with dyslipidemia, a maximum dose of 0.4 mg/day was well tolerated for up to 
52 weeks. 
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when pemafibrate is administered. Other risks to the patients are the risks inherent 
to any clinical study with an unapproved drug such as unexpected adverse clinical or laboratory 
events. 
Because of the mechanism of action, 2 important potential risks are identified. Since other 
fibrates have been shown to increase the risk for cholelithiasis, pemafibrate could also increase 
the risk of cholelithiasis. Other fibrates have been shown to increase the risk for rhabdomyolysis 
when co-administered with statins. Rhabdomyolysis has not been reported with the use of 
pemafibrate, and no difference has been observed in the incidence of musculoskeletal-related 
AEs between patients with and without co-administered statins. Although rare, the risk of 
rhabdomyolysis cannot be excluded when pemafibrate is co-administered with statins, especially 
in patients with severe renal impairment, as there is limited experience to date with the combined 
use of pemafibrate and statins in such patients. In this study, patients with severe renal 
impairment will be excluded from participation. 
Other potential risks include elevated transaminases (ALT, AST), decreases in red blood cell 
(RBC) count and hemoglobin, and musculoskeletal and connective tissue disorders (eg, 
myopathy, myalgia, and increased creatine kinase [CK]). 
Because of significant increases in plasma concentrations of pemafibrate in patients with severe 
hepatic disorders, patients with liver disease will be excluded from the study. Concomitant use of 
cyclosporine, rifampicin, or other OATP inhibitors will be prohibited in the study (Section 8.2), 
as co-administration of pemafibrate with cyclosporine and single doses of rifampicin have 
resulted in increases in pemafibrate exposure due to inhibition of OATP1B1 or OATP1B3 by 
these drugs. 
Although initiation of bile acid sequestrants is discouraged while on study drug, should 
combined therapy with bile acid sequestrants be deemed necessary, pemafibrate should be taken 

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2 hours before or 4-6 hours after the intake of bile acid sequestrants (Section 8.2.2), as the 
absorption of pemafibrate may otherwise be reduced. 
All participants in this study will be treated with a statin and/or another LDL-C-lowering drug or 
will be statin intolerant with LDL-C ≤ 100 mg/dL in accordance with the best standard-of-care 
and in compliance with local guidelines and recommendations. In addition to standard-of-care 
treatment, half of the participants in this study may derive a direct benefit from being treated 
with pemafibrate, which has already demonstrated favorable lipid profile changes at the doses 
tested, although it has yet to be determined whether this lipid improvement confers clinical 
benefit (ie, reduction in atherosclerotic CV events). All participants taking part in the study may 
derive general medical benefit from careful and close monitoring by medical personnel during 
the study. Safety will be ensured by assessing participants for AEs and laboratory test results.  
Pemafibrate may be able to address the significant unmet medical need of preventing CV events 
in high-risk patients with T2D. Given the favorable safety profile, the careful monitoring during 
the study visits, including phone visits, ongoing safety monitoring by the Sponsor and Data 
Safety Monitoring Board (DSMB), and the absence of any other agent that has demonstrated a 
reduction in CV events with TG lowering in the population to be tested, the Sponsor feels the 
risks to the study participants are minimized and justified, compared with the potential benefits 
that the successful clinical development of pemafibrate could provide for patients. 

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5. 
TRIAL OBJECTIVES AND ENDPOINTS 
Abundant laboratory, clinical, and genetic evidence implicates HTG in the development of 
atherosclerotic vascular disease. Furthermore, epidemiologic and currently available clinical 
study data demonstrate that among patients with dyslipidemia, the combination of elevated TG 
and low HDL-C identifies individuals at greatest CV risk. These data have generated the 
hypothesis that reducing TG levels in the appropriate patient population can prevent vascular 
events. To date, however, no randomized clinical study has directly addressed whether TG 
reduction can lower vascular event rates in patients with hypertriglyceridemia and low HDL-C.  
5.1. 
Primary Objective 
The primary scientific aim of the PROMINENT study is to assess whether treatment with the 
SPPARM-α, K-877 (pemafibrate), will prevent MI, ischemic stroke, unstable angina requiring 
unplanned revascularization, and CV death in participants with T2D who have elevated TGs and 
HDL-C levels and are at high risk for future CV events. Participants will be on moderate- to 
high-intensity statin therapy (atorvastatin ≥ 40 mg/day, rosuvastatin ≥ 20 mg/day, 
simvastatin ≥ 40 mg/day, or pitavastatin 4 mg/day) or meet LDL-C criteria (by chart review) 
within 12 months prior to enrollment. 
Specifically, the primary objective of the study is to determine whether pemafibrate administered 
at a dose of 0.2 mg twice daily will delay the time to first occurrence of any component of the 
clinical composite endpoint of:  
• nonfatal MI 
• nonfatal ischemic stroke 
• hospitalization for unstable angina requiring unplanned coronary revascularization, or  
• CV death 
At the time of the Screening/Enrollment Visit (Visit 1), participants must be either: 
1. Receiving treatment with a stable dose (ie, for at least 12 weeks) of a qualifying 
moderate-to high intensity statin (atorvastatin ≥ 40 mg/day, rosuvastatin ≥ 20 mg/day, 
simvastatin ≥ 40 mg/daya, or pitavastatin 4 mg/day), or  
2. Have evidence of LDL-C ≤ 70 mg/dL (1.81 mmol/L) by local laboratory determination 
within the previous 12 monthsb, or  
3. Statin intolerantc and have evidence of LDL-C ≤ 100 mg/dL (2.59 mmol/L) by local 
laboratory determination within the previous 12 months. 
a Participants enrolled on simvastatin > 40 mg/day must have been taking and tolerating that dose 
for at least 12 months. 

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b If untreated or on stable dosing (ie, for at least 12 weeks) of another lipid-lowering regimen that 
may include a statin with or without ezetimibe and/or a proprotein convertase subtilisin/kexin 
type 9 (PCSK9) inhibitor. 
c Statin intolerance is defined as: the inability to tolerate at least 2 statins: 1 statin at the lowest 
daily starting dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, 
lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg or pitavastatin 2 mg), AND another statin 
at any dose, due to skeletal muscle-related symptoms, other than those due to strain or trauma, 
such as pain, aches, weakness, or cramping, that begins or increases during statin therapy and 
stops when statin therapy is discontinued. Participants not receiving a daily regimen of a statin 
(e.g., 1-3 times weekly) could also be considered “statin intolerant” if they cannot tolerate a 
cumulative weekly statin dose of 7 times the lowest approved tablet size, and the criteria outlined 
above are also met. 
5.1.1. 
Primary Endpoint 
The primary efficacy endpoint is the time from randomization to the first occurrence of any 
component of the clinical composite endpoint of:  
• Nonfatal MI 
• Nonfatal ischemic stroke 
• Hospitalization for unstable angina requiring unplanned coronary revascularization 
• Cardiovascular death 
5.2. 
Secondary Objective 
The secondary scientific aim of this study is to investigate 1) the efficacy (time to first 
occurrence) of a number of secondary CV and diabetes-related vascular and nonvascular 
endpoints in the study population, and 2) the efficacy (as measured by the percent change from 
baseline) for a number of lipid measures. 
5.2.1. 
Group A: Clinical Endpoints 
The group A (clinical) endpoints are time to first occurrence of: 
1. Any component of the 3-component composite endpoint of non-fatal MI, non-fatal 
stroke, or cardiovascular death 
2. Any component of the primary endpoint or hospitalization for heart failure (HF) 
3. Any component of the primary endpoint or all-cause mortality 
4. Any component of the primary endpoint, any coronary revascularization, or 
hospitalization for HF 

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5. Any new or worsening peripheral artery disease (PAD), defined as incidence of lower 
extremity revascularization, intermittent claudication, rest pain, lower extremity ischemic 
ulceration, or major amputation with either ankle-brachial index ≤ 0.9 or other diagnostic 
testing (eg, toe-brachial index, angiogram, or other imaging study) 
5.2.2. 
Group B: Lipid Endpoints 
The group B (lipid) endpoints are time to first occurrence of: 
• The change from Screening/Enrollment Visit (Visit 1) to Month 4 Visit (Visit 5) for the 
following lipid biomarkers: TC, TG, HDL-C, non-HDL-C (calculated), VLDL-C 
(calculated), ApoA1, ApoC3, and ApoE; and 
• The change from Randomization Visit (Visit 2) to Month 6 Visit (Visit 6) for non-fasting 
remnant cholesterol 
* Very low-density lipoprotein cholesterol (VLDL-C) is calculated as TC minus HDL-C 
minus LDL-C, where LCL-C is measured by a direct homogenous method. 
5.3. 
Tertiary Objective 
The tertiary aim of this study is to investigate the effect of pemafibrate on various lipid factors, 
inflammatory biomarkers, and other circulating biomarkers. 
5.3.1. 
Tertiary Endpoints 
Tertiary endpoints include microvascular endpoints (ie, diabetic retinopathy and diabetic 
nephropathy as defined below) as well as exploratory mechanistic studies evaluating differences 
in average achieved levels and change from baseline between pemafibrate and placebo arms in: 
• Core lipid parameters (total cohort): TG, HDL-C, calculated and directly measured 
LDL-C, calculated VLDL-C and non-HDL-C, TC, ApoB, ApoE, and directly measured 
remnant cholesterol 
• Advanced lipid parameters (total cohort): ApoA1, ApoC3, LDL-C by 
beta-quantification (preparative ultracentrifugation [PUC]), lipoprotein particles (nuclear 
magnetic resonance [NMR] size, concentrations, and subfractions), HDL-TG and 
LDL-TG by PUC, and directly measured small dense low-density lipoprotein cholesterol 
(sdLDL-C) and low-density lipoprotein associated TG (LDL-TG) 
• Inflammatory and glycemic parameters (total cohort): High-sensitivity C-reactive 
protein (hsCRP), fasting glucose, hemoglobin A1c (HbA1c), and fibroblast growth 
factor-21 (FGF-21) 
• Expanded exploratory lipid and non-lipid parameters (US/Canada subcohort): 
ApoA5, ApoB48, angiopoietin-like 3 (ANGPTL3), ANGPTL4, PCSK9 mass, 
cytokeratin-18 (CK-18), and type IV collagen 

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Microvascular endpoints will also be examined. These will include diabetic retinopathy, 
defined as use of retinal laser treatment, anti-vascular endothelial growth factor therapy, or 
vitrectomy due to development of and/or deterioration in diabetic retinopathy and blindness; 
and diabetic nephropathy, defined as an increase in microalbumin/creatinine ratio to 
> 30 mg/g among those without microalbuminuria at baseline, or categorical change from 
baseline albuminuria (normo-, micro-, or macroalbuminuria), doubling of creatinine from 
baseline, creatinine level > 6.0 mg/dL, estimated glomerular filtration rate (eGFR) 
< 15 mL/min/1.73 m2, or initiation of renal replacement therapy (dialysis or transplant) 
among all participants. 

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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
Hypertriglyceridemia is associated with increased CV risk, appears to play a causal role in 
atherothrombosis, and can be effectively reduced with the novel SPPARM-α pemafibrate. 
Importantly, more than 70% of high-risk patients with diabetes have TG levels above values 
considered “optimal” by international prevention guidelines. To date, however, no definitive 
study data have established that lowering TGs by treatment with any available agent can reduce 
CV event rates.  
The Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN patiENts with 
diabeTes (PROMINENT) study is a randomized, double-blind, placebo-controlled, international 
study evaluating the ability of pemafibrate to prevent CV events among 10,000 male and female 
adults with T2D and moderate hypertriglyceridemia with low HDL-C, and on background 
moderate- to high-intensity statin therapy (atorvastatin ≥ 40 mg/day, rosuvastatin ≥ 20 mg/day, 
simvastatin ≥ 40 mg/day, or pitavastatin 4 mg/day) unless meeting LDL-C criteria with or 
without statin intolerance. Fasting TG levels must be ≥ 200 mg/dL (2.26 mmol/L) but 
< 500 mg/dL (5.65 mmol/L) and HDL-C must be ≤ 40 mg/dL (1.03 mmol/L). Two-thirds of the 
enrolled study population will have prior evidence of systemic atherosclerosis (secondary 
prevention cohort) while one-third will not (primary prevention cohort, age ≥ 50 years [male] or 
≥ 55 years [female]). PROMINENT will be conducted in 20-25 countries to ensure 
generalizability and allow for the enrollment and follow-up period to complete in 5 years. 
The primary endpoint will be the first occurrence of nonfatal MI, nonfatal ischemic stroke, 
hospitalization for unstable angina requiring unplanned coronary revascularization, or CV death. 
The study is event-driven such that after 1,092 events have been confirmed, with a minimum of 
200 events accrued in women, and assuming a conservative 1% annual loss to follow-up, there 
will be 90% power to detect clinically meaningful relative reductions in the primary endpoint of 
at least 18% in the pemafibrate group. In addition to spontaneous adverse event (AE) reporting, 
systematic surveillance for liver disease and muscle AEs will occur.  
This study will include the following: a Pre-Screening Visit (Visit 0), a Screening/Enrollment 
Visit (Visit 1), a 21-day (maximum 35 day) Placebo Run-In Period, a Randomization Visit 
(Visit 2), a Treatment Period consisting of approximately 30 visits (post-randomization Visits 3 
through 33, as applicable), a Common Study End Date (CSED) Visit, and a Post-Study Safety 
Call.  
During the Pre-Screening Visit (Visit 0; Week -6), participants will provide informed consent to 
participate in the study and follow-up. After consent, the site will be asked to submit medical 
records for a qualifying CVD event if applicable and entry criteria including: documentation of 
diabetes; documentation of statin intolerance, if applicable; and prior TG, HDL-C, and LDL-C 
levels, if available, within the last 12 months. Screening lab values may be used if prior local 
laboratory documentation is unavailable. At the Screening/Enrollment Visit (Visit 1; Week -3), 
participants will be queried regarding their medical histories (including clinical and lifestyle CV 
risk factors and alcohol use) and concomitant medication use, and will be screened against the 
inclusion/exclusion criteria. A physical examination comprising a general review of body 

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systems will be performed. Additionally, fasting blood samples will be collected from all 
participants for eligibility assessment, including a serum pregnancy test in women of child-
bearing potential (WOCP). Where local regulations permit, study participants may be asked to 
arrive fasting at the Pre-Screening Visit (Visit 0) such that activities of the Screening/Enrollment 
Visit (Visit 1) can be performed concurrently with the Pre-Screening Visit. For expediency, 
participants meeting all applicable inclusion and exclusion criteria at the end of the 
Screening/Enrollment Visit (Visit 1), other than screening TG, HDL-C, and other exclusionary 
lab testing, can be enrolled into the Placebo Run-In Period while awaiting results of qualifying 
laboratory testing. Placebo tablets will be dispensed to participants at Visit 1 along with 
administration instructions for the Placebo Run-In Period, which is designed to select compliant 
individuals for long-term follow-up and adherence. The placebo dosing card will contain 
sufficient placebo tablets for a maximum duration of 35 days. 
On a one-time basis, at the optional Retesting Visit (Visit 1.1), participants may undergo 
retesting for borderline lipid values, specifically TG 175-199 mg/dL (1.98-2.25 mmol/L) or 
500-650 mg/dL (5.65-7.34 mmol/L) and/or HDL-C 41-45 mg/dL (HDL-C 1.06-1.16 mmol/L).  
Rescreening of participants for failure to meet other eligibility criteria (eg, HbA1c > 9.5%, 
severe hypertension, or medical instability of concurrent clinical condition) may occur once only. 
Prior to Randomization, serious adverse events (SAEs) and primary endpoints will be recorded 
and adjudicated, respectively. Thereafter, all AEs and endpoints will be assessed. 
Participants who continue to be eligible, are compliant with medication during the Placebo 
Run-In Period, and have completed submission of relevant medical records will return for the 
Randomization Visit (Visit 2; Week 0) to be randomly allocated in a 1:1 ratio to receive either 
pemafibrate at a dose of 0.2 mg twice daily or a matching placebo tablet to be taken twice daily. 
A non-fasting sample for lipid testing will be collected, and the participant will complete a 
quality of life questionnaire. Importantly, in addition to other eligibility criteria, randomized 
participants must have the following: 
• Medical record documentation of diabetes longer than 12 weeks duration 
• Medical record documentation of a qualifying CV event (if secondary prevention cohort) 
• TG levels ≥ 200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.65 mmol/L) 
• HDL-C ≤ 40 mg/dL (1.03 mmol/L) 
• LDL-C ≤ 70 mg/dL (1.81 mmol/L) if not on qualifying statin regimen or ≤ 100 mg/dL 
(2.59 mmol/L) if documented statin intolerant 
At 2-weeks post randomization (Visit 3), sites will perform a well-being telephone visit to 
provide general support and to reinforce dosing instructions. Adverse events and endpoints will 
also be collected. If a participant reports or is reported to have an efficacy endpoint, then 
additional data about the nature and date of the event, and the treatment and care provided during 
and after the event will be collected by the investigator. 

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Throughout the treatment period, beginning with Month 2 (Visit 4), telephone visits will 
alternate with in-person visits occurring approximately every 2 months after Month 10. During 
each telephone call and in-person visit, concomitant medication use will be reviewed, and the 
participant will be queried for AEs and efficacy events. During the in-person visits, in addition, 
physical examinations will be performed and vital signs will be measured, change in risk factors 
will be documented, and study drug compliance will be determined by tablet count.  
At the Months 4 and 12 visits, at annual visits thereafter (ie, Months 24, 36, 48, and 60, as 
applicable) and at the CSED Visit, fasting blood samples and urine sample will be collected for 
safety and efficacy assessments. After Month 12, blood samples will also be collected for safety 
assessment (chemistry panel only) at each intervening in-person visit (eg, Months 16, 20, 28, 32, 
etc.) throughout the study. Frequency of these additional blood safety measurements may be 
reduced to once annually after DSMB review of blood safety data. In addition, WOCP will 
undergo serum pregnancy testing. At the Month 6 visit an on-treatment, non-fasting sample will 
be collected. Participants will complete a quality of life questionnaire annually and at the first in-
person visit after a study endpoint occurs. 
Lipid parameters, as outlined in Section 11.3, will be measured in all participants. 
At Screening/Enrollment, Randomization, and Month 4 Visits, a blood sample will be collected 
for archiving in countries and sites approved by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Research Ethics Committee (REC) and regulatory 
authorities, as applicable. 
Throughout the course of the study, several steps will be taken to minimize changes in 
LDL-lowering therapies including frequent monitoring of ApoB with guided institution of 
additional lipid lowering therapy for evidence of persistent ApoB elevation when evident. 
Details of managing LDL-lipid lowering therapy during the study are outlined in Section 8.2.2. 
The CSED Visit will be scheduled within a 60-day window after the study termination is 
announced, irrespective of the date that the participants were randomized. At the CSED Visit, 
participants will undergo physical examinations, risk factors will be documented, and study drug 
compliance will be determined by unused tablet count. Additionally, WOCP will undergo a 
serum pregnancy test. Finally, fasting blood and urine samples will be collected from all 
participants for safety and efficacy assessments (per Appendix A in Section 21.1). A Post Study 
Safety Call will follow 30 days later to collect any post study efficacy events and SAEs. The end 
of study is defined as the last in-person visit of the last participant. 
Participants will be followed for an average period of approximately 4 years after randomization 
(estimated study duration: 5 years). The study will be completed when the required number of 
adjudicated and confirmed primary endpoints have accrued. The aim is to collect a complete set 
of data from all participants from the time of randomization to the end of the study. Participants 
should be encouraged to continue taking their assigned study medication during the entire 
treatment period, with as little change to background medication as possible, even if they 
experience an adverse event or event which constitutes a study endpoint. Participants who 
discontinue their medication for any reason and are not able to recommence therapy should still 
continue to be followed for the collection of data and samples. 

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PROMINENT will be conducted to fulfill all international standards of Good Clinical Practice 
(GCP) to ensure that a positive finding will lead to changes in the care of at-risk participants 
globally and to a labeling indication for CV event reduction for pemafibrate by worldwide 
regulatory authorities. 
A by-visit description of the study procedures is presented in Section 10, and efficacy and safety 
assessments are described in Section 11 and Section 12, respectively. The study plan is shown in 
Table 4. 
 

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Table 4: 
Study Design and Schedule of Assessments 
 
Pre- 
screen 
Placebo Run-In Perioda  
Treatment Period 
CSED 
Visitb 
Post- 
Study 
Safety 
Callc 
Screening/ 
Enrollment 
Retest 
Random
-ization 
Visit 
0 
1 
1.1 
2 
3 
4 
5 
6 
7 
9 
V8(M10), 
V10 (M14), 
V12 (M18), 
V14 (M22), 
V16 (M26), 
V18 (M30), 
V20 (M34), 
V22 (M38), 
V24 (M42), 
V26 (M46), 
V28 (M50), 
V30 (M54), 
V32 (M58), 
V34 (M62) 
V11 (M16), 
V13 (M20), 
V17 (M28), 
V19 (M32), 
V23 (M40), 
V25 (M44), 
V29 (M52), 
V31 (M56) 
V15 (M24), 
V21 (M36), 
V27 (M48), 
V33 (M60) 
Week (W) 
 or Month (M) 
-6W 
-3W 
 
0 
2W 
M2 
M4 
M6 
M8 
M12 
Study Visit Window 
Within 
6W 
prior 
to V2 
Up to 6W 
from V0 
Up to 
2W 
from 
V1 
3W to 
5W 
from V1 
±3D 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
Withi
n 
60Db 
Within 
30Dc 
In-Person Visit 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X c 
X c 
X 
 
Telephone Visitd 
 
 
 
 
Xe 
X 
 
 
 
 
X 
 
 
 
X 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data and 
Medical Historyf 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical records 
submissionh 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular risk 
factors and alcohol use 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Concomitant medications 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
Questionnaireg 
 
 
 
Xg 
 
 
 
 
 
Xg 
 
Xg 
Xg 
Xg 
 

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Pre- 
screen 
Placebo Run-In Perioda  
Treatment Period 
CSED 
Visitb 
Post- 
Study 
Safety 
Callc 
Screening/ 
Enrollment 
Retest 
Random
-ization 
Visit 
0 
1 
1.1 
2 
3 
4 
5 
6 
7 
9 
V8(M10), 
V10 (M14), 
V12 (M18), 
V14 (M22), 
V16 (M26), 
V18 (M30), 
V20 (M34), 
V22 (M38), 
V24 (M42), 
V26 (M46), 
V28 (M50), 
V30 (M54), 
V32 (M58), 
V34 (M62) 
V11 (M16), 
V13 (M20), 
V17 (M28), 
V19 (M32), 
V23 (M40), 
V25 (M44), 
V29 (M52), 
V31 (M56) 
V15 (M24), 
V21 (M36), 
V27 (M48), 
V33 (M60) 
Week (W) 
 or Month (M) 
-6W 
-3W 
 
0 
2W 
M2 
M4 
M6 
M8 
M12 
Study Visit Window 
Within 
6W 
prior 
to V2 
Up to 6W 
from V0 
Up to 
2W 
from 
V1 
3W to 
5W 
from V1 
±3D 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
Withi
n 
60Db 
Within 
30Dc 
In-Person Visit 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X c 
X c 
X 
 
Telephone Visitd 
 
 
 
 
Xe 
X 
 
 
 
 
X 
 
 
 
X 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam/ 
Vital signsh 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Dispense study drugi 
 
Xi 
 
Xi 
 
 
X 
 
X 
X 
 
X 
X 
 
 
Compliance check 
 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Blood sample for 
archivalj 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Non-fasting blood 
samplek 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Fasting blood samplek 
 
X 
X 
 
 
 
X 
 
 
X 
 
Xl 
Xl 
X 
 
Urine sample  
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xl 
X 
 
Pregnancy test in 
WOCPm 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X  
X 
 

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Pre- 
screen 
Placebo Run-In Perioda  
Treatment Period 
CSED 
Visitb 
Post- 
Study 
Safety 
Callc 
Screening/ 
Enrollment 
Retest 
Random
-ization 
Visit 
0 
1 
1.1 
2 
3 
4 
5 
6 
7 
9 
V8(M10), 
V10 (M14), 
V12 (M18), 
V14 (M22), 
V16 (M26), 
V18 (M30), 
V20 (M34), 
V22 (M38), 
V24 (M42), 
V26 (M46), 
V28 (M50), 
V30 (M54), 
V32 (M58), 
V34 (M62) 
V11 (M16), 
V13 (M20), 
V17 (M28), 
V19 (M32), 
V23 (M40), 
V25 (M44), 
V29 (M52), 
V31 (M56) 
V15 (M24), 
V21 (M36), 
V27 (M48), 
V33 (M60) 
Week (W) 
 or Month (M) 
-6W 
-3W 
 
0 
2W 
M2 
M4 
M6 
M8 
M12 
Study Visit Window 
Within 
6W 
prior 
to V2 
Up to 6W 
from V0 
Up to 
2W 
from 
V1 
3W to 
5W 
from V1 
±3D 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
±2W 
Withi
n 
60Db 
Within 
30Dc 
In-Person Visit 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X c 
X c 
X 
 
Telephone Visitd 
 
 
 
 
Xe 
X 
 
 
 
 
X 
 
 
 
X 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsn 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy eventso 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: Apo= apolipoprotein; AE= adverse event; ALP= alkaline phosphatase; ALT= alanine aminotransferase; ANGPTL= angiopoietin-like; AST= aspartate 
aminotransferase; BMI= body mass index; BUN= blood urea nitrogen; CBC= complete blood count; CK= creatine kinase; CK-18= cytokeratin-18; CSED= Common Study End 
Date; CV= cardiovascular; CVD= cardiovascular disease; D=day; EQ-5D-5L= European Quality of Life–5 Dimensions 5 Level Questionnaire; eGFR= estimated glomerular 
filtration rate; FGF-21= fibroblast growth factor – 21; GGT= gamma glutamyl transpeptidase; HbA1c= Hemoglobin A1c; HF= heart failure; hsCRP= high-sensitivity C-reactive 
protein; HCG= human chorionic gonadotropin; HDL-C= high-density lipoprotein cholesterol; IEC= Institutional Ethics Committee; IRB= Institutional Review Board; LDH= 
lactate dehydrogenase; LDL-C= low-density lipoprotein cholesterol; M=month; NMR= nuclear magnetic resonance; PAD: peripheral artery disease; PUC: preparative 
ultracentrifugation; REC= Research Ethics Committee; SAE= serious adverse event; sdLDL-C= small dense low-density lipoprotein cholesterol; TG=triglyceride(s); TSH= 
thyroid stimulating hormone; T4= thyroxine; W=week; WOCP: Women of child-bearing potential 
a A 21-day Placebo Run-In Period (maximum 35 days) begins at the Screening/Enrollment Visit (Visit 1).  
b The CSED Visit will be scheduled within a 60-day window after study termination is announced, irrespective of the date that the participants were randomized. Participants will 
continue study medications through the CSED Visit unless the study is stopped for evidence of increased hazard. 
c The Post-Study Safety call will occur approximately 30 days after the CSED Visit, during which final AEs and post study efficacy events will be collected. 

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d Telephone visits will alternate with in-person visits occurring approximately every 2 months; after Month 10; the Month 6 visit is an in-person visit for non-fasting blood 
collection. 
e Visit 3 will be a well-being telephone call conducted at Week 2 (±3 days) after the Randomization Visit to provide participant support and reinforce dosing. During this 
telephone call, SAEs and efficacy endpoints (see footnote o) will be recorded. 
f May occur up to Randomization Visit. Medical history/medical record submission includes: qualifying at least 1 TG level is ≥ 150 mg/dL (1.69 mmol/L), and at least 1 HDL-C 
level is ≤ 45 mg/dL (1.16 mmol/L); qualifying type 2 diabetes diagnosis; qualifying CVD event; evidence of LDL-C ≤ 100 mg/dL (2.59 mmol/L) within 12 months if 
documented statin intolerant, or LDL-C ≤ 70 mg/dL (1.81 mmol/L) within 12 months if not on qualifying moderate- to high-intensity statin (atorvastatin ≥ 40 mg/day, 
rosuvastatin ≥ 20 mg/day, simvastatin ≥ 40 mg/day, or pitavastatin 4 mg/day); and documentation of statin intolerance (if applicable). See Section 10.1 for details on required 
evidence and acceptable documentation. 
g Self-administered Quality of Life questionnaire will be completed at the Randomization Visit, annually, at the first in-person visit after a study endpoint occurs, and at the CSED 
Visit. 
h The physical examination comprised a brief routine examination of body systems (eg, general appearance, head and neck, chest and lungs, etc.). Vital signs include blood 
pressure and heart rate, height (Visit 1 and CSED Visit only), body weight, and waist circumference; the BMI will be calculated. Height will only be measured at Visit 1 and the 
CSED Visit. Vital signs should be collected after the participant has been resting for 5 minutes in a seated position. 
i At Visit 1 (Screening/Enrollment Visit), only placebo tablets will be dispensed to all enrolled participants for the Placebo Run-In Period (maximum 35 days), along with 
administration instructions for the Placebo Run-In Period. At the other indicated visits, randomized participants will receive either pemafibrate or placebo according to their 
treatment assignment. 
j Fasting (Visit 1 and Visit 5) and non-fasting (Visit 2) blood samples for archival will be collected from consenting participants at sites in countries where allowed by local 
regulations and where approved by the IRB/IEC/REC and regulatory authorities, as applicable; samples will be stored in a biobank at the Brigham and Women's Hospital for 
future biomarker studies (all consenting participants) and genetic testing (only participants who consent additionally to genetic testing). 
k Blood samples will be collected for safety and efficacy assessments (See Appendix A in Section 21.1 for details):  
• 
Safety laboratory tests: biochemistry panel (including electrolytes [K, Na, Cl], AST, ALT, GGT, ALP, total bilirubin, direct bilirubin, CK, total protein, LDH, uric acid, 
creatinine, calculated eGFR, BUN) and hematology (CBC with differential), TSH, and free T4.  
• 
Core and advanced lipid parameters (total cohort): TG, HDL-C, LDL-C (direct and calculated), calculated VLDL-C and non-HDL-C, TC, ApoB, ApoA1, ApoC3, ApoE, 
directly measured remnant cholesterol; LDL-C by beta quantification (PUC), lipoprotein particles (NMR size, concentrations, and subfractions), HDL-TG and LDL-TG 
by PUC, and directly measured sdLDL-C and LDL-TG; 
• 
Inflammatory and glycemic parameters (total cohort): fasting glucose, HbA1c, hsCRP, and FGF-21. 
• 
Expanded exploratory lipid and non-lipid parameters (US/Canada subcohort): ApoA5, ApoB48, ANGPTL3, ANGPTL4, PCSK9 mass, CK-18, and type IV collagen. 
l After the first year (Month 12), fasting blood and urine samples will be collected for safety laboratory assessment and for lipid profiles and albumin/creatinine assessments at 
annual in-person visits (ie, Month 24/Visit 15; Month 36/Visit 21; Month 48/Visit 27, and Month 60/V33 as applicable). Fasting or non-fasting blood samples for safety 
assessment (chemistry panel only) will be collected at each in-person visit after Month 12. Frequency of these additional blood safety measurements may be reduced to once 
annually after DSMB review of blood safety data. Urine samples need not be fasting but are collected at time points when participants are fasting for other laboratory 
assessments. 
m Pregnancy testing will be performed by serum testing (beta-HCG) at all specified time points. Testing need not be fasting but specimens are collected at time points when 
participants are fasting for other laboratory assessments. 
n SAEs will be collected up to and including the Randomization Visit, with serious and non-serious AEs collected thereafter. 
o Primary and secondary efficacy events include: MI, ischemic stroke, coronary revascularization, CV death, total mortality, hospitalization for HF, non-ischemic stroke, diabetic 
retinopathy, diabetic nephropathy, and PAD (see Section 11.1 and Section 11.2 for definitions of efficacy events). 

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6.2. 
Number of Participants 
Approximately 10,000 participants will be randomized at approximately 750 investigational 
centers in 20-25 countries. Approximately 20% of participants will be women. 
6.3. 
Treatment Assignment 
All participants who successfully complete the 21-day Placebo Run-In Period with 
≥75% adherence to placebo tablets will be eligible for randomization to pemafibrate or placebo 
at the Randomization Visit (Visit 2). Participants who meet all inclusion criteria and none of the 
exclusion criteria will be randomized in a 1:1 ratio to study drug by the responsible site 
investigator using an interactive computer system. The randomization process will involve 
stratification by sex, prior history of CVD (primary vs. secondary prevention cohorts), and statin 
use at baseline, defined as those who are taking no statin at baseline or are statin intolerant 
compared to all others. There will be recruitment caps such that no more than one-third of the 
study population will consist of participants without prior CVD (primary prevention cohort). 
6.4. 
Study Drug Dose Adjustment Criteria 
Not applicable. 
6.5. 
Study Withdrawal 
6.5.1. 
Overall Study Termination 
The closeout phase of the study will be initiated when approximately 1,092 adjudicated and 
confirmed primary endpoints have accrued with a minimum of 200 events in women, or in 
accordance with DSMB recommendations, should there be evidence of futility or excess harm to 
participants. In addition, if in the opinion of the Sponsor, the clinical observations in the study 
suggest it may be unwise to continue, the study may be terminated. In addition, the Sponsor may 
terminate the study at any time. 
6.5.2. 
Study Termination at Investigational Sites 
If it becomes apparent that participant enrollment at a specific investigational site is 
unsatisfactory with respect to quality or quantity, or data recording is repeatedly inaccurate or 
incomplete, the Sponsor has the right to terminate the study and remove all study materials from 
that investigational site. A written statement will be provided to the investigator, the 
IRB/IEC/REC, 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. 

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7. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Study participants will be adult men and women with T2D and who are at high risk (primary 
prevention cohort; one-third of randomized participants) or very high risk (secondary prevention 
cohort; two-thirds of randomized participants) of incurring a major CVD event based on study 
inclusion criteria. 
7.1. 
Participant Inclusion Criteria 
Participants must meet all of the following criteria for enrollment into the study: 
1. Fasting TG ≥ 200 mg/dL (2.26 mmol/L) and < 500 mg/dL (5.65 mmol/L) at Visit 1 
(Screening/Enrollment Visit) or Visit 1.1 (Retest) 
2. HDL-C ≤ 40 mg/dL (1.03 mmol/L) at Visit 1 (Screening/Enrollment Visit) or Visit 1.1 
(Retest) 
3. Type 2 diabetes of longer than 12 weeks duration documented in medical records, for 
example: local laboratory evidence through medical record review of elevated HbA1c 
(≥ 6.5% [48 mmol/mol]), elevated plasma glucose (fasting ≥ 126 mg/dL [7.0 mmol/L], 
2-hour ≥ 200 mg/dL [11.1 mmol/L] during oral glucose tolerance testing, or random 
value ≥ 200 mg/dL with classic symptoms, or currently taking medication for treatment 
of diabetes; AND either 
a) Age ≥ 50 years if male or ≥ 55 years if female (primary prevention cohort), OR 
b) Age ≥ 18 years and established systemic atherosclerosis (secondary prevention 
cohort), defined as any 1 of the following: 
i. Prior MI or ischemic (non-hemorrhagic) stroke 
ii. Coronary angiographic lesion of ≥ 60% stenosis in a major epicardial 
vessel or ≥ 50% left main stenosis 
iii. Asymptomatic carotid disease with ≥ 70% carotid artery stenosis  
iv. Symptomatic carotid disease with ≥ 50% carotid artery stenosis 
v. Symptomatic lower extremity PAD (ie, intermittent claudication, rest pain, 
lower extremity ischemic ulceration, or major amputation with either 
ankle-brachial index ≤ 0.9 or other diagnostic testing [toe-brachial index, 
angiogram, or other imaging study]) 
vi. Prior arterial revascularization procedure (including coronary, carotid, or 
peripheral angioplasty/stenting, bypass, or atherectomy/endarterectomy) 
4. In addition, by Visit 1 (Screening/Enrollment Visit), participants must be either:  

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a) Receiving treatment with a stable dose (ie, for at least 12 weeks) of a qualifying 
moderate- to high-intensity statin (atorvastatin ≥ 40 mg/day, rosuvastatin 
≥ 20 mg/day, simvastatin ≥ 40 mg/day*, or pitavastatin 4 mg/day); or  
b) Have evidence of LDL-C ≤ 70 mg/dL (1.81 mmol/L) by local laboratory 
determination within the previous 12 months#, or 
c) Statin intolerant+ and have evidence of LDL-C ≤ 100 mg/dL (2.59 mmol/L) by local 
laboratory determination within the previous 12 months. 
* Participants enrolled on simvastatin > 40 mg/day must have been taking and tolerating that 
dose for at least 12 months. 
# If untreated or on stable dosing (ie, for at least 12 weeks) of another lipid-lowering 
regimen that may include a statin with or without ezetimibe and/or a PCSK9 inhibitor. 
+ Statin intolerance is defined as: the inability to tolerate at least 2 statins: 1 statin at the 
lowest daily starting dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 
10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg or pitavastatin 2 mg), AND 
another statin at any dose, due to skeletal muscle-related symptoms, other than those due to 
strain or trauma, such as pain, aches, weakness, or cramping, that begins or increases during 
statin therapy and stops when statin therapy is discontinued. Participants not receiving a 
daily regimen of a statin (eg, 1-3 times weekly) could also be considered “statin intolerant” 
if they cannot tolerate a cumulative weekly statin dose of 7 times the lowest approved tablet 
size, and the criteria outlined above are also met. 
5. Ability to understand and comply with study procedures and give written informed 
consent. 
7.2. 
Participant Exclusion Criteria 
Presence of exclusionary criteria will be assessed at the Screening/Enrollment Visit (Visit 1), 
which is then followed by a 21-day Placebo Run-In Period preceding randomization into the 
study. Participants are excluded from participation if any of the following criteria apply: 
1. Current or planned use of fibrates or agents with PPAR-α agonist activity (eg, 
saroglitazar) within 6 weeks (42 days) of Visit 1 (Screening/Enrollment Visit). Note: 
PPAR-γ agonists (eg, glizatones such as pioglitazone and rosiglitazone) are allowed 
2. Known sensitivity to PPAR-α agonists or tablet excipients 
3. Initiation of, or change in, current TG-lowering therapy within 12 weeks of Visit 1 (if 
applicable). Note: TG-lowering therapy is defined as niacin > 100 mg/day or dietary 
supplements or prescription omega-3 fatty acids > 1 g/day 
4. Type 1 diabetes mellitus 
5. Uncontrolled diabetes mellitus as defined by a HbA1c > 9.5% [80 mmol/mol] at Visit 1 
(Screening/Enrollment Visit) 
6. Untreated or inadequately treated hypothyroidism [thyroid stimulating hormone (TSH) 
> 2.0 X the ULN or Free T4 ≤ ULN] or hyperthyroidism; controlled thyroid disease 
(permitted) requires normal TSH and stable therapy for at least 4 weeks 

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7. Recent CVD event (eg, MI or stroke) within 8 weeks of Visit 2 (Randomization Visit) 
8. Recent or planned vascular intervention within 8 weeks of Visit 2 (Randomization Visit) 
9. New York Heart Association Class IV HF 
10. Known homozygous familial hypercholesterolemia (heterozygous is permitted) or 
familial hypoalphalipoproteinemia 
11. Documented previous occurrence of myositis/myopathy  
12. Unexplained CK > 5 X ULN 
13. Liver disease defined as cirrhosis or Child-Pugh class B and C, or ALT or 
AST > 3 X ULN 
14. Biliary obstruction or hyperbilirubinemia (ie, total bilirubin > 2 X ULN, except with a 
documented diagnosis of Gilbert’s disease) 
15. Chronic renal insufficiency, defined by an eGFR < 30 mL/min/1.73 m2 by the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or kidney transplant, 
regardless of renal function 
16. Unexplained anemia (hematocrit ≤ 30%) 
17. Uncontrolled hypertension (seated systolic blood pressure > 160 mmHg and/or diastolic 
blood pressure > 100 mmHg) at Visit 2 (Randomization Visit) 
18. History of chronic active hepatitis B or hepatitis C, or known infection with human 
immunodeficiency virus (HIV); participants with documented hepatitis C resolution after 
treatment are permitted 
19. Active malignancy, except non-melanoma skin cancer or carcinoma in situ of the cervix, 
within the last 2 years 
20. Prior organ transplant or any condition likely to lead to organ transplantation in the next 
5 years 
21. Current or anticipated chronic use of cyclosporine, rifampicin, or other inhibitors of 
organic anion transporting polypeptides (OATP)1B1, or OATP1B3 
22. History of alcoholism or unwillingness to limit alcohol intake to < 15 alcoholic beverages 
(or units) per week or < 5 alcoholic beverages (or units) during a single occasion for men 
and < 8 alcoholic beverages (or units) per week or < 4 alcoholic beverages (or units) 
during a single occasion for women during the study period. Note: One alcoholic 
beverage (unit) is defined as 12 oz. (350 mL) of beer, 5 oz. (150 mL) of wine, or 1.5 oz. 
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23. History of hereditary problems of galactose intolerance, Lapp lactase deficiency, or 
glucose-galactose malabsorption 
24. Women who are pregnant, lactating, planning to be pregnant or lactating during the study 
period, or WOCP who are not using an acceptable method of contraception 
WOCP are adult females who are sexually active with a non-sterilized male partner 
unless she meets 1 of the following criteria as documented by the investigator:  
• history of hysterectomy or tubal ligation prior to signing the informed consent form 
(ICF); or  
• menopause, defined as either a) age > 50 years old and ≥ 1 year since last menstrual 
period or documented follicle-stimulating hormone (FSH) level in the post-
menopausal range or b) for women ≤ 50 years old, ≥ 2 years since her last menstrual 
period without an alternative medical cause, and documented FSH level in the post-
menopausal range 
To be eligible, WOCP must have a negative pregnancy test at Visit 1 
(Screening/Enrollment Visit) and agree to use an adequate method of contraception 
during the study and for 1 additional menstrual cycle following the final study visit. 
Adequate methods of contraception for WOCP include: oral, implanted or injectable 
contraceptive hormones; mechanical products (eg, intrauterine device [IUD]); or barrier 
methods (eg, diaphragm, condoms, cervical cap) with spermicide. Local regulatory 
authorities or IRB/IEC/REC may impose additional restrictions on acceptable 
contraceptive methods which must be applied by relevant sites and be documented in the 
investigator study documents. The participant’s understanding of the contraceptive 
requirements must be documented by the investigator. 
25. A medical condition, other than vascular disease, with life expectancy < 3 years, which 
might prevent the participant from completing the study 
26. Any factors likely to limit adherence to the study medications and procedures, such as 
substance abuse, dementia, plans to move within the next 2 years, and/or history of 
noncompliance with medication or scheduled appointments, and 
27. Participation in another clinical study at the time of informed consent, or has received an 
investigational drug within 90 days before signing the informed consent for this study. 
Participants with uncontrolled diabetes, uncontrolled hypertension, uncontrolled thyroid disease, 
recent CVD event or revascularization procedure, or other medical instability due to an 
intervening medical condition may be re-evaluated for re-screening at the investigator’s 
discretion once remedies have been instituted and the participant is stable for least 4 weeks 
(28 days) at the time of the repeat Pre-Screening Visit (Visit 0). Re-screening may occur on a 
one-time basis only and should occur after a discussion with the 
 Medical Monitor. 

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7.3. 
Study Drug Discontinuation 
It will be necessary to make a distinction between participants who prematurely discontinue 
study drug treatment and those who withdraw from the study. All study drug discontinuations 
should be considered temporary interruptions because participants are allowed to restart 
medication at any time if the condition leading to study drug interruption has resolved, eg, a 
woman who becomes pregnant while in the study can resume study drug when she is no longer 
pregnant or breastfeeding. 
Participants who discontinue study drug are not required to withdraw from the study and should 
continue all in-person visits and telephone contacts to monitor for AEs and the occurrence of 
potential endpoint events until the CSED Visit. At a minimum, vital signs should be obtained at 
in-person visits, but blood draws are at the investigator’s discretion until the participant resumes 
study drug. 
If the participant discontinues study drug, the reason should be captured and could include the 
following: 
1. The participant meets any of the criteria specified in Section 7.3.1 
2. The participant begins to take any medication(s) that is contraindicated by the protocol 
3. The participant develops an AE that, in the opinion of the investigator, would 
compromise the participant’s safety to continue the study drug 
4. The participant becomes pregnant 
5. The participant withdraws consent 
6. The participant requests discontinuation of the study drug for any reason, or 
7. In the investigator’s judgment, it is in the participant’s best interest 
Although a participant 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 
participant’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. 
7.3.1. 
Study Drug Discontinuation Criteria for Persistent Abnormal 
Clinical Laboratory Values 
If at any time during the study a participant develops elevations in ALT or AST > 3 X ULN, or 
CK >5 X ULN, the study site will receive an alert from the central laboratory. 
Study drug should be discontinued immediately and permanently when any of the 
following criteria are met: 
• ALT or AST > 8 X ULN 

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• ALT or AST > 3 X ULN with bilirubin > 2 X ULN 
• ALT or AST > 3 X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
• Rhabdomyolysis regardless of CK value 
Study drug should be discontinued temporarily and requires repeating laboratory testing 
when any of the following criteria are met: 
• ALT or AST > 3 X ULN 
• CK > 10 X ULN 
Participants should undergo repeat laboratory measurements as soon as possible, within 72 hours 
(unless otherwise specified). Repeat laboratory measurements will include those tests outlined in 
Section 12.1.2.2.1 and Section 12.1.2.2.2. Local laboratory measurements may be used to 
facilitate follow-up. 
If the repeat ALT or AST is > 3 X ULN with INR > 1.5, study drug should be discontinued 
permanently. If the INR is <1.5 but the ALT or AST is > 5 X ULN and persists beyond 2 weeks, 
study drug should be discontinued permanently. If the ALT or AST values recover without 
meeting the discontinuation criteria, study drug can be resumed at the investigator’s discretion. 
For CK > 10 X ULN, if the repeat CK elevation remains > 5 X ULN and is not explained by 
exercise or trauma, study drug should be discontinued permanently. If the CK elevation remains 
> 5 X ULN and is explained by exercise or trauma, the patient may continue therapy and be 
followed until they have returned to baseline, or the investigator considers them clinically stable. 
If exercise- or trauma-related elevation does not resolve, the study drug should be discontinued 
permanently. If the CK values recover without meeting the discontinuation criteria, study drug 
can be resumed at the investigator’s discretion. 
Study drug can be continued, but requires repeating laboratory testing when the following 
criterion is met: 
• CK > 5 X ULN but < 10 X ULN 
Participants should undergo repeat laboratory measurements as soon as possible, within 72 hours 
(unless otherwise specified). Repeat laboratory measurements will include those tests outlined in 
Section 12.1.2.2.2. Local laboratory measurements may be used to facilitate follow-up.  
If the CK elevation remains > 5 X ULN and is not explained by exercise or trauma, study drug 
should be discontinued permanently. If the CK elevation remains > 5 X ULN and is explained by 
exercise or trauma, the patient may continue therapy and be followed at least weekly until CK 
values fall below 5 X ULN, at which time the study drug may be resumed by the investigator. If 
exercise- or trauma-related elevation does not resolve, the study drug should be discontinued 
permanently. 

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7.4. 
Follow-up after Early Study Drug Discontinuation or Withdrawal 
The participant has the right to withdraw from the study at any time. Nevertheless, in this study, 
investigators will be trained to minimize full withdrawals from study wherever possible. Every 
attempt will be made to prevent missing data and to obtain complete follow up of all participants 
at the end of the study. Participants who interrupt or discontinue study drug will be encouraged 
to remain in the study and asked to conduct the remaining study visits as outlined in the protocol 
to the end of the study if possible, or at a minimum to maintain contact with the investigator and 
site to allow for the assessment of the occurrence of primary endpoint events.   
Participants who choose to withdraw consent will be asked to document their withdrawal of 
consent in writing and acknowledge that they have been offered options for limited participation. 
For participants who withdraw consent, assessment of the participant’s health status at the end of 
the study will be performed in compliance with local privacy laws, regulations, and practices and 
may include a phone call to the participant or next-of-kin to ascertain vital status and occurrence 
of primary endpoint events.  
Although a participant 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 
participant’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. 
Withdrawn participants will not be replaced. 
7.4.1. 
Lost-to-Follow-up 
As adherence to the protocol, ascertainment of primary study endpoints, vital status, and 
minimization of participants who are lost-to-follow-up are paramount, participant contact 
information will be collected centrally as specified in the written informed consent for 
participation in the study. Text messaging, newsletters, and a web-based study participant portal 
may be employed for purposes of retention, compliance, and to minimize participants being lost-
to-follow-up. Local IRB/IEC/REC regulations will apply. 
For participants who are lost-to-follow-up (ie, those participants whose life or death status is 
unclear because they fail to appear for study visits without stated intention to withdraw or fail to 
contact the site), the investigator must show due diligence in the steps taken to contact 
participants. Steps taken may include telephone calls to the participant or next-of-kin, e-mail, or 
registered letters. For participants who are lost-to-follow-up, the site will be required to complete 
the Missed Visit eCRF at regularly scheduled study visits and to document, in a separate eCRF 
designed for this purpose, the attempts made to contact the participant. If contact is reinitiated, it 
is possible for the participant to return for clinic visits with resumption of study activities based 
upon their original randomization date. 

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8. 
TREATMENT OF PARTICIPANTS 
8.1. 
Description of Study Drug 
Pemafibrate 0.2 mg tablets and matching placebo will be provided as investigational medicinal 
products (Table 5). 
Table 5: 
Investigational Product 
Product Name: 
Pemafibrate 
Placebo 
Dosage Form: 
Tablet 
Tablet 
Unit Dose 
0.2 mg 
0 mg 
Route of Administration 
Oral 
Oral 
Physical Description 
7.1 mm round, white film-
coated tablets 
7.1 mm round, white film-
coated tablets 
Sponsor 
Kowa Research Institute 
Kowa Research Institute 
Packager 
Catalent CTS, LLC 
Catalent CTS, LLC 
 
8.2. 
Concomitant Medications 
Any medications administered during the study period must be documented in the Concomitant 
Medication eCRF. Participants may not take part in any other investigational drug study while 
participating in this study and must not have taken any other investigational drug within 90 days 
prior to Pre-screening Visit (Visit 0). 
Fibrates or agents with PPAR-α agonist activity during the study are contraindicated (see 
Section 8.2.1). 
Initiation of the following non-study medications is strongly discouraged during the study, with 
the exception of compelling medical need for: 
• Niacin (>100 mg/day) 
• Dietary supplements or prescription omega-3 fatty acids (>1 g/day) 
• Bile acid sequestrants 

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o Although initiation of bile acid sequestrants is discouraged while on study drug, 
should combined therapy with bile acid sequestrants be deemed necessary, 
pemafibrate should be taken 2 hours before or 4-6 hours after the intake of bile 
acid sequestrants (Section 8.2.2), as the absorption of pemafibrate may otherwise 
be reduced. For participants entering the study already on sequestrants, this same 
interval of dose administration with pemafibrate should be initiated. 
With the exception of fibrates or other agents with PPAR-α agonist activity (eg, saroglitazar), 
use of the above-listed medications is permitted during the study if the participant has been 
receiving these medications at stable dosing for at least 12 weeks prior to Visit 1 
(Screening/Enrollment Visit). 
Caution is recommended when coadministering medications that are strong CYP3A4 or strong 
CYP2C8 inhibitors, as there are limited data available. In a Phase 1 study in healthy volunteers, 
strong CYP3A4 inhibition increased peak and total exposure of K-877 by approximately 2-fold. 
Coadministration of K-877 with a moderate CYP2C9 and CYP3A4 inhibitor increased peak and 
total exposure by <2-fold. In a Phase 1 study in healthy volunteers, strong CYP2C8 inhibition 
increased peak and total exposure of K-877 by approximately 2-fold. In vitro, CYP3A4, 
CYP2C9, and CYP2C8 contribute similarly to the metabolism of K-877. 
Information on supplemental intake of omega-3 fatty acids and niacin will be collected at each 
visit. 
8.2.1. 
Contraindicated Medications 
The following medications are contraindicated in participants taking study medications: 
• Fibrates or other agents with PPAR-α agonist activity (eg, saroglitazar) 
If the participant is considered to need such treatment then the investigator should discuss this 
with the Medical Monitor. If the treatment is considered unavoidable, the participant should 
discontinue study medication before initiating treatment with fibrates or other PPAR-α agonists, 
but continue to attend follow-up visits. 
• Cyclosporine, rifampicin, or other inhibitors of OATP1B1 or OATP1B3 
When these medications are used temporarily, the study drugs should be interrupted until the 
completion of the intercurrent treatment. 
8.2.2. 
Statins and Other LDL-Lowering Therapies 
An elevation in LDL-C without increase in number of LDL-C particles has been observed during 
pemafibrate administration. In Phase 2 studies, this increase in LDL concentration is associated 
with a favorable shift in LDL particle size distribution: an increase in large and medium LDL 
subclasses, a decrease in smaller LDL subclasses, and importantly, with an overall decrease in 
non-HDL-C and decrease in Apo B (decreased particle number). Nonetheless, off-protocol LDL-
C measurement and changes in statin dosing or addition of other LDL-C lowering therapies may 
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will be taken to minimize changes in LDL-lowering therapies during the course of the study 
(Figure 3) and to ensure standardization across clinical sites. These steps will identically be 
implemented for all study participants, regardless of allocation to active therapy or to placebo. 
1. The baseline statin regimen must be 1 of 3 agents at moderate- to high-intensity (atorvastatin 
≥ 40 mg/day, rosuvastatin ≥ 20 mg/day, simvastatin ≥ 40 mg/day, or pitavastatin 4 mg/day) 
dosing unless there is local laboratory evidence within the past 12 months of LDL-C 
≤ 100 mg/dL (2.59 mmol/L) for participants who are proven statin intolerant or LDL-C 
≤ 70 mg/dL (1.81 mmol/L) for participants who are untreated or on another lipid-lowering 
regimen that may include a maximally tolerated dose of a statin with or without ezetimibe 
and/or PCSK9 inhibitors. 
2. ApoB will be monitored frequently during the first year and annually thereafter. 
3. Although investigators will remain blinded to the ApoB value, whenever a value > 90 mg/dL 
AND either ≥ 20% increase from the prior value or ≥ 40% increase from the baseline value 
occurs, investigators will be alerted and instructed to confirm study drug or other lipid 
lowering therapy compliance, retest ApoB at the next in-person visit, and if ApoB elevation 
is still present institute 1 of 3 possible therapy optimizations in the recommended order listed 
below:  
a. Add ezetimibe 10 mg/day (if participant is not already receiving) 
b. Increase statin dose by increments listed in Figure 3 until the maximum 
permissible dosing is reached, or switch to a more potent statin 
c. Add other LDL-lowering therapy 
4. Change in lipid-lowering therapies that occur without the trigger described in step 3 above 
will be strongly discouraged. 
5. In addition, intensive education on these issues and reinforcement of the protocol will be a 
core feature of investigator meetings and webinars conducted throughout the study. 

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Figure 3: 
Approaches to Minimize Changes in Statins and Other LDL-Lowering 
Therapies During the Study  
 
Thus, these steps, including requirement for baseline moderate- to high-intensity lipid lowering 
therapy, implementation of LDL-C entry thresholds for those not on a qualifying moderate- to 
high-intensity therapy (atorvastatin ≥ 40 mg/day, rosuvastatin ≥ 20 mg/day, simvastatin 
≥ 40 mg/day, or pitavastatin 4 mg/day), central monitoring of Apo B, study-wide standardization 
of changes to lipid-lowering therapy, and intensive investigator education will be utilized to 
address potential concerns and minimize changes in lipid therapy that would deviate from the 
protocol. All changes to lipid-lowering therapies will be documented in the electronic data 
capture (EDC) system, along with the justification for the change (Section 18.1). 
8.2.3. 
Rescue Therapy for Persistently Elevated TG During the Study 
In the event that TG levels rise during follow-up to ≥ 800 mg/dL (9.03 mmol/L), investigators 
will be alerted. Investigators will ensure compliance with study drug and other prescribed lipid 
lowering therapy prior to repeat lab testing at the next in-person visit. If TG elevation of 
≥ 800 mg/dL (9.03 mmol/L) persists, investigators will be advised to reinforce diet and exercise 
and consider add on therapy with niacin or prescription omega-3 fatty acids (per local lipid 
guidelines). 

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8.2.4. 
Other Study Restrictions 
Dietary Supplements 
Participants will be discouraged from initiation of dietary supplements containing niacin or 
omega-3 fatty acids (eg, flaxseed, fish, krill, or algal oils) during the study. Specifically, 
initiation of dietary supplements containing more than 1 g/day of omega-3 fatty acids will be 
prohibited. Dietary supplements must be recorded in the EDC system.  
Alcohol Consumption 
Beginning at the Screening/Enrollment Visit (Visit 1) and each visit thereafter, all participants 
will be instructed to refrain from excessive alcohol consumption. Self-reported alcohol 
consumption will be reviewed throughout the study. Excessive alcohol consumption is defined 
as: 
• For men, an average of ≥ 15 alcoholic beverages (or units) per week or > 5 alcoholic 
beverages (or units) during a single occasion 
• For women, ≥ 8 alcoholic beverages (or units) per week or > 4 alcoholic beverages (or 
units) during a single occasion. 
One alcoholic beverage (unit) is defined as 12 oz. (350 mL) of beer, 5 oz. (150 mL) of wine, or 
1.5 oz. (45 mL) of liquor. 
8.3. 
Treatment Compliance 
At each in-person visit, participants will be reminded by the sites of the importance of adhering 
to their treatment regimen for the entire duration of the study. Any interruptions of therapy 
should be as brief as possible and only for clinically-indicated reasons, such as AEs. Study 
medication can be re-started at any time in participants willing to resume treatment. 
Discontinuations will be discouraged and should be based on compelling clinical reasons.   
For every participant, an assessment of compliance with study drug must be obtained at each 
scheduled in-person visit. Compliance is defined as ≥ 75% for the Placebo Run-In Period and 
≥ 80% during the treatment period.  
Study medication will be dispensed in amounts exceeding the amount required until the next 
scheduled study visit. Participants will be instructed to return all unused study medication at the 
next visit. Compliance to the study drug regimen will be evaluated by tablet count of unused 
tablets and will be documented in the eCRF. If compliance falls below 80% during the 
post-randomization period, the investigator or designee will assess potential factors leading to 
the lack of compliance and counsel the participant. At the end of the study, the final study drug 
compliance will be calculated by unused tablet count. 
8.4. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study with limited access to the 
randomization code. Neither the investigator, site staff, Sponsor, 
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Cardiovascular Disease Prevention (CCVDP), nor the individual participants will be aware of 
which treatment a given participant receives. The treatment codes will be held by 
 and 
the IVRS/IWRS service provider. 
All participants who successfully complete the Placebo Run-In Period with ≥75% compliance 
will be eligible for randomization to pemafibrate or placebo. The responsible investigator will 
use an interactive computer system (Interactive Voice Response System [IVRS] or Interactive 
Web Response System [IWRS]) for randomization. The randomization process will involve 
stratification by sex, prior history of CVD (primary vs. secondary prevention cohorts), and statin 
use at baseline, defined as those who are taking no statin at baseline or are statin intolerant 
compared to all others at the Screening/Enrollment Visit. One-third of the study population will 
comprise participants without prior CVD and will constitute the primary prevention cohort. 
Blinding of Laboratory Results 
All lipid profiles will be blinded (values not provided) to participants, investigators, and other 
supporting staff at research sites, blinded personnel of the Study Sponsor, and blinded staff at the 
coordinating center, with the exception of the laboratory personnel and unblinded safety 
monitoring personnel. 
Emergency Unblinding 
In an emergency, when knowledge of the participant’s treatment assignment is essential for the 
clinical management and welfare of the participant, the investigator may request the participant’s 
treatment assignment for unblinding. Prior to unblinding, the investigator should assess the 
relationship of the AE to the administration of the study drug. If the blind is broken for any 
reason, the investigator must record on the appropriate eCRF the date and reason for breaking the 
blind. There is no antidote for the investigational drug, so unblinding is not expected to have an 
impact on the medical evaluation and intervention needed. 
The process for breaking the blind will be handled through the IVRS/IWRS. If possible, attempts 
should be made to discuss with the Medical Monitor prior to unblinding. The blind may be 
broken only for the participant in question. Any site that breaks the blind under inappropriate 
circumstances may be asked to discontinue their participation in the study. Study drug must be 
discontinued but the unblinded participant must be retained in passive follow-up. 
Both the Sponsor and 
 must be notified immediately if a participant and/or investigator 
is unblinded during the study. 

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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
Following a 21-day Placebo Run-In Period (maximum 35 days) designed to select compliant 
individuals for long-term follow-up and adherence, eligible participants will be randomized to 
receive either pemafibrate 0.2 mg twice daily or an identical matching placebo. The assigned 
investigational product is to be administered twice daily on an outpatient basis beginning the day 
after the Randomization visit (Visit 2) until the end of the study. 
The Sponsor will supply sufficient pemafibrate 0.2 mg film-coated tablets and matching placebo 
to allow the participants to complete the study. The lot numbers of the study drug will be 
recorded in the final CSR. 
All pemafibrate and matching placebo tablets are 7.1 mm round, white film-coated tablets. To 
ensure that study blinding can be maintained, each tablet is indistinguishable by size, markings, 
and weight. Each pemafibrate tablet contains 0.2 mg of pemafibrate, and each pemafibrate and 
matching placebo tablet contains the following excipients: lactose monohydrate, croscarmellose 
sodium, microcrystalline cellulose, magnesium stearate, hypromellose, hydroxypropyl cellulose, 
triethyl citrate, light anhydrous silicic acid (also known as colloidal anhydrous silica or colloidal 
silicon dioxide), titanium oxide (also known as titanium dioxide), and carnauba wax. 
9.2. 
Study Drug Packaging and Labeling 
Study drug packaging will be completed by an independent clinical packager, Catalent CTS, 
LLC (Catalent). The packager will be supplied with both the pemafibrate 0.2 mg tablets and the 
matching placebo tablets for packaging into child-resistant blister packs.  
Study drug will be packaged in clear polyvinyl chloride/aluminum foil blister cards and kept 
inside a cardboard sleeve. Participants will have an approximately 1-month supply of study drug 
in each blister card, and will receive an adequate supply of study drug at each visit to ensure 
proper dosing until the next scheduled visit. 
Study drug will be labeled to maintain double blind study design during the treatment period 
according to country-/state-/province-specific requirements for each location, as applicable. For 
example, the label may include, but not be limited to the following information: 
• Name and address of the Sponsor and packager 
• Study reference code (eg, protocol number) allowing identification of the investigational 
site and investigator 
• Blank space to write participant’s initials 
• Blank space for site/investigator number 

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• Route of administration, quantity of dosage units, and pharmacological form, as 
appropriate 
• Unique code number that will allow appropriate blinded assignment of the correct clinical 
trial material kit via the randomization code 
• Lot number (as applicable) 
• Directions for use 
• The statement: “Caution - New Drug - Limited by Federal (US) Law to Investigational 
Use” 
• The statement “Keep out of reach of children” 
• Storage conditions 
• Expiration date (as applicable) 
Study drug labeling and packaging for the Placebo Run-In Period will be identical to the study 
drug labeling and packaging for the double blind treatment phase. 
9.3. 
Study Drug Storage 
At the investigative sites, study drugs must be stored at room temperature, 68°F to 77°F (20°C to 
25°C). Temporary excursions between 59°F (15°C) and 86°F (30°C) are permitted. Study drugs 
must be stored in the original package in a pharmacy or locked in a secure storage facility, 
accessible only to those individuals authorized by the investigator to dispense the drug. 
9.4. 
Study Drug Preparation 
Not applicable, as the study drug formulation will be tablets and will be provided to the 
investigational centers to dispense directly to the participants.  
9.5. 
Study Drug Administration 
Participants will self-administer their assigned study drug daily over the course of the study 
treatment period. Participants will take an oral dose of pemafibrate 0.2 mg or matching placebo 
tablet twice daily starting the day after completion of Visit 2. Participants may take the study 
drug in either a fed or fasted state (before or after meals); however, participants should be 
instructed by the sites to try and remain consistent with the time of dosing for all doses 
throughout the study. Participants will be instructed by the site to follow dosing instructions on 
the drug packaging, and to return all remaining unused study drug and packages at the next visit. 
Participants 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 (eg, misuse or 
overdose) as a protocol deviation. For each participant, the number of tablets dispensed, taken, 
and returned will be recorded on the site’s Drug Accountability Log and recorded in the eCRF. 
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drug count and the start and end date of therapy. Participants will be considered compliant if they 
have taken ≥ 75% and ≥ 80% of the intended regimen during Placebo Run-In and Treatment 
Periods, respectively. 
During the active treatment period, if compliance is < 80%, the participant will be counseled by 
the site on the importance of compliance with the study drug administration. 
9.6. 
Study Drug Accountability 
The study drug will be shipped to the study site. The investigator must inventory and 
acknowledge receipt of all shipments. The investigator or designee will keep accurate dispensing 
records. At the conclusion of the study, study site personnel will account for all used and unused 
study drug. The investigator will agree not to distribute study drug to any participant, except 
those participants participating in the study. 
9.7. 
Study Drug Handling and Disposal 
All study drug supplies will be returned to the shipper or the local depot and processed for 
destruction by the packager. 

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10. 
STUDY PROCEDURES 
10.1. 
Pre-Screening Visit (Visit 0)  
At the Pre-Screening Visit (Visit 0), the following procedures will be performed: 
• Discuss study details, study procedures, and potential benefits and risks with the 
participant and thereafter obtain written informed consent 
• Record participant demographics and medical history  
• Review and submit medical records for the following (see Section 7.1): 
o Qualifying at least 1 TG level is ≥ 150 mg/dL (1.69 mmol/L) within 12 months 
o Qualifying at least 1 HDL-C level is ≤ 45 mg/dL (1.16 mmol/L) within 12 months 
o Qualifying type 2 diabetes by either diagnosis, laboratory parameters, or anti-
diabetic medicines  
o Qualifying CVD event (secondary prevention cohort); submitted any time prior to 
the Randomization Visit (Visit 2) 
o LDL-C ≤ 70 mg/dL (1.81 mmol/L) if not on qualifying moderate- to high-
intensity statin [atorvastatin ≥ 40 mg/day, rosuvastatin ≥ 20 mg/day, simvastatin 
≥ 40 mg/day, or pitavastatin 4 mg/day] regimen) or ≤ 100 mg/dL (2.59 mmol/L) if 
documented statin intolerant within 12 months 
o Statin intolerance (if applicable) 
• Schedule the Screening/Enrollment Visit (Visit 1) up to 3 weeks from Visit 0 (may be 
extended up to 6 weeks, if needed) or same day if the participant arrives fasting 
• Instruct the participant to fast for ≥ 8 hours immediately prior to the next visit (ie, nothing 
by mouth, except water and essential medications) 
Participants may proceed to the Screening/Enrollment Visit (Visit 1) and enter the Placebo Run-
In Period without submission of qualifying events, qualifying lipids, and statin intolerance (when 
applicable), but may not be randomized without complete submission of these records.  
Ascertainment of Qualifying TG and HDL-C 
Study sites are encouraged to determine qualifying TG and HDL-C in PROMINENT by 
obtaining pre-screening evidence of fasting or non-fasting TG and HDL-C that are documented 
by the investigator through local laboratory values within the previous 12 months (Figure 4). If at 
least 1 pre-screening TG level is ≥ 150 mg/dL (1.69 mmol/L), and at least 1 pre-screening HDL-
C level is ≤ 45 mg/dL (1.16 mmol/L), then the participant may proceed to the 

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Screening/Enrollment Visit (Visit 1) at which time fasting TG and HDL-C levels and eligibility 
labs will be obtained and the Placebo Run-In Period will begin.  
Thus, the screening approach that will be adopted in PROMINENT (Figure 4) begins with pre-
screening evidence of fasting or non-fasting TG levels that are documented by the investigator 
through local laboratory values within the previous 12 months. If at least 1 pre-screening TG 
level is ≥ 150 mg/dL (1.69 mmol/L), and at least 1 HDL-C level is ≤ 45 mg/dL (1.16 mmol/L), 
then fasting levels obtained at the Screening/Enrollment Visit (Visit 1) using standardized 
methodology (5 minutes in the seated position, < 1 minute tourniquet time) will determine 
eligibility. For expediency, participants meeting all applicable inclusion and exclusion criteria at 
the end of the Pre-screening Visit, other than pre-screening (chart documented) TG, HDL-C, and 
other exclusionary lab testing, may proceed with the Screening/Enrollment Visit (Visit 1) and 
have qualifying laboratory testing performed at Visit 1 and enroll in the Placebo Run-In Period. 
If results of qualifying laboratory testing meet all applicable inclusion and exclusion criteria, the 
participants will proceed with the Randomization Visit (Visit 2) or the Retesting Visit (Visit 1.1), 
if applicable. 
Figure 4: 
Screening Approach - Ascertainment of Qualifying TG and HDL-C 
 
 

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10.2. 
Screening/Enrollment Visit (Visit 1) 
A 21-day (maximum 35 day) Placebo Run-In Period will begin at Visit 1. The purpose of this 
Placebo Run-In Period is to ensure that participants are compliant with study medications, and 
are able to adhere to study procedures. 
The Screening/Enrollment Visit (Visit 1) should occur within 3 weeks of the Pre-Screening Visit 
(Visit 0), but may be extended up to within 6 weeks of Visit 0, if needed. At this visit, clinical 
eligibility and exclusion criteria will be confirmed, including relevant medical history and 
concomitant medication use. The following procedures will be performed at the 
Screening/Enrollment Visit (Visit 1): 
• Complete submission of medical records, if not completed at Visit 0 
• Review inclusion and exclusion criteria 
• Document CV risk factors and alcohol use 
• Review concomitant medication use 
• Perform a physical examination (eg, general appearance, head and neck, chest and lungs, 
etc.) 
• Collect vital signs (blood pressure, heart rate, height, body weight, waist circumference, 
and body mass index [BMI] [to be calculated]) 
• Instruct participants on study drug administration 
• Dispense placebo tablets for the Placebo Run-In Period 
• Confirm that the participant has fasted per instructions provided during the previous visit 
• Collect fasting blood samples for safety, eligibility, and baseline efficacy assessment (per 
Appendix A in Section 21.1): chemistry, hematology, thyroid studies, lipids, and other 
tertiary exploratory parameters (Section 11.3) 
• Collect a fasting blood sample for archiving (in countries and at sites where it is 
approved by the IRB/IEC/REC) and other regulatory authorities, as applicable 
• Collect urine sample (for creatinine and microalbumin) 
• Collect serum for pregnancy testing (WOCP only) 
• Query participant and record any reported or observed SAEs 

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• Query participant and record any CV efficacy events (see Section 11.1 and Section 11.2 
for definitions of efficacy events) 
• The Randomization Visit (Visit 2) should be scheduled for 21 days after the 
Screening/Enrollment Visit, but may be extended to 35 days if necessary 
• Participants should be instructed by the site to be non-fasting for Visit 2 lab tests 
Note: All participants leave the Screening/Enrollment Visit with the placebo blister card and will 
start taking tablets for the Placebo Run-In Period. Results of entry TG level, HDL-C, and all 
other exclusionary laboratory testing may require up to 4 business days to return. If any 
eligibility laboratory results return outside the eligibility range (Figure 4), the participant will be 
notified that they are no longer eligible to participate. Retesting for TG and HDL-C 
(Section 10.3), if necessary, will also occur during the Placebo Run-In Period. 
10.2.1. 
Re-screening (if applicable) 
Participants with uncontrolled diabetes, uncontrolled hypertension, uncontrolled thyroid disease, 
recent CVD event or revascularization procedure, or other medical instability due to an 
intervening medical condition prior to randomization, may be re-evaluated for re-screening at the 
investigator’s discretion once remedies have been instituted and the participant is stable for at 
least 4 weeks (28 days) at the time of the repeat Pre-Screening Visit (Visit 0). Re-screening for 
medical instability may occur on a one-time basis only and should occur after a discussion with 
the 
 Medical Monitor. Re-screening of participants for non-medical instability 
issues after 4 weeks may occur on a one-time basis after discussion with the 
 Medical 
Monitor. 
10.3. 
Retesting Visit (Visit 1.1) (if applicable) 
Retesting for qualifying TG and HDL-C levels will be permissible per the guidelines described 
as shown Figure 4. 
Retesting in cases of borderline levels of fasting TG will be permissible on a one-time basis if 
the initial value measured at Visit 1 is in the range of 175-199 (1.98-2.25 mmol/L) or 
500-650 mg/dL (5.65-7.34 mmol/L). The fasting retest value must be ≥ 200 mg/dL and 
< 500 mg/dL for the participant to be eligible for participation in the study. Retesting for 
borderline levels of HDL-C will also be permissible on a one-time basis if the initial value 
measured at Visit 1 is in the range of 41-45 mg/dL (1.06-1.16 mmol/L). The fasting retest value 
must be ≤ 40 mg/dL. 
Participants do not need to qualify for both TG and HDL-C entry criteria on a single blood draw.  
This visit will solely include collection of a fasting lipid sample for screening lipid levels (TG 
and HDL-C). 
10.4. 
Randomization Procedures and the Randomization Visit (Visit 2) 
All participants who successfully complete the Placebo Run-In Period with ≥ 75% adherence to 
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Visit (Visit 2) will involve collection of key medical, social, and anthropometric information 
from the participant, as well as a brief physical examination and collection of blood samples for 
the non-fasting lipid panel.  
The following procedures will be performed at the Randomization Visit (Visit 2): 
• Review inclusion and exclusion criteria and confirm eligibility 
• Document complete medical history 
• Document CV risk factors and alcohol use 
• Review concomitant medication use 
• Administer the EQ-5D-5L quality of life questionnaire 
• Perform a physical examination (eg, general appearance, head and neck, chest and lungs, 
etc.) 
• Collect vital signs (blood pressure, heart rate, body weight, waist circumference, and 
BMI [to be calculated]) 
• Perform a compliance check through unused Placebo Run-In tablet count 
• Randomize participants and dispense study drug 
• Collect a non-fasting blood sample for safety and efficacy assessments (see Appendix A 
in Section 21.1 for details): chemistry, hematology, thyroid studies, lipids, and other 
tertiary exploratory parameters (Section 11.3) 
• Collect a non-fasting blood sample for archiving (in countries and at sites where it is 
approved by the IRB/IEC/REC) and other regulatory authorities, as applicable 
• Collect urine samples (for creatinine and microalbumin) 
• Collect blood for serum pregnancy testing (WOCP only) 
• Query participant and record any reported or observed SAEs 
• Query participant and record any CV efficacy events (see Section 11.1 and Section 11.2 
for definitions of efficacy events) 
 
Randomization 
The site investigator will use an interactive computer system for randomization. The 
randomization process will involve stratification by sex, prior history of CVD (primary vs. 
secondary prevention cohorts), and statin use at baseline, defined as those who are taking no 
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No more than one-third of the study population will comprise participants without prior CVD 
(primary prevention cohort). The DSMB and Executive Committee (EC) will monitor participant 
profiles and may increase or restrict enrollment of certain subgroups to control this proportion.  
10.5. 
Treatment Period Telephone Visits: Week 2 and at 4-Month 
Intervals  
In order to improve retention, provide support, and reinforce study medication dosing, a brief 
telephone call (Visit 3) will be conducted 2 weeks (± 3 days) after the Randomization Visit. 
Subsequent telephone visits will be conducted at 4-month intervals beginning 1 month after 
randomization (Month 2) and continuing to the end of the study. Thus, Visits 3, 4, 8, 10, 12, 14, 
16, 18, 20, 22, 24, 26, 28, 30, 32, and 34 will be conducted by telephone. All telephone visits 
after Visit 3 will have a 2 week window (ie, ± 2 weeks on either side of the scheduled visit). 
During each telephone call, the following information will be gathered: 
• Review concomitant medication use 
• Query participant and record any reported AEs 
• Query participant and record any CV efficacy events (see Section 11.1 and Section 11.2 
for definitions of efficacy events) 
• Instruct participants to bring all study supplies with them to the next in-person visit 
• Instruct participants to fast for ≥ 8 hours immediately prior to the next in-person visit (ie, 
nothing by mouth, except water and essential medications) 
10.6. 
Treatment Period In-Person Visits: 4-Month Intervals Starting at 
Month 4  
In-person visits will continue to occur every 4 months starting at Month 4 after randomization 
(with the addition of a Month 6 visit) and will continue until the conclusion of the study. Thus, 
Visits 5, 6, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, and 33 will take place in person and 
will have a 2-week window (ie, can take place ±2 weeks on either side of the scheduled visit). 
Each in-person visit will involve the following procedures: 
• Document CV risk factors and alcohol use 
• Review concomitant medications 
• Perform a physical examination (eg, general appearance, head and neck, chest and lungs, 
etc.) 
• Collect vital signs (blood pressure, heart rate, body weight, waist circumference, and 
BMI [to be calculated]) 
• Collect unused study drug and determine study drug compliance by unused tablet count 

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• Dispense study drug 
• Query participant and record any reported or observed AEs 
• Query participant and record any CV efficacy events (see Section 11.1 and Section 11.2 
for definitions of efficacy events) 
• Instruct participants to bring all study supplies with them to the next in-person visit 
• Instruct participants to fast for ≥ 8 hours immediately prior to the next in-person visit (ie, 
nothing by mouth, except water and essential medications) 
At the Month 4 Visit (Fasting), in addition to the in-person visit procedures listed above: 
• Confirm that the participant has fasted 
• Collect fasting blood samples for safety and efficacy assessments (see Appendix A in 
Section 21.1 for details): chemistry, hematology, thyroid studies, lipids, and other tertiary 
exploratory parameters (Section 11.3) 
• Collect a fasting blood sample for archiving (in countries and at sites where it is 
approved by the IRB/IEC/REC) and other regulatory authorities, as applicable 
• Collect urine samples (for creatinine and microalbumin) 
• Perform serum pregnancy testing (WOCP only) 
At the Month 6 Visit (Non-fasting), in addition to the in-person visit procedures listed above: 
• Collect a non-fasting blood sample for safety and efficacy assessments (See Appendix A 
in Section 21.1 for details): chemistry, hematology, thyroid studies, lipids, and other 
tertiary exploratory parameters (Section 11.3) 
• Perform serum pregnancy testing (WOCP only) 
At the Month 12 Visit (Fasting), in addition to the in-person visit procedures listed above: 
• Administer the EQ-5D-5L quality of life questionnaire 
• Collect fasting blood samples for safety and efficacy assessments (see Appendix A in 
Section 21.1 for details): chemistry, hematology, thyroid studies, lipids, and other tertiary 
exploratory parameters (Section 11.3) 
At subsequent Annual Visits (Fasting), in addition to the in-person visit procedures listed 
above: 
• Confirm that the participant has fasted 

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• Collect fasting blood samples for safety and efficacy assessments (see Appendix A in 
Section 21.1 for details): chemistry, hematology, thyroid studies, lipids, and other tertiary 
exploratory parameters (Section 11.3) 
• Collect urine samples (for creatinine and microalbumin) 
• Perform serum pregnancy testing (WOCP only) 
At subsequent in-person visits after Month 12, beginning at Month 16 Visit (Fasting or 
Non-fasting), in addition to the in-person visit procedures listed above: 
• Collect fasting or non-fasting blood samples for safety assessment (chemistry panel only) 
10.7. 
Common Study End Date (CSED) Visit 
Study close out will begin after 1,092 adjudicated and confirmed primary endpoint events have 
accrued, with a minimum of 200 events in women. The estimated total study duration will be 
approximately 5 years. The CSED Visit will be scheduled within a 60-day window after the 
study termination is announced, irrespective of the date that the participant was randomized.  
The CSED Visit is required for all participants. During scheduling of this visit, participants will 
be instructed to fast for ≥ 8 hours immediately prior to this visit (ie, nothing by mouth, except 
water and essential medications). 
In the rare case that the CSED Visit cannot occur within the 60-day timeframe following the 
study termination, attempts to contact the participant must be recorded on a special contact form, 
until/unless appropriate information is obtained. The following procedures will be performed at 
the CSED Visit: 
• Document CV risk factors and alcohol use 
• Review concomitant medication use 
• Administer the EQ-5D-5L quality of life questionnaire 
• Perform a physical examination (eg, general appearance, head and neck, chest and lungs, 
etc.) 
• Collect vital signs (blood pressure, heart rate, body weight, height, waist circumference, 
and BMI [to be calculated]) 
• Collect unused study drug and determine study drug compliance by unused tablet count 
• Query participant and record any reported or observed AEs 
• Query participant and record any CV efficacy events (see Section 11.1 and Section 11.2 
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• Collect fasting blood samples for safety and efficacy assessments (see Appendix A in 
Section 21.1 for details): chemistry, hematology, thyroid studies, lipids, and other tertiary 
exploratory parameters (Section 11.3) 
• Collect urine samples (for creatinine and microalbumin) 
• Collect serum for pregnancy testing (WOCP only) 
The CSED Visit will be followed 30 days later by a Post-Study Safety telephone call to collect 
any final AEs unless the participant had interrupted or discontinued study drug greater than 
30 days before the CSED Visit. 

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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Monitoring for the Occurrence of Cardiovascular Events 
Monitoring for the occurrence of CV events will occur through querying the participant at each 
study visit. Documentation in the form of medical records will be collected and used in endpoint 
adjudication. Formal definitions for the individual components of the primary endpoint, all-cause 
mortality, and hospitalization for HF are provided below: 
Endpoint Definitions and Documentation 
Clinical endpoints defined as primary or secondary efficacy parameters will be assessed 
beginning with the day of randomization. Although excluded from the efficacy assessments, 
clinical endpoint events occurring between the Screening/Enrollment Visit (ie, the time of 
informed consent) and randomization will also be identified. All potential clinical endpoint 
events are collected for all randomized participants through study completion/CSED Visit 
whether or not the participant is currently receiving study drug. A complete description of the 
endpoints, data to be collected, and methodology for adjudication of both primary and secondary 
endpoints will be detailed in a Clinical Endpoint Committee (CEC) Charter. Primary endpoint 
definitions are included below.   
It is important to note, that the study medication will not be interrupted for reported or 
confirmed primary or secondary endpoints.  
Definition of Myocardial Infarction 
Acute MI: The definition of MI used in PROMINENT is consistent with the Third Universal 
Definition of MI.61 The term MI should be used when there is evidence of myocardial necrosis in 
a clinical setting consistent with acute myocardial ischemia. Under these conditions, any 1 of the 
following meets the diagnosis for MI:  
Spontaneous MI: Detection of a rise and/or fall in cardiac biomarker values (preferably cardiac 
troponin [cTn]), with at least 1 value above the 99th percentile of the upper reference limit (URL) 
and with at least 1 of the following: 
• Symptoms of ischemia 
• New or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle 
branch block (LBBB) 
• Development of pathological Q waves in the electrocardiogram (ECG)* 
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
• Identification of an intracoronary thrombus by angiography or autopsy 

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*Note: While the Universal Criteria for MI includes criteria for silent MI, for the purposes of this 
study, reports of silent MI will not be adjudicated as an MI, and will not be included in the study 
composite primary endpoint. 
Cardiac death MI: Cardiac death with symptoms suggestive of myocardial ischemia and 
presumed new ischemic ECG changes or new LBBB, but death occurred before cardiac 
biomarkers were obtained, or before cardiac biomarker values would be increased. 
Percutaneous Coronary Intervention (PCI)-related MI is arbitrarily defined by elevation of 
cTn values (> 5 X 99th percentile URL) in participants with normal baseline values (≤ 99th 
percentile URL) or a rise of cTn values > 20% if the baseline values are elevated and are stable 
or falling. In addition, either: 1) symptoms suggestive of myocardial ischemia; or 2) new 
ischemic ECG changes; or 3) angiographic findings consistent with a procedural complication; 
or 4) imaging demonstration of new loss of viable myocardium or new regional wall motion 
abnormality are required.   
Stent thrombosis associated with MI, when detected by coronary angiography or autopsy in 
the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with at 
least 1 value above the 99th percentile URL. 
Coronary artery bypass grafting (CABG)-related MI is arbitrarily defined by elevation of 
cardiac biomarker values (> 10 X 99th percentile URL) in participants with normal baseline cTn 
values (≤ 99th percentile URL). In addition, either: 1) new pathological Q waves or new LBBB; 
or 2) angiographic documented new graft or new native coronary artery occlusion; or 3) imaging 
evidence of new loss of viable myocardium or new regional wall motion abnormality.  
Universal Clinical Classification of MI: Each MI identified will be classified into 1 of the 
following clinical categories:  
• Type 1: Spontaneous MI  
Spontaneous MI related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, 
or dissection with resulting intraluminal thrombus in 1 or more of the coronary arteries 
leading to decreased myocardial blood flow or distal platelet emboli with ensuing 
myocyte necrosis. The participant may have underlying severe coronary artery disease 
(CAD), but on occasion non-obstructive or no CAD.  
• Type 2: MI secondary to an ischemic imbalance 
In instances of myocardial injury with necrosis where a condition other than CAD 
contributes to an imbalance between myocardial oxygen supply and/or demand (eg, 
coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-
/brady-arrhythmias, anemia, respiratory failure, hypotension, or hypertension with or 
without LVH). 
• Type 3: MI resulting in death when biomarker values are unavailable 

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Cardiac death with symptoms suggestive of myocardial ischemia and presumed new 
ischemic ECG changes or new LBBB, but death occurring before blood samples could be 
obtained, before cardiac biomarker could rise, or in rare cases, cardiac biomarkers were 
not collected. 
• Type 4a: MI related to percutaneous coronary intervention (PCI) 
Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn 
values > 5 X 99th percentile URL in participants with normal baseline values (< 99th 
percentile URL) or a rise of cTn values ≥ 20% if the baseline values are elevated and are 
stable or falling. In addition, either: 1) symptoms suggestive of myocardial ischemia; or 
2) new ischemic ECG changes or new LBBB; or 3) angiographic loss of patency of a 
major coronary artery or a side branch or persistent slow- or no-flow or embolization; or 
4) imaging demonstration of new loss of viable myocardium or new regional wall motion 
abnormality are required.  
• Type 4b: MI related to stent thrombosis 
Myocardial infarction associated with stent thrombosis is detected by coronary 
angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall 
of cardiac biomarkers values with at least 1 value above the 99th percentile URL. 
• Type 4c: MI related to stent restenosis 
MI associated with stent restenosis, as detected by coronary angiography or at autopsy, 
occurring > 48 hours after PCI, without evidence of stent thrombosis, but with symptoms 
suggestive of myocardial ischemia, and with elevation of cTn values to > 99th percentile 
of the URL. This classification also requires: 1) Does not meet the criteria for any other 
classification of MI; 2) presence of a ≥ 50% stenosis at the site of the previous successful 
stent PCI or a complex lesion and no other significant obstructive CAD of greater 
severity following (a) initially successful stent deployment or (b) dilation of a coronary 
artery stenosis with balloon angioplasty to < 50% stenosis.  
• Type 5: MI related to CABG. 
Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac 
biomarker values > 10 X 99th percentile URL in participants with normal baseline cTn 
values (< 99th percentile URL). In addition, either: 1) new pathological Q waves or new 
LBBB, or 2) angiographic documented new graft or new native coronary artery 
occlusion, or 3) imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality.  
ECG Manifestation of Acute Myocardial Ischemia (in the Absence of LVH and LBBB): 
• ST Elevation - New ST elevation at the J-point in 2 contiguous leads with the cut-points: 
≥ 0.1 mV in all leads other than leads V2-V3 where the following cut points apply: 
≥ 0.2 mV in men ≥ 40 years; ≥ 0.25 mV in men < 40 years, or ≥ 0.15 mV in women. 

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• ST depression and T-wave changes – New horizontal or down-sloping ST depression 
≥ 0.05 mV in 2 contiguous leads; and/or T inversion ≥ 0.1 mV in 2 contiguous leads with 
prominent R waves or R/S ratio >1. 
Criteria for Prior Myocardial Infarction 
Any 1 of the following criteria meets the diagnosis for prior MI: 
• Pathological Q waves with or without symptoms in the absence of non-ischemic causes 
• Imaging evidence of a region of loss of viable myocardium that is thinned and fails to 
contract, in the absence of a non-ischemic cause  
• Pathological findings of a prior MI 
ECG Changes Associated with Prior MI 
• Any Q wave in leads V2–V3 ≥ 0.02 sec or QS complex in leads V2 and Vr 
• Q wave ≥ 0.03 sec and ≥ 0.1 mV deep or QS complex in Leads 1, II, aVL, aVF or V4–V6 
in any 2 leads of a contiguous lead grouping (1, aVL; V1–V6; II, III, aVF) 
• R wave ≥ 0.04 sec in V1–V2 and R/S ≥ 1 with a concordant positive T-wave in absence 
of conduction defect 
Definition of Nonfatal Ischemic Stroke 
The definition of stroke used here is drawn from the definitions proposed by Hicks et al. and 
Sacco et al.62, 63  Stroke is defined as the acute onset of focal neurological dysfunction caused by 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction.  
A stroke is the acute onset of a new persistent neurological deficit attributed to an obstruction in 
cerebral blood flow with no apparent nonvascular cause (eg, tumor, trauma, infection). Available 
neuroimaging studies will be considered to support the clinical impression and to determine if 
there is a demonstrable lesion compatible with an acute stroke. To the extent possible, all strokes 
will be classified as ischemic, hemorrhagic, or unknown. While all types of strokes will be 
adjudicated by the CEC, only ischemic strokes will be included in the primary endpoint. 
For the diagnosis of stroke, the following criteria should be fulfilled: 
1. Rapid onset of a focal neurological deficit not related to any other known non-
cerebrovascular process with at least 1 of the following: 
• Change in level of consciousness 
• Hemiplegia 
• Hemiparesis 

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• Numbness or sensory loss affecting 1 side of the body 
• Dysphasia/aphasia 
• Hemianopia 
• Amaurosis fugax 
• Other new neurological sign/symptom(s) consistent with stroke 
• If the timing of onset is uncertain, a diagnosis of stroke may be made provided that there 
are no plausible non-stroke causes for the clinical presentation. 
AND 
2. Duration of a focal/global neurological deficit that is EITHER: 
• ≥ 24 hours,  
OR 
• < 24 hours if: 
− Resolution of symptoms is due to least 1 of the following interventions: 
1. Pharmacologic: intravenous or intra-arterial thrombolysis 
2. Non-pharmacologic: (ie, neuro-interventional procedure such as 
intracranial angioplasty)  
OR 
• Available brain imaging clearly documents a new hemorrhage or infarct 
OR 
• The neurological deficit results in death 
 
Ideally, at least 1 of the following should be present to confirm the diagnosis of stroke: 
1. Neurology or neurosurgery specialist 
2. Brain imaging procedure (at least 1 of the following): computed 
tomography (CT) scan, magnetic resonance imaging (MRI) scan, or 
cerebral vessel angiography 
3. Lumbar puncture (ie, spinal fluid analysis diagnostic of intracranial 
hemorrhage) 

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If the acute focal signs represent a worsening of a previous deficit, these signs must have either: 
1. Persisted for more than 1 week; or 
2. Persisted for more than 24 hours and were accompanied by an appropriate new 
MRI or CT scan finding 
Strokes are sub-classified as follows: 
Ischemic (non-hemorrhagic): An acute episode of focal cerebral, spinal, or retinal dysfunction 
caused by infarction of central nervous system tissue. Hemorrhage may be a consequence of 
ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic 
transformation and not a hemorrhagic stroke.  
Hemorrhagic: An acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage. Hemorrhage in the brain is 
documented by neuroimaging or autopsy or lumbar puncture. Note that subdural hematomas are 
intracranial hemorrhagic events and not strokes.  
Undetermined: An acute episode of focal or global neurological dysfunction caused by presumed 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction, but with 
insufficient information to allow categorization as either ischemic or hemorrhagic. 
Definition of Hospitalization for Unstable Angina Requiring Unplanned Revascularization 
Hospitalization for unstable angina requiring unplanned revascularization is defined as an 
unscheduled hospitalization for the management of unstable angina, occurring within 24 hours of 
the most recent symptoms. Hospitalization is defined as an admission to an inpatient unit or a 
visit to an emergency department that results in a 24-hour stay (or a change in calendar date if 
the hospital admission or discharge times are not available). Symptoms of myocardial ischemia 
at rest (chest pain or equivalent) or an accelerating pattern of angina with frequent episodes 
associated with progressively decreased exercise capacity are required.  
For the diagnosis of hospitalization for unstable angina requiring unplanned revascularization, 
the following criteria are required: 
• Worsening ischemic discomfort (rest angina, or severe angina (Canadian Cardiovascular 
Society (CCS) classification severity ≥ Class III) new in onset (<2 months) or increasing 
angina intensity, duration, and/or frequency, with an increase in severity of at least 1 CCS 
class to at least CCS III) 
• Unscheduled hospitalization 
• No elevation in cardiac biomarkers 

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• An attempt (even if unsuccessful) at percutaneous or surgical coronary revascularization 
during the index hospitalization, or after a transfer to another institution that then 
performs those procedures, provided that there is no interceding home discharge 
Definitions of Cardiovascular, Non-Cardiovascular, and Undetermined Cases of Death 
The classifications for death are drawn from Hicks et al. 62 Death is classified into 1 of 3 
categories: CV, non-CV, or undetermined cause of death. The intent is to identify 1 of these 
categories as the underlying cause of death. The key priority is differentiating between CV and 
non-CV causes of death. Death attribution can be difficult, particularly for sudden death, even 
when witnessed. Sudden deaths are usually attributed to sudden cardiac death (CV death) or 
death due to an undetermined cause. The underlying cause of death (the attributable cause of 
death) and the most proximate event associated with death may overlap substantially. Generally, 
the attributable cause of death is preferred.  
Cardiovascular death can be due to: acute MI; sudden cardiac death; HF; stroke; a CV 
procedure; CV hemorrhage; or other CV cause.   
Cardiovascular death due to acute MI:  Death by any CV mechanism (eg, arrhythmia, sudden 
death, HF, stroke, pulmonary embolus, PAD within 30 days after an acute MI, related to the 
immediate consequences of the MI, such as progressive HF or recalcitrant arrhythmia. There 
may be assessable (attributable) mechanisms of CV death during this time period, but for 
simplicity, if the CV death occurs within 30 days of an acute MI, it will be considered a death 
due to MI. 
Note: Acute MI should be verified to the extent possible by the diagnostic criteria outlined for 
acute MI or by autopsy findings showing recent MI or recent coronary thrombosis. Death 
resulting from a procedure to treat an MI (PCI or CABG), or to treat a complication resulting 
from MI, should also be considered death due to acute MI. Death resulting from an elective 
coronary procedure to treat myocardial ischemia (ie, chronic stable angina) or death due to an MI 
that occurs as a direct consequence of a CV investigation/procedure/operation should be 
considered a death due to a CV procedure.  
Cardiovascular death due to sudden cardiac death: Death that occurs unexpectedly and not 
within 30 days of an acute MI. Sudden cardiac death includes the following scenarios:  
• Death witnessed and occurring without new or worsening symptoms 
• Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, 
unless the symptoms suggest acute MI 
• Death witnessed and attributed to an identified arrhythmia (eg, captured on an 
electrocardiographic recording, witnessed on a monitor, or unwitnessed but found on ICD 
review) 
• Death after unsuccessful resuscitation from cardiac arrest (eg, ICD unresponsive sudden 
cardiac death, pulseless electrical activity arrest) 

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• Death after successful resuscitation from cardiac arrest and without identification of a 
specific cardiac or non-cardiac etiology 
• Unwitnessed death in a participant seen alive and clinically stable ≤ 24 hours before 
being found dead without any evidence supporting a specific non-CV cause of death 
(information about the participant’s clinical status preceding death should be provided if 
available) 
• Unless additional information suggests an alternate specific cause of death (eg, Death due 
to Other Cardiovascular Causes), if a participant is seen alive ≤ 24 hours before being 
found dead, sudden cardiac death should be recorded. For participants who were not 
observed alive within 24 hours of death, undetermined cause of death should be recorded 
(eg, a participant found dead in bed, but who had not been seen by family members for 
> 24 hours) 
Cardiovascular death due to HF: Death associated with clinically worsening symptoms and/or 
signs of HF, regardless of HF etiology. Note: Deaths due to HF can have various etiologies, 
including single or recurrent MIs, ischemic or nonischemic cardiomyopathy, hypertension, or 
valvular disease.  
Death due to stroke: Death after a stroke that is either a direct consequence of the stroke or a 
complication of the stroke. Note: acute stroke should be verified to the extent possible by the 
diagnostic criteria outlined for stroke.  
Cardiovascular death due to CV procedure: Death caused by the immediate complication(s) 
of a CV procedure. 
Cardiovascular death due to CV hemorrhage: Death related to hemorrhage, such as a non-
stroke intracranial hemorrhage (eg, subdural hematoma), non-procedural or non-traumatic 
vascular rupture (eg, aortic aneurysm), or hemorrhage resulting in cardiac tamponade.   
Cardiovascular death due to other CV causes: Cardiovascular death not included in the above 
categories with specific, known cause (eg, pulmonary embolism [PE], PAD).  
Definition of Non-CV Death: When death is due to a non-CV cause, a CV cause of death is 
excluded.   
• Pulmonary (excludes malignancy) 
• Renal  
• Gastrointestinal (disease of the esophagus, stomach, or intestines [excludes malignancy]) 
• Hepatobiliary (disease of the liver, gall bladder, or biliary ducts [excludes malignancy]) 
• Pancreatic (disease of the pancreas [excludes malignancy]) 

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• Infection (including sepsis) 
• Inflammatory/immune (death attributable to an inflammatory or immune-mediated 
disease or process, including SIRS, immunological, and autoimmune disease and 
disorders. Includes anaphylaxis from environmental allergies) 
• Hemorrhage (bleeding that is not considered CV hemorrhage or stroke 
• Non-CV procedure or surgery (death caused by the immediate complications of a non-
CV procedure or surgery) 
• Trauma (death attributable to trauma, including homicide)  
• Suicide 
• Non-prescription drug reaction or overdose 
• Prescription drug reaction or overdose (includes anaphylaxis) 
• Neurological (excludes malignancy, as well as death from ischemic stroke, hemorrhagic 
stroke, or undetermined cause of stroke, or CV hemorrhage of central nervous system) 
• Malignancy (leukemia, lymphoma, or other malignancy) 
• Other (death attributable to a cause other than those listed in this classification; specify 
organ system) 
Undetermined cause of death: Causality may be difficult to determine if information available 
from the time of death is minimal or non-existent. It may be difficult to determine causality if 2 
lethal conditions may contribute to death equally. In this circumstance, 1 condition should be 
chosen, taking into consideration the population being studied in PROMINENT. 
Definition of Hospitalization for HF 
Hospitalization for HF is a secondary endpoint of the study and is defined as an event where the 
participant is admitted to the hospital with a primary diagnosis of HF where the length of stay is 
at least 24 h (or extends over a calendar date if the hospital admission and discharge times are 
unavailable), where the participant exhibits new or worsening symptoms of HF on presentation, 
has objective evidence of new or worsening HF, and receives initiation or intensification of 
treatment specifically for HF. 
Definition of Peripheral Artery Disease 
Peripheral artery disease (lower extremity) is also a secondary endpoint of the study and is 
defined as the occurrence of lower extremity peripheral vascular intervention or new or 
worsening PAD defined as the new occurrence of 1) revascularization; 2) intermittent 
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ankle-brachial index ≤ 0.9 or other diagnostic testing (eg, toe-brachial index, angiogram, or other 
imaging study). 
11.2. 
Monitoring for the Occurrence of Diabetes-Related Events and 
Parameters 
New or progressive diabetic retinopathy is confirmed when medical records document use of 
retinal laser treatment, antivascular endothelial growth factor therapy, or vitrectomy due to 
development of and/or deterioration of diabetic retinopathy. Initial reports of diabetic retinopathy 
will be collected by querying the participant at each study visit.  
New and or progressive diabetic nephropathy is confirmed by laboratory evidence of an 
increase in microalbumin/creatinine ratio to ≥ 30 mg/g among those without microalbuminuria at 
baseline, and categorical change from baseline albuminuria (normo-, micro-, or 
macroalbuminuria), doubling of creatinine from baseline, creatinine level > 6.0 mg/dL, eGFR 
<15 mL/min/1.73 m2, or initiation of renal replacement therapy (dialysis or transplant), among 
all participants. Laboratory data obtained during safety laboratory collections will be used for 
laboratory values and participants will be queried at each study visit for initiation of renal 
replacement therapy. 
11.3. 
Monitoring of Tertiary Efficacy Endpoints (Biomarkers) 
Tertiary exploratory markers include core lipid parameters, advanced lipid parameters, 
inflammatory and glycemic parameters, and expanded lipid and non-lipid parameters as noted 
below: 
• Core lipid parameters (total cohort): TG, HDL-C, calculated and directly measured 
LDL-C, calculated VLDL-C and non-HDL-C, TC, ApoB, ApoE, and directly measured 
remnant cholesterol 
• Advanced lipid parameters (total cohort): ApoA1, ApoC3, LDL-C by 
beta-quantification (PUC), lipoprotein particles (nuclear magnetic resonance [NMR] size, 
concentrations, and subfractions), HDL-TG and LDL-TG by PUC, and directly measured 
sdLDL-C and LDL-TG 
• Inflammatory and glycemic parameters (total cohort): hsCRP, fasting glucose, 
HbA1c, and FGF-21 
• Expanded exploratory lipid and non-lipid parameters (US/Canada subcohort): 
ApoA5, ApoB48, ANGPTL3, ANGPTL4, PCSK9 mass, CK-18, and type IV collagen 
Lipid markers critical to the central hypotheses (including core lipid parameters and advanced 
lipid parameters) are measured frequently throughout the course of the study and most often 
measured in the fasting state unless otherwise specified below. Likewise, inflammatory and 
glycemic exploratory biomarkers are measured frequently throughout the study in the entire 
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Expanded tertiary exploratory biomarkers (listed above) will be measured in a subcohort of 
participants (all randomized participants in the US and Canada) at the Screening/Enrollment 
Visit (for randomized participants only) at Month 4 and Month 12. 
Appendix A (Section 21.1) provides a schedule of biomarker testing in the study.  
Fasting Lipid Profile 
A fasting lipid profile is obtained at the Screening/Enrollment Visit (Visit 1), Month 4 (Visit 5), 
Month 12 (Visit 9), annually thereafter and at the CSED Visit. 
Non-Fasting Lipid Profile 
A non-fasting lipid profile will be measured at the Randomization and Month 6 Visits.  
11.4. 
Future Genetic Testing 
Genetic material (buffy coat or extracted DNA) will be stored for future genetic testing from 
consenting participants. This sample is further contingent upon local regulations, which may 
prohibit genetic samples from being collected or shipped outside the country.  
Results of genetic testing will not be reported to the participant, relatives, or attending physician 
and will not be recorded in the participant’s medical records. The participant may withdraw 
consent for genetic testing at any time up to analysis, even after the sample has been obtained. In 
the event of withdrawal of consent, the biorepository will be notified to pull and destroy the 
sample.  
For all samples collected for genetic testing, precautions are to be taken to maintain 
confidentiality by de-identifying the sample with the participant and preventing the genetic data 
from being linked to the identity of the participant. 
11.5. 
Archival of Blood Samples  
A fasting blood sample will be obtained for archiving at Visit 1 (Screening/Enrollment Visit), a 
non-fasting sample at Visit 2 (Randomization), and a fasting sample at Visit 5 (4 months). Total 
blood draw volumes for these archived specimens will be 22 mL at Visit 1, and 16 mL at each of 
Visit 2 and Visit 5 visits. The blood samples will be collected only at sites in countries where 
allowed by local regulations and where approved by the IRB/IEC/REC and relevant regulatory 
authorities. These blood samples may be used for exploratory purposes. 

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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
12.1.1. 
Vital Signs and Physical Examination 
Vital signs will be measured and physical examinations performed at the Screening/Enrollment 
and Randomization Visits, at all in-person visits conducted during the treatment period, and at 
the CSED Visit as indicated in the schedule of assessments (Table 4). Vital signs measurements  
will consist of the following: blood pressure, heart rate, height (Visit 1 and CSED Visit), body 
weight, and waist circumference; the BMI will be calculated based on baseline height and the 
most recent recorded weight. Vital signs should be collected after the participant has been resting 
for 5 minutes in a seated position. To avoid inter-observer variability, every effort should be 
made to ensure that the same individual who made the initial baseline determinations completes 
all safety evaluations. Physical examinations will be comprised of a general review of body 
systems. 
12.1.2. 
Laboratory Assessments 
The central laboratory will provide all collection materials and instruction for sample collection, 
packaging, and shipment. 
Where indicated in the schedule of assessments (Table 4) and the Appendix, samples for clinical 
laboratory procedures will be obtained after fasting for at least 8 hours, when possible and 
appropriate. For purposes of this study, fasting is defined as nothing to take in by mouth except 
water and any essential medications (ie, prescribed concomitant medications that may be taken 
with water only). Prescribed concomitant medications that must be taken with food or after 
meals should not be taken until after blood sampling. 
At Randomization Visit (Visit 2), any participants that have lipid laboratory values outside the 
exclusionary limits (following retesting) specified in the protocol exclusion criteria (Section 7.2) 
may not participate further in the study. After randomization, the investigator will be blinded to 
lipid laboratory test values and only notified if the values exceed clinical alert levels. In this case, 
clinically appropriate follow-up procedures will occur at the discretion of the investigator. 
A detailed summary of laboratory testing is provided in the Appendix. 
12.1.2.1. Safety Laboratory Tests 
The safety laboratory tests include: 
1. Chemistry panel including electrolytes (K, Na, Cl), AST, ALT, GGT, ALP, total 
bilirubin, direct bilirubin, calculated eGFR, BUN, CK, total protein, LDH, uric 
acid, and creatinine 
2. Hematology with complete blood count (CBC), including RBC count, 
hemoglobin, hematocrit, white blood cell count, white cell differential, and 
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3. Thyroid studies, including TSH and free T4 
4. Urinalysis, including creatinine, albumin, and chemistry panel 
Safety laboratory testing with the exception of urinalysis will occur at the Screening/Enrollment 
Visit, Randomization Visit, Months 4, 6 and 12 Visits, at annual visits thereafter, and at the 
CSED Visit. Additionally, at each 4-month interval (during in-person visits) after year 1, a 
chemistry panel will be collected for safety testing. A urinalysis will performed at the 
Randomization Visit, Months 4, and annually thereafter. 
Summary statistics of safety laboratory testing will be reviewed by the DSMB in important 
subgroups such as participants requiring CYP3A and CYP2C8 inhibitors. Should these data 
demonstrate no adverse safety signal, the frequency of safety blood laboratory testing after 
year 1 will be reduced to once annually, ie, the chemistry panel testing at intervening in-person 
visits will be discontinued. 
12.1.2.2. Reporting of Critical Laboratory Values 
Critical laboratory values are values that may warrant medical intervention to avoid possible 
harm to the participants. Critical laboratory values for the study are defined in the below 
subsections. The research site will be notified expeditiously (eg, fax, phone, etc.) by the central 
laboratory in the event of a critical laboratory value (high or low). 
12.1.2.2.1. Liver Function Test Elevations 
Refer to Section 7.3.1 for details on study drug discontinuation procedures related to elevated 
liver function results.  
Repeat evaluation should include AST, ALT, prothrombin time/INR, total bilirubin, alkaline 
phosphatase, gamma-glutamyltransferase, creatinine, CK, and complete viral hepatitis screen. 
The participant 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. 
12.1.2.2.2. Creatine Kinase Elevations 
Refer to Section 7.3.1 for details on study drug discontinuation procedures related to elevated 
CK results. 
The participant should be questioned about symptoms (eg, muscle or tendinous pain, cramping, 
or weakness) and potential causes for the CK elevation (eg, 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 
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Abnormalities should be followed until they have returned to baseline, or the investigator 
considers them clinically stable. 
12.1.3. 
Pregnancy Screen 
Serum pregnancy testing will occur at the Screening/Enrollment Visit (Visit 1), Randomization 
(Visit 2), Month 4 (Visit 5), Month 6 (Visit 6), Month 12 (Visit 9), and at subsequent in-person 
visits including the CSED for all WOCP.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Events  
An AE is any untoward or unfavorable medical occurrence in a human participant, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the participant’s participation in the research, whether or not 
considered related to the participant’s participation in the research. 
Any medical condition that is present at the time the participant is consented but does not 
deteriorate should not be reported as an AE. However, if it deteriorates or worsens significantly 
at any time during the study, it should be recorded as an AE. 
12.2.1.2. Serious Adverse Events  
An adverse event is categorized as serious if it: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization OR prolongs an existing hospitalization 
• is associated with a persistent or significant disability or incapacity or with a congenital 
anomaly or birth defect, or 
• is a medically significant event, as determined by the Principal Investigator, even if it 
does not meet any of the other criteria for seriousness 
Death is considered an outcome of an adverse event, and as such, the cause of death should be 
recorded as the adverse event. ‘Death’ should not be reported as an event term unless the cause 
of death is unknown at the time of reporting. If ‘death’ is reported as an event, the investigator 
should update the event term to the cause of death when this information becomes available. 
Life threatening: An adverse event is considered ‘life-threatening’ if, in the view of either the 
investigator or Sponsor, its occurrence places the participant at immediate risk of death. It does 
not include an adverse event that, had it occurred in a more severe form, might have caused 
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Hospitalization or prolongation of hospitalization: Kowa considers ‘hospitalization’ as 
admission to a hospital for any inpatient care, or an emergency room stay with a duration of 
24 hours or longer. The definition of hospitalization does not include: 
• an emergency room visit for less than 24 hours or admission to an outpatient facility 
• a hospitalization that was elective or pre-planned for a pre-existing condition and not 
related to worsening of an underlying condition 
• a hospitalization for social reasons and not related to a change in the participant’s general 
condition 
Medically significant/important medical event: An important medical event that may not be 
immediately life-threatening or result in death or hospitalization, but based on medical judgment 
may jeopardize the participant and may require medical or surgical intervention to prevent any of 
the outcomes listed above (ie, death, life-threatening, hospitalization, prolongation of 
hospitalization, persistent or significant disability/incapacity or congenital anomaly).  
12.2.2. 
Adverse Event Severity 
The intensity of the AE will be rated by the investigator as mild, moderate, or severe using the 
following criteria:  
Mild: an event that is transient and easily tolerated by the participant, requires minimal or no 
treatment, and does not interfere with the participant’s daily activities.  
Moderate: an event that causes the participant discomfort and may cause some interference in 
the participant’s usual activities.  
Severe: an event that causes considerable interference with the participant’s usual activities, may 
require drug therapy or other treatment. 
12.2.3. 
Relationship to Study Drug 
An investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE. The investigator should decide whether, in his or her 
medical judgment, there is a reasonable possibility that the event may have been caused by the 
investigational product. If no valid reason exists for suggesting a relationship, then the AE 
should be classified as “unrelated.” If there is any valid reason, even if undetermined, for 
suspecting a possible cause-and-effect relationship between the investigational product and the 
occurrence of the AE, then the AE should be considered “related.” 
The following guidance should be used by investigators when assessing relationship: 
Related: 
• Occurs within a reasonable temporal sequence to administration of study drug  
• Cannot be explained by concurrent disease or other drugs or chemicals  

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• Improves or disappears on stopping or reducing study drug (de-challenge)  
• Reappears on repeated exposure to study drug (re-challenge)  
• Is an unusual event that is known to be associated with the drug or this class of 
compound, and cannot be explained by other therapy or the participant’s physical 
condition 
• Unlikely to be attributed to concurrent disease or other drugs or a clinically reasonable 
response on withdrawal (de-challenge)  
Unrelated: 
• Occurs with a temporal relationship to administration of study drug which makes a causal 
relationship improbable 
• Other drugs, chemicals or underlying disease provide plausible explanations of causality 
• Is known to be associated with the participant’s clinical condition, or with other 
medication taken by the participant 
12.2.4. 
Action Taken Due to AE 
The following are actions taken to treat the AE and actions taken on study treatment as a result of 
the AE, and must be recorded in the event of an AE: 
Action taken to treat the AE 
• None 
• Treatment required 
• Hospitalization 
• Participant withdrawn 
• Other (specify) 
Action taken with study treatment 
• Drug interrupted 
• Drug withdrawn 
• Not applicable, or 
• Unknown 

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12.2.5. 
Adverse Event Outcomes 
The following are AE outcomes, and must be recorded in the event of an AE: 
• Resolved: The event has recovered 
o Note: An SAE/AE stop date should be provided 
• Resolved with sequelae: The study participant 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 participant 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 participant 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 (eg, “sudden cardiac death”). Adverse events resulting in 
death are SAEs 
• Not resolved: The participant 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 participant. 
12.2.6. 
Adverse Event Collection Period 
The SAE reporting period for safety surveillance begins when the participant is initially included 
in the study (date of first signature of informed consent) and will continue until the Post-Study 
safety call, 30 days after the CSED Visit. Adverse events occurring prior to and inclusive of the 
randomization visit and following the CSED Visit will comprise SAEs only; otherwise, all AEs 
will be recorded. 
12.2.7. 
Adverse Events of Special Interest  
Adverse events of particular interest as they pertain to pemafibrate will include muscle-related 
AEs and liver disease. Adverse event forms will be used to collect additional relevant clinical 
information at each study visit at which AEs will be assessed. Instructions for entry of these 
events will be provided in the eCRF Completion Guidelines. 

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12.2.8. 
Pregnancy 
If a participant becomes pregnant during the study, she must discontinue the study drug, but the 
investigator must follow up the pregnancy until the pregnancy outcome is available. Her 
obstetrician should be made aware of her study participation. The investigator should request 
information about the pregnancy outcome, including any possible fetal abnormalities and 
congenital defects. If a congenital abnormality or abortion (spontaneous) is reported, then it 
should be reported as an SAE.  
Specific instructions for entry of these events will be provided in the eCRF Completion 
Guidelines. 
12.3. 
Recording Adverse Events 
12.3.1. 
Detection and Initial Report of Adverse Events 
All participants will be monitored at the local study sites on a regular basis during the course of 
study involvement. Routine in-person and telephone follow-up visits offer the opportunity for 
PROMINENT study sites to ascertain any untoward medical events that might meet the criteria 
of an adverse event. Both in-person and telephone visits ask whether the participant has 
experienced any adverse events. All AEs are reported by completing an Adverse Event/Endpoint 
Form in the eCRF. A record of the type of AE, onset date, seriousness, severity (mild, moderate, 
or severe), and causality will be entered by the study site. 
12.3.2. 
Trial Endpoints and Adverse Events  
Primary endpoints are routinely assessed during in-person and telephone follow-up visits. Many 
of these clinical events will meet the criteria for serious adverse events. Endpoints will be 
reported by completing an Adverse Event/Endpoint Form in the eCRF. 
12.3.3. 
Reporting Adverse Events 
12.3.3.1. Investigator Responsibilities 
Within 24 hours of receiving initial or additional information on SAEs, pregnancies, and special 
situations (ie, overdose, medication errors, off-label use, abuse, and suspected transmission of an 
infectious agent), the investigator should complete the relevant eCRF pages in the EDC system. 
Specific instructions for entry of these events will be provided in the eCRF Completion 
Guidelines.  
The following minimum information must be reported: 
• AE that meets the definition for serious 
• Participant identification/randomization number 
• Investigator/site number 
• Study drug (pemafibrate vs. placebo) 

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In addition, the following information must be provided to the Sponsor with the initial report: 1) 
the date the investigator (or other site personnel) became aware of the event; and 2) the causality 
assessment.   
Supporting source documents must be thoroughly blinded to protect the confidentiality of 
participants participating in the study before such documents are provided to the Sponsor or 
designated staff. Participant identifiers that should be redacted include but are not limited to 
participants’ names, relatives’ names, personal addresses, phone numbers, medical record, and 
accession numbers. 
Once reported, automatic updates will be sent to the Sponsor and designated study staff. Initial 
reports will often not be complete. Central study staff will guide the site regarding the 
completion of an SAE form along with retrieval of the pertinent medical records for 
determination of a final diagnosis. Study site staff may contact participants directly to determine 
the resolution of AEs, if necessary. 
In the event that the EDC is unavailable, and the 24-hour reporting timeline cannot be 
accommodated, such events will be reported by faxing the back-up paper SAE and/or pregnancy 
report form to 
 Lifecycle Safety using the provided fax cover sheet and the appropriate 
fax number provided for your country. Once the EDC system becomes available, the investigator 
will enter SAEs reported on the paper SAE and/or pregnancy report form into the EDC system as 
soon as possible. 
Additionally, sites must follow the requirements of their institutional IRB/IEC/REC for reporting 
AEs. 
12.3.3.2. Sponsor Responsibilities 
Reporting of SAEs will be done by the Sponsor (or designee) in accordance with their safety 
management plan and regulatory requirements. 
The PROMINENT DSMB will review AEs that occur in the conduct of PROMINENT, and may 
issue statements or guidance about the conduct of the study broadly or to individual sites. These 
statements will be reported by the Sponsor and sites as required. Refer to Section 12.4 for further 
details on the DSMB. 
Additional SAE reporting for all participants will occur for central and/or local IRB/IEC/REC 
requirements, as relevant. 
Primary endpoint events in this study will be waived from expedited reporting to health 
authorities, investigators, or IRBs/IECs/RECs; refer to Appendix B (Section 21.2) for a list of 
SMQ terms exempt from expedited reporting.  
Medication errors, pregnancies and uses outside what is foreseen in the protocol, including 
misuse and abuse of the product, shall be subject to the same obligation to report as adverse 
events. 

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12.4. 
Data Safety Monitoring Board (DSMB) 
Due to the potential risks to study participants, the size and multicenter nature of the study, and 
the fact that this is a Phase 3 clinical study, the study will have a formal and independent DSMB. 
The DSMB will be established by the EC and will include, at a minimum, members with specific 
expertise in the management of CVD and diabetes and familiarity with clinical study conduct, 
and a biostatistician with specific expertise in the design, analysis, and safety monitoring of 
multicenter clinical studies. The DSMB will operate under a charter agreed to by the Sponsor 
and will have the responsibility of monitoring outcome measurements/endpoints, AEs, and 
SAEs, and recommending termination of the study if it appears at any point during the study that 
the participants (or a subgroup of participants) are being placed at undue risk as a result of their 
participation.  
The DSMB will meet (face-to-face or by teleconference) semi-annually to review accumulated 
data on safety and efficacy, and if appropriate, conduct an interim analysis of the data. Blinded 
data reports will be prepared by the data coordinating center (DCC) and un-blinded reports, if 
needed, will be prepared by the un-blinded DCC statistician prior to each meeting of the DSMB. 
Reports to the DSMB will include comparisons of baseline characteristics between treatment 
groups, displays of cumulative recruitment by study time, comparisons of post-randomization 
laboratory values by treatment group, and rates of AEs by treatment group, both overall and 
within system organ class (SOC). The DSMB will also receive summaries of lipid levels and 
concomitant lipid therapy dosing changes by treatment arm throughout the study to monitor 
imbalance in use of statins or other LDL-C lowering therapies. Summary statistics of safety 
laboratory testing will also be reviewed by the DSMB in important subgroups such as 
participants requiring CYP3A and CYP2C8 inhibitors. Should these data demonstrate no adverse 
safety signal, the frequency of safety blood laboratory testing after year 1 will be reduced to once 
annually, ie, the chemistry panel testing at intervening in-person visits will be discontinued. 
Interim analyses of rates of the primary outcome, as well as rates of the individual components 
of the composite endpoint, and the prespecified secondary endpoints will also be prepared for 
presentation to the DSMB. The reports will be reviewed initially with DSMB members blinded 
to treatment group assignments. If, however, aggregate data suggests a trend toward harm in 1 
treatment group, or at the request of the Sponsor’s safety group, an un-blinded interim analysis 
may be requested and reviewed by the DSMB. Refer to Section 14.7 for further details. 
Guidelines for the possible early termination of the study will be formulated by the DSMB, with 
a formal charter agreed upon prior to study enrollment. The proceedings of each meeting of the 
DSMB will be recorded in minutes. Any participant-specific protected health information 
reviewed by the DSMB will be kept completely confidential. Access to the closed session 
minutes of the DSMB meetings by Executive/Operations Committee (OC) Members, clinical site 
investigators, or members of the DCC, will be prohibited until after the database for the study 
has been locked and the study has been unblinded. A formal report will be submitted by the 
DSMB to the EC, with a recommendation that the study be continued, modified in a manner to 
enhance participant safety, or terminated. 

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13. 
PATIENT REPORTED OUTCOMES 
13.1. 
Quality of Life Assessment 
Patient-reported quality of life assessments will be evaluated in this study using the following 
questionnaires: 
• European Quality of Life – 5 Dimensions (EQ-5D-5L)  
EQ-5D-5L will be completed at the Randomization Visit, annually thereafter, at the first 
in-person visit after a primary and secondary endpoint occurs, and at the CSED Visit. The data 
collected may be used in pharmacoeconomics assessment. 

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14. 
STATISTICS 
14.1. 
Stratification and Randomization 
Participants willing and eligible to be randomized will be stratified by the following: sex, prior 
history of CVD (primary vs. secondary prevention cohorts), and statin use at baseline, defined as 
those who are taking no statin at baseline or are statin intolerant compared to all others. Within 
each strata, participants will be randomized with equal probability to active K-877 or placebo. 
14.2. 
Sample Size and Power 
The study was designed using an event-driven approach where all participants are followed until 
a sufficient number of events have accrued. Regardless of the rate of major CV events in the 
placebo group, the study must accrue 1,071 adjudicated and confirmed major CV events (with a 
minimum of 200 events accrued in women) in order to have 90% power to detect a 18% 
reduction in the rate with pemafibrate, based on a 2-sided test with alpha=0.05. The sample size 
has been increased by 1.9% to maintain 90% power in the presence of interim monitoring. 
Consequently, we stipulate that the study will require accrual of 1,092 total primary events.   
Using the approach of Lachin and Foulkes under the assumption of a uniform hazard we can 
estimate the duration of the study.64 We will use the following assumptions: 
1. The recruitment will be uniform over a 30-month period. Each randomized participant 
will be asked to continue blinded treatment until the study completion (when sufficient 
endpoints have been accrued).  
2. Unless otherwise specified, power is set at 90% to detect the specified effect. 
3. As these participants have strong affiliations with their treatment centers and will have 
been tested in a Placebo Run-In Period, low rates of loss to follow-up are anticipated. 
Power calculations assume a 1% loss to follow-up.  
4. Sample size is assumed to be 10,000 randomized participants (5000 receiving 
pemafibrate and 5000 receiving placebo).  
Based on previous studies, it is anticipated that annual event rates will be between 3.5 and 4.5 
per 100 person-years in the placebo group. We expect a higher event rate in the secondary 
prevention cohort (~2/3 with prior CVD) than the primary prevention cohort (~1/3 with no prior 
CVD). For example, a total annual event rate in the placebo group of 4.5 per 100 person years 
could be achieved via an event rate of 5.2 per 100 person years in the secondary prevention 
group and 3 per 100 person years in the primary prevention group. 
Under these assumptions, Lachin and Foulkes show that the power of the study with N total 
randomized participants in the pemafibrate and placebo groups combined is: 
𝑃𝑜𝑤𝑒𝑟= Φ−1(√𝑁|𝜆𝑒−𝜆𝑐| −3.92ඥΨ(𝜆)
തതത 
ඥ2Ψ(𝜆𝑒) + 2Ψ(𝜆𝑐)
) 

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where Φ is the standard normal distribution function, and ψ(λ) is defined as follows: 
Ψ(𝜆) = 𝜆(𝜆+ 0.05)/(1 −
ቂexp൫−𝑇𝑟(𝜆+ 0.05)൯−exp ቀ−𝑇𝑓(𝜆+ 0.05)ቁቃ
2(𝜆+ 0.05)
) 
λe is the incidence rate in the pemafibrate group, 
λc is the incidence rate in the placebo group, 
Tr is the recruitment duration (assumed to be 30 months), Tf is the follow-up duration, and 
𝜆̅ = .5𝜆𝑒−.5𝜆𝑐 
These power calculations are based on the Intent-to-Treat (ITT) population analyses. As such, 
they incorporate the effects of noncompliance. We estimate, based on experience observed in 
other studies that in addition to those who drop out, 10% of the pemafibrate group will 
discontinue active therapy, but that none of the placebo group will initiate pemafibrate therapy 
(drop-in). The impact of noncompliance on power can be evaluated from interpolation using 
Table 6. For example, if the true rate of major CV events in persons meeting eligibility criteria 
but not on pemafibrate is 3.5 per 100-person years, and fully compliant pemafibrate reduces this 
rate by 20%, we estimate a rate of the primary endpoint of 2.9 per 100 person-years in the 
pemafibrate group and 3.5 per 100 person-years in the placebo group. This would correspond to 
an observed 18% reduction in the active treatment group relative to placebo with the above 
noncompliance and drop-in rates. The proposed study would thus require 5 years of follow-up to 
have power above 90% to detect the anticipated effect on observed event rates and ITT analyses, 
as summarized in Table 6. 
With respect to the above assumptions on accrual and drop out, and the range of event rates in 
the placebo group shown in Table 6, the proposed study with 10,000 randomized participants 
would be expected to require approximately 5 years of follow-up (approximate placebo event 
rate=3.7/100 person-years) under the assumption of a 18% reduction in hazard associated with 
pemafibrate. 
Table 6: 
Number of Events and Estimated Study Duration in Years to Achieve 90% 
Power with 10,000 Randomized Participants 
Relative Rate 
Events 
(adjusted for 
Monitoring)  
Rate of Major Cardiovascular Events in the Placebo Group 
(per 100 person-years) 
3.5 
4.0 
4.5 
0.85 
1626 
7.6 years 
6.7 years 
6.0 years 
0.82 
1092 
5.2 years 
4.7 years 
4.3 years 
0.80 
865 
4.3 years 
3.9 years 
3.6 years 
 

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14.3. 
Demographics and Baseline Characteristics 
The randomized design and large sample size of 10,000 should provide a balanced distribution of 
demographic and baseline characteristics between the 2 treatment groups. Nonetheless, initial 
analyses will be conducted to identify any chance imbalances in the distribution of these 
characteristics. In particular, these analyses will form part of the routine monitoring of the study 
and will be regularly reported to the DSMB. For continuous and ordinal variables, including age 
and baseline levels of risk factors including lipid levels, blood pressure, BMI, duration of 
diabetes, and baseline HbA1c, comparisons between treatment groups will be made using the 
Wilcoxon rank-sum test. For categorical variables, including sex, race, current and former 
cigarette smoking, past history of CVD, congestive heart failure (CHF), atrial fibrillation, 
peripheral vascular disease, hypertension, and concomitant therapies, comparisons between 
treatment groups will be made using Chi-square tests. These hypothesis tests are intended for 
data monitoring and quality control, and not to determine which baseline covariates to include in 
efficacy analyses. 
14.4. 
Primary Analyses 
The primary endpoint of the study is the time from randomization to the first occurrence of any 
component of the clinical composite endpoint of nonfatal MI, nonfatal ischemic stroke, CV 
death, and hospitalization for unstable angina requiring urgent coronary revascularization. The 
primary analysis of the study will use a likelihood ratio test based on a proportional hazards 
model stratified on sex, prior history of CVD (primary vs. secondary prevention cohorts), and 
statin use at baseline, defined as those who are taking no statin at baseline or are statin intolerant 
compared to all others, to test the null hypothesis of no association between assignment to 
pemafibrate and the rate of the primary endpoint.  
The ITT population will serve as the primary analysis population and will include all randomized 
participants who received at least 1 dose of study treatment. Participants will be analyzed 
according to their randomized treatment group, regardless of whether they adhere to their 
assigned treatment. Statistical significance will be based on a 2-sided test with level 0.05. The 
estimated relative hazard in the pemafibrate group compared to the placebo group with an 
accompanying 95% CI will quantify the treatment effect.65 If this relative hazard is less than 1, 
then 100*(1-estimated relative hazard) will be defined as the percent reduction in hazard 
associated with pemafibrate treatment.  
Rates of occurrence of the primary endpoint will be defined as the total number of participants 
who have this event in a treatment group per 100 person-years of follow-up, counting all time 
from randomization until the first of the event, death, end of trial, or withdrawal of consent, 
whichever comes first. Estimates of the probability of the primary endpoint by time after 
randomization within treatment groups will be based on the method of Kaplan and Meier.66 We 
will also use the proportional hazards model to control for baseline factors that might influence 
the rate of the primary endpoint (eg, age, race, sex, baseline comorbidities, and concomitant 
medications), as control for these variables may yield more efficient estimates of relative 
treatment effects.67 If Kaplan-Meier plots of event-free survival by study time, or related plots of 
log(-log)(survival), indicate violations of the proportional hazards assumption, or a formal test of 
trend in the scaled Schoenfeld residuals indicates such a violation, then weighted log-rank tests 
will be used according to strategies described by Pecková and Fleming.68 However, even in the 

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presence of an apparent violation of the proportional hazards assumption, the primary analysis 
described above gives a valid (although perhaps not optimal) test of the main study hypothesis 
and will remain the primary analytic strategy, with these weighted log-rank tests serving as 
sensitivity analyses. 
14.5. 
Secondary and Tertiary Analyses 
In addition to the primary comparisons of pemafibrate treatment with placebo, prespecified 
secondary and tertiary endpoints will also be compared between the treatment groups. All 
secondary endpoints will only be evaluated if primary endpoint is positive. The total secondary 
endpoint alpha of 0.05 will be allocated between the secondary endpoint groups as specified in 
the Statistical Analysis Plan. 
Additional analyses will separately evaluate whether the relative effects of pemafibrate versus 
placebo on primary and secondary endpoints is uniform over the follow-up period. These 
evaluations will be based on the tests for significant interactions between study time and 
treatments proposed by Cox,65 as well as consideration of trends in scaled Schoenfeld residuals 
in the proportional hazards model. Specifically, residuals will be plotted and a significant rank 
correlation of residuals with time will be indicative of a changing effect.71 In the presence of 
significant correlation, separate effects by time period will be reported. However, even with a 
significant correlation of residuals with time, the best overall estimate of the effect of treatment 
will be the estimate obtained from the proportional hazards model without the interaction.  
To assess the effect of non-informative censoring on the primary outcome, analyses will be 
performed following the reference-based method outlined by Carpenter, Roger, and Kenward69 
and detailed in the Statistical Analysis Plan using the piece-wise exponential method described 
by Lipkovich at al.70 For those participants who were lost-to-follow-up, event status after the 
time of last observation is imputed using the distribution of retrieved dropouts for each arm. 
Retrieved dropouts are defined as participants who are no longer taking study drug but have 
agreed to continue to be followed. Other imputation models for missing data will also be 
explored for their effect on the primary outcome, including models that use the entire placebo 
group as the reference. 
Separate proportional hazards models will also be used to compare the effects of pemafibrate 
treatment on time to each of the individual components of the composite primary endpoint. 
Analyses will use methods of competing risks survival analysis and compare the relative effects 
of randomized treatments on the different components of the composite outcome.72, 73 The 
approach of Lunn and McNeil72 provides a readily accessible implementation of a classical 
approach to competing risk analysis developed by Kalbfleisch and Prentice.74 
Secondary lipid efficacy endpoints will be analyzed using analysis of covariance (ANCOVA) 
with a retrieved dropout based pattern mixture model. Participants with missing data will be 
imputed using the distribution of retrieved dropouts for each arm, where retrieved dropouts are 
defined as participants who are no longer taking study drug but have agreed to continue to be 
followed. Imputed data will be analyzed using an ANCOVA model with baseline measurement 
as a covariate and the treatment arm and randomization strata as fixed effects.  

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While all primary analyses are on the ITT population, a Per-Protocol population will also be 
analyzed which will be limited to participants with no major protocol deviations. Sensitivity 
analyses for the primary efficacy endpoint will also be conducted examining the effect of 
compliance and escalation of other lipid-lowering medications. Longitudinal analyses will 
quantify the impact of pemafibrate on lipid levels, biomarkers of inflammation, and glycemic 
parameters and other pre-specified exploratory lipid and non-lipid biomarkers (Tertiary 
Endpoints: Section 5.3.1). 
We will also assess whether any effects on these biomarkers mediate observed benefits or risks 
of pemafibrate on clinical outcomes in the study. 
14.6. 
Subgroup Analyses 
Additional planned exploratory analyses include evaluation of whether treatment effects vary 
across categories of baseline covariates. Key pre-specified subgroup analyses will examine 
treatment effect by sex, prior CVD, and baseline statin use. Other subgroups of interest include 
region, age, race, baseline lipid levels, and other baseline biomarker levels. Within each 
subgroup, we will use proportional hazards models to estimate the relative rate of the primary 
endpoint associated with active treatment versus placebo. Both crude analyses and models 
including limited baseline covariates will be fitted. To test for the significance of modification of 
treatment effects by a baseline characteristic, we will include interaction terms between this 
characteristic and treatment in the proportional hazards model, with statistical significance 
determined by a likelihood ratio test comparing models with and without the interaction terms 
between treatment and the categories of a specific covariate.  
Subgroup analyses will be conducted regardless of whether or not the overall analyses of 
treatment effects are significant. Our approach to interpretation of subgroup analyses has always 
been very cautious and recognizes that, even in large studies, it is not likely to be possible to 
identify reliably subgroups of participants in whom treatment is especially effective or 
ineffective. In the absence of prior evidence for real heterogeneity, the overall study result may 
provide the best evidence for the presence of a benefit in a subgroup. Our approach thus 
corresponds to an informal empirical Bayes procedure in which effects in an outlying subgroup 
require interpretation in light of the overall treatment effect. 
14.7. 
Planned Interim Analyses 
While the frequency of meetings and the approach to interim monitoring will be the choice of the 
DSMB, we anticipate at least twice yearly meetings to monitor recruitment and retention, with 
quarterly safety reports. To preserve alpha and to minimize the likelihood of an inflated effect 
estimate associated with early stopping, preplanned efficacy analyses will occur at accrual of 
approximately 50% and 75% of the planned study primary endpoints. The design of the study, 
including evaluation of the implications of interim monitoring on study power, considered that 
stopping boundaries would be based on the Haybittle-Peto method. Under this approach, the 
Z-values for the boundary at the 50% and 75% information times would be ±3.29, corresponding 
to 2-sided p-values of 0.001. Additionally, the DSMB will also consider the direction of effect 
for each of the components of the primary endpoint as well as the sensitivity analysis for loss-to-
follow-up, ensuring that the point estimate for each is consistent with the composite result and 
there is no concern for safety. The DSMB will also consider the direction of the effect in women, 

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again ensuring consistency with the overall result and no concern for safety. Specifically, in 
order for the study to be stopped early, the estimated HR for the pemafibrate group compared to 
placebo must be < 1 for each component of the primary endpoint as well as for the subgroup of 
women. Further, the HR of 1.36 seen in ACCORD59 must not be in the 95% CI for the primary 
endpoint in the subgroup of women. 
As a guideline for considering a recommendation to stop the study early because of convincing 
evidence of inefficacy (futility), preplanned inefficacy bounds will also be considered at accrual 
of approximately 30%, 50%, and 75% of planned study endpoints. Based upon the Linear 10% 
Inefficacy Boundary approach described by Freidlin, Korn, and Gray75, the inefficacy boundary 
will be crossed if the observed relative hazard of the primary endpoint associated with 
pemafibrate assignment is greater than 1.000 at the first interim futility analysis, greater than 
0.996 at the second interim futility analysis, or greater than 0.988 at the third interim futility 
analysis and the 95% CI excludes the expected effect. Simulations performed by Freidlin et al 
indicate that their Linear 10% Inefficacy Boundary approach is associated with a less than 1% 
loss of power due to inefficacy monitoring. Further, their approach is more conservative than a 
10 or 30% conditional power approach in later follow-up (ie, after 70% of information is 
accrued). However, the Linear 10% Inefficacy Boundary approach is more aggressive than a 
10% (or even a 20%) conditional power rule at earlier information accrual points, so a more 
conservative boundary may be preferred at the first interim futility analysis. 

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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
PROMINENT will be coordinated through an academic-industry partnership between 
investigators in the CCVDP at the Brigham and Women’s Hospital and Harvard Medical School 
(Boston, US) and Kowa Research Institute, Inc., or its designees. The study structure will include 
a Scientific Advisory Committee (SAC) with specific knowledge of PPAR-α biology and with 
responsibilities including the evaluation and amendment of the study design before launch; a 
study Steering Committee (SC) to include members from all participating countries; an EC with 
responsibilities for the overall enrollment, conduct, and completion of the study; an OC with 
responsibilities for daily management and interactions with the study Contract Research 
Organization (CRO), central laboratory, biorepository, and drug dispensary; a blinded CEC; a 
DCC; and a fully independent DSMB. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. It is understood that the monitor will contact and visit the investigator regularly and 
will be allowed, to inspect the various records of the study. It will be the monitor’s responsibility 
to inspect the eCRFs at regular intervals throughout the study to verify adherence to the protocol 
and the completeness, accuracy and consistency of the data; and adherence to the ICH GCP and 
local regulations on the conduct of clinical research. The monitor should have access to 
laboratory reports, study medication, records associated with it, and other medical records 
needed to verify the entries on the eCRF. 
15.1.1. 
Committees 
Steering Committee 
The SC will include the Principal Investigators and designated representatives from the 
investigative team (CCVDP) and the CRO (
), key representatives from the Study 
Sponsor (Kowa) as well as key representatives (including investigators) from each region that 
are deemed to have clinical and methodological expertise (national coordinators). The SC will 
meet as needed, with an estimated frequency of twice per year. 
Executive Committee 
The EC will include the Principal Investigators and a limited number of designated 
representatives from the investigative team (CCVDP), Sponsor, and key opinion leaders (KOLs). 
The EC will be responsible for evaluating overall execution of the study, review of 
recommendations from the DSMB, evaluation and approval of all proposed substudies, and will 
oversee study publications. The EC will meet, as required, through completion of the study, with 
an estimated frequency of 2 times per year. 
Operations Committee 
The OC will include the Principal Investigators and members of the investigative team including 
the project manager, senior research coordinators, senior database analysts, and research 

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assistants as well as designated members from the CRO and the Sponsor. The OC will be 
responsible for ensuring that study execution and management is of the highest quality, and will 
monitor recruitment, compliance, and the adjudication process and address the day-to-day issues 
arising in the study. This committee will meet by telephone and/or in person on a weekly basis, 
as needed, through completion of the study.  
Clinical Endpoint Committee 
The CEC will conduct a blinded review of all potential primary and secondary endpoint events to 
confirm that the data support the endpoint designation. The committee members who perform the 
review of the endpoint events will not be investigators in the study. Any differences between 
reviewer designations will be adjudicated in conference calls or regular meetings. A separate 
CEC Manual of Operations will fully describe the methods used by the CEC. 
Scientific Advisory Committee 
The SAC will be composed of the Principal Investigators and designated representatives from 
the investigative team (CCVDP), key representatives from the Study Sponsor, and KOLs 
determined by the Study Sponsor. The SAC will meet once every year and will provide scientific 
guidance to the SC. 
15.1.2. 
Data Coordinating Center and Treatment Masking 
The DCC will work with the CRO to oversee data collection, monitoring, and reporting to the 
study committees and DSMB. With the CRO, the DCC will provide reports to the EC as needed. 
Both the Progress Report and the Quality Control Report will pool participants across treatment 
groups to maintain the study blind. 
15.1.3. 
Data and Safety Monitoring Board (DSMB) 
Due to the potential risks to study participants, the size and multicenter nature of the study, and 
the fact that this is a Phase 3 clinical study, the study will have a formal and independent DSMB. 
The DSMB will be established by the EC and will include, at a minimum, members with specific 
expertise in the management of CVD and diabetes and familiarity with clinical study conduct, 
and a biostatistician with specific expertise in the design, analysis, and safety monitoring of 
multicenter clinical studies. The DSMB will operate under a charter agreed to by the Sponsor 
and will have the responsibility of monitoring outcome measurements/endpoints, AEs, SAEs, 
and lipid levels and concomitant lipid therapy dosing changes by treatment arm to monitor 
imbalance in use of statins or other LDL-C lowering therapies. Additionally, the DSMB will 
have the responsibility of recommending termination of the study if it appears at any point 
during the study that the participants (or a subgroup of participants) are being placed at undue 
risk as a result of their participation.  
Refer to Section 12.4 for further details on the DSMB. 
15.2. 
Audits and Inspections 
Kowa and/or its authorized representatives, a regulatory authority, an IRB/IEC/REC may visit 
the sites to perform audits or inspections, including source-data verification. The purpose of an 

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audit or inspection includes, but is not limited to a systematic and independent examination of all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, ICH GCP 
guidelines, and applicable regulatory requirements. The investigator should contact Kowa 
immediately if contacted by a regulatory agency about an inspection. 

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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCPs and all applicable regulatory requirements, Kowa, or their 
designee, may conduct quality assurance audits of the investigators and supporting vendors. 
Please see Section 15.2 for more details regarding the audit process.  
Investigators who become aware of quality issues at their site, including misuse or abuse of 
medication by study participants, should record these in the EDC. 

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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/IEC/REC as appropriate, before being implemented by 
the investigator. The written approval/favorable opinion from the IRB/IEC/REC must be 
received by the investigator and the Sponsor before the investigator can enroll any participants 
into the study. 
The Principal Investigator or the Sponsor is responsible for informing the IRB/IEC/REC of any 
amendment to the protocol in accordance with local requirements. In addition, the IRB/IEC/REC 
must approve all advertising used to recruit participants for the study. The protocol must be re-
approved by the IRB/IEC/REC upon receipt of amendments, and annually, as per local 
regulations. 
As required by local regulation, the investigator or the Sponsor will report promptly to the 
IRB/IEC/REC, any new information that may adversely affect the safety of participants or the 
conduct of the study. Similarly, the investigator or the Sponsor will submit written summaries of 
the study status to the IRB/IEC/REC annually, or more frequently, if requested by the 
IRB/IEC/REC. Upon completion of the study, the investigator or the Sponsor will provide the 
IRB/IEC/REC with a brief report of the outcome of the study, if required. 
The Sponsor or its representative will provide Regulatory Authorities, Ethics Committees, and 
investigators with safety updates/reports according to local regulations and guidelines, including 
Suspected Unexpected Serious Adverse Reactions (SUSARs), where relevant. 
The Principal Investigator or the Sponsor is also responsible for providing the IRB/IEC/REC 
with reports of any serious adverse drug reactions from any other study conducted with the 
investigational product in accordance with local regulations. Kowa or 
 will provide the 
necessary adverse event drug reaction reports to the Principal Investigators for submission to the 
IRB/IEC/REC. 
17.2. 
Ethical Conduct of the Study 
Informed consent will be obtained from the study participants and the study will be conducted in 
accordance with the ethical principles in the Declaration of Helsinki (64th General Assembly, 
Fortaleza, Brazil, October, 2013), the GCP guidelines (CPMP/ICH/135/95), and the applicable 
drug and data protection laws and regulations of the countries in which the study will be 
conducted.  
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described herein and to adhere to the principles of GCP, which is an international ethical and 
scientific quality standard for designing, conducting, recording, and reporting studies that 
involve the participation of human participants. This study will be conducted in compliance with 
GCP and the applicable national regulations so as to assure that the rights, safety, and wellbeing 

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of the study participants are protected, consistent with the ethical principles that have their origin 
in the Declaration of Helsinki. 
17.3. 
Written Informed Consent 
Before any study-specific procedures or assessments are conducted, participants who have had 
the protocol fully explained by the responsible investigator and who are willing to participate in 
the study must read, sign, and date an ICF. The Principal Investigator(s) at each center will 
ensure that the participant is given full and adequate oral and written information about the 
nature, purpose, and possible risks and benefits of the study. Participants must also be notified 
that they are free to discontinue from the study at any time. The participant should be given the 
opportunity to ask questions and allowed time to consider the information provided. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the participant. 
As described in the informed consent documents, participation in the genetic biobanking portions 
of the study will be on an “opt-out” basis and are not a requirement for participation in the main 
study.  
The ICF will be used to explain the risks and benefits of study participation to the participant in 
simple terms before the participant will be entered into the study. The ICF contains a statement 
that the consent is freely given, that the participant is aware of the risks and benefits of entering 
the study, and that the participant is free to withdraw from the study at any time. The ICF will 
describe all levels of participation, including passive follow-up and contact of participants who 
stop attending study visits to confirm vital status and endpoint occurrence at study end. Written 
consent must be given by the participant and/or legal representative, after the receipt of detailed 
information on the study.  
The investigator is responsible for ensuring that informed consent is obtained from each 
participant or legal representative and for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to the 
administration of study medication. The investigator will provide each participant with a copy of 
the signed and dated consent form. 

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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Electronic Data Capture 
An EDC system will be developed and used to collect and transmit source data throughout the 
course of the study. This system will be compliant with 21 Code of Federal Regulations (CFR), 
Part 11 and will meet all relevant governmental regulations. The system will be maintained by 
 System functionality will be thoroughly tested and validated prior to implementation. 
Furthermore, to ensure compliance with standards of use of electronic study data, standard 
operating procedures will be maintained for the use of the system, an audit trail of data changes 
will ensure that there is no modification of entered data without documentation, and security 
systems will be maintained to protect against unauthorized access. Furthermore, adequate 
procedures will be used to back up the data and safeguard the blinding of the study.  
The EDC system will be used in each of the following steps to create, modify, maintain, archive, 
retrieve, and/or transmit source data: 
• Creation of eCRFs  
• Resolution of data discrepancies through data queries and checks  
• Monitoring of drug distribution 
• Reporting of AEs and endpoints 
 
Data generated within this clinical study will be handled according to the relevant SOPs of the 
Data Management and Biostatistics Departments of 
   
All eCRF data will be entered into electronic forms at the study center. Data collection will be 
completed by authorized study-center staff designated by the investigator. Appropriate training 
and security measures will be completed with the investigator and all authorized study center 
staff prior to the study being initiated and any data being entered into the system for any study 
participants. 
All data must be entered in English. The eCRFs should always reflect the latest observations on 
the participants in the study. Therefore, the eCRFs are to be completed by the sites as soon as 
possible during or after the participant’s visit to allow for site monitoring of the data. To 
avoid inter-observer variability, every effort should be made to ensure that the same individual 
who made the initial baseline determinations completes all efficacy and safety evaluations. The 
investigator must verify that all data entries in the eCRFs are accurate and correct. If some 
assessments are not done, or if certain information is not available or not applicable or unknown, 
the investigator should indicate this in the eCRF. The investigator will be required to 
electronically sign off on the clinical data.   
The 
 Monitor will review the eCRFs and evaluate them for completeness and 
consistency. The eCRF will be compared with the source documents to ensure that there are no 
data discrepancies. All entries, corrections, and changes are to be made by the investigator or 

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his/her designee. The Monitor cannot enter data in the eCRFs. Once clinical data in the eCRF 
have been submitted to the central server, corrections to the data fields will be audit trailed, 
meaning that the reason for change, the name of the person who performed the change, together 
with time and date will be logged. Roles and rights of the site staff responsible for entering the 
clinical data into the eCRF will be determined in advance. If additional corrections are needed, 
the responsible Monitor, Data Manager, or designee will raise a query in the EDC application. 
The appropriate study center staff will answer the query. The entire chain of events will be audit 
trailed by the EDC application, including the name of each person who makes entries into the 
system, along with the time and date stamp for each entry. 
The eCRF is essentially considered a data entry form or copy and should not constitute the 
original (or source) medical records.   
The investigator is responsible for maintaining source documents. These will be made available 
for review by the Study Monitor at each monitoring visit. The investigator must submit a 
completed eCRF for each participant screened for the study. All supportive documentation 
submitted with the eCRF, such as laboratory or hospital records, should be clearly identified with 
the study and participant number. Any personal information, including participant name, should 
be removed or rendered illegible to preserve individual confidentiality. 
Electronic case report form records will be automatically appended with the identification of the 
creator, by means of their unique UserID. Specified records will be electronically signed by the 
investigator to document his/her review of the data and acknowledgement that the data are 
accurate. This will be facilitated by means of the investigator’s unique UserID and password; 
date and time stamps will be added automatically at time of electronic signature. If an entry on 
an eCRF requires change, the correction should be made in accordance with the relevant 
software procedures. All changes will be fully recorded in a protected audit trail, and a reason for 
the change will be required. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 18.1). Concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO DD). Concomitant diseases/medical history will be coded using MedDRA, 
Version 18.1. 
18.2. 
Source documents 
As the eCRF serves as a data entry form, it does not constitute the original or source medical 
record of the participant. The data entered into the eCRF must be derived from source 
documents, which provide evidence for the existence of the participant and substantiate the 
integrity of the data collected and recorded in the eCRF. Source documents constitute all 
documents used by the investigator or hospital that relate to the participant’s medical history, the 
participant’s fulfillment of the inclusion and exclusion criteria, and all records covering the 
participant’s participation in the study. They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, participant files, etc. The investigator will prepare and maintain 
adequate and accurate source documents to record all observations and other pertinent data for 
each participant randomized into the study. 

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All supportive documentation submitted with the eCRF, such as laboratory or hospital records, 
should be clearly identified with the study and participant number. Any personal information, 
including participant name, should be removed or rendered illegible to preserve individual 
confidentiality. 
Source documents are filed at the study site. Data entered into the eCRFs that are transcribed 
from source documents must be consistent with the source documents, or the discrepancies must 
be explained. Current medical records on the participant must be available. The investigator may 
need to request previous medical records or transfer records.  
18.3. 
Inspection of Records 
Kowa, or its designee, will be allowed to conduct site visits for the purpose of monitoring any 
aspect of the study. The investigator agrees to allow the Monitor to inspect the drug storage area, 
study drug supply, drug accountability records, participant charts and study source documents, 
and other records relating to study conduct. 
The investigator will allow the Sponsor, CRO, and authorized regulatory authorities to have 
direct access to all documents pertaining to the study, including individual participant medical 
records, as appropriate. 
18.4. 
Retention of Records 
It is the investigator’s responsibility to maintain essential study documents (ie, protocol and 
amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other supporting 
documentation). The study site should plan on retaining such documents for approximately 
15 years after study completion. The study site should retain such documents for at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region, or at least 2 years after the formal 
discontinuation of clinical development of the IMP. These documents should be retained for a 
longer period if required by the applicable regulatory requirements, or the hospital, institution, or 
private practice in which the study is being conducted. Participant identification codes (ie, 
participant names and corresponding study numbers) should be retained for the same period of 
time. If acceptable to the Sponsor, these documents may be transferred to another responsible 
party, who must agree to abide by the retention policies. In such a case, written notification of 
transfer must be submitted to the Sponsor.   
The investigator must contact the Sponsor prior to disposing of any study records. No records 
may be disposed of without the written approval of the Sponsor. 
If it becomes necessary for Kowa or the Regulatory Authority to review any documentation 
relating to the study, the investigator must permit access to such records. 

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19. 
PUBLICATION POLICY 
The EC is responsible for the reporting and publication of the study results. Kowa will be 
provided a reasonable opportunity to review such manuscripts prior to journal submission, as set 
forth in the Clinical Research Start-Up Activities Agreement between the Brigham and Women’s 
Hospital, Inc. and Kowa Research Institute, Inc. effective August 1, 2014. The results of the 
study will be published, irrespective of whether the endpoints are met, or whether the results are 
regarded as positive or negative. For clarity and transparency, and as explicitly described in the 
EC Charter for the PROMINENT study, for any issues related to publication or presentation of 
the study results, the Sponsor will be free to make recommendations to the EC, but the voting 
academic members of the EC will make the final determination as to whether or not such 
recommendations will be implemented. As such, the academic members of the EC have final 
responsibility and decision making authority for all aspects of study presentation and publication. 
Confidentiality, publication, and patent applications related to unpublished study-related 
information and unpublished information given to the site investigators by Kowa shall be 
handled as set forth in the Clinical Research Start Up Activities Agreement. 

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population-based prospective studies. J Cardiovasc Risk. 1996;3:213-9. 
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36. Thomsen M, Varbo A, Tybjaerg-Hansen A, Nordestgaard BG. Low nonfasting 
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37. TG, HDL Working Group of the Exome Sequencing Project NHL, Blood I, Crosby J, 
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39. Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the 
crossroads of obesity, diabetes and cardiovascular disease. Atheroscler. 2009;205:1-8. 

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40. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic 
review and meta-analysis. Lancet. 2010;375:1875-84. 
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44. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of 
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45. European Association for Cardiovascular P, Rehabilitation, Reiner Z, Catapano AL, De 
Backer G, et al. Guidelines ESCCfP and Committees. ESC/EAS Guidelines for the 
management of dyslipidaemias: the Task Force for the management of dyslipidaemias of 
the European Society of Cardiology (ESC) and the European Atherosclerosis Society 
(EAS). Eur Heart J. 2011;32:1769-818. 
46. Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of 
hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrin 
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47. Shimano H, Arai H, Harada-Shiba M, et al. Proposed guidelines for hypertriglyceridemia 
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48. Gotoda T, Shirai K, Ohta T, et al. Diagnosis and management of type I and type V 
hyperlipoproteinemia. J Atheroscler and Thromb. 2012;19:1-12. 
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50. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of 
hypertriglyceridaemia: implications for definition, diagnosis, and management. The 
Lancet Diabetes & Endocrinol. 2014;2:655-66. 
51. Wong ND, Glovaci D, Wong K, et al. Global cardiovascular disease risk assessment in 
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States, 1990-2010. N Engl J Med. 2014;370:1514-23. 
53. Emerging Risk Factors C, Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting 
blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis 
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54. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular 
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21. 
APPENDICES 

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21.1. 
Appendix A: Schedule of Laboratory Testing 

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21.2. 
Appendix B: Serious Adverse Event Endpoints Exempted from 
Regulatory Reporting 
SMQ Terms (PTs unless otherwise specified) for exemption from expedited reporting are as 
follows: 
Myocardial Infarction 
Diagnoses 
Acute coronary syndrome  
Acute myocardial infarction 
Infarction 
Myocardial infarction 
Myocardial necrosis 
Papillary muscle infarction 
Post procedural myocardial infarction 
Silent myocardial infarction 
 
Lesions 
Coronary artery embolism  
Coronary artery occlusion 
Coronary artery reocclusion 
Coronary artery restenosis 
Coronary artery stenosis 
Coronary artery thrombosis 
Coronary bypass thrombosis 
Coronary vascular graft occlusion 
In-stent coronary artery restenosis 
Stent thrombosis 

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Unstable Angina 
Acute coronary syndrome  
Angina pectoris 
Angina unstable 
Anginal equivalent 
Coronary artery insufficiency 
Myocardial ischemia 
Postinfarction angina 
Subendocardial ischemia 
 
Ischemic Stroke 
Diagnoses 
Basal ganglia infarction 
Basal ganglia stroke  
Brain stem infarction 
Brain stem ischemia 
Brain stem stroke 
Cerebellar infarction 
Cerebellar ischemia 
Cerebral infarction 
Cerebral ischemia 
Cerebral thrombosis 
Cerebrovascular accident 
Cerebrovascular disorder 

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Cerebrovascular insufficiency 
Embolic cerebral infarction 
Embolic stroke 
Infarction 
Ischemic cerebral infarction 
Ischemic stroke 
Lacunar infarction 
Lacunar stroke 
Lateral medullary syndrome 
Post procedural stroke 
Stroke in evolution 
Thalamic infarction 
Thrombotic cerebral infarction 
Thrombotic stroke 
Reversible ischemic neurological deficit 
Transient ischemic attack 
 
Lesions 
Basilar artery occlusion 
Basilar artery stenosis 
Basilar artery thrombosis 
Brain stem embolism 
Brain stem thrombosis 
Carotid arterial embolus 
Carotid artery insufficiency 

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Carotid artery occlusion 
Carotid artery restenosis 
Carotid artery stenosis 
Carotid artery thrombosis 
Cerebellar artery occlusion 
Cerebellar artery thrombosis 
Cerebellar embolism 
Cerebral artery embolism 
Cerebral artery occlusion  
Cerebral artery restenosis 
Cerebral artery stenosis 
Cerebral artery thrombosis 
Cerebral thrombosis 
Cerebral vascular occlusion 
Cerebrovascular stenosis 
Carotid artery thrombosis 
Precerebral artery occlusion 
Precerebral artery thrombosis 
 
CV Death 
Cardiac death 
Sudden cardiac death 
Sudden death 
 

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LLTs under Death PT 
Death occurring in less than 24 hours from onset of symptoms, not otherwise explained 
Death unascertained 
Death unattended 
Death unexplained 
Death unexplained (NOS) 
Unattended death 
Unknown cause of death