Conditions: Hypercholesteremia
Keywords: LDL-C Lipid Regulator
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 105
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the efficacy, safety, and tolerability of multiple doses of gemcabene 600 mg QD compared to placebo in patients with hypercholesterolemia not adequately controlled on high-intensity or moderate-intensity stable statin therapy. Patients with HeFH, ASCVD, or otherwise uncontrolled, may be included with baseline LDL-C value ≥ 100 mg/dL. Subjects were randomized 1:1 to gemcabene 600 mg once daily (QD) or placebo.

Detailed description:

Arms:
arm 1: Participants on stable statin therapy received matching placebo orally, once daily for 12 weeks. arm 2: Participants on stable statin therapy received 600 milligrams (mg) of Gemcabene orally, once daily for 12 weeks.

Interventions: intervention 1: Gemcabene intervention 2: Placebo
Intervention descriptions: intervention 1: Two 300 mg tablets and 1 placebo tablet administered orally, once daily for 12 weeks. intervention 2: Three placebo tablets administered orally once daily for 12 weeks.

Protocol document:
Prot_001.pdf: 
Title: A 12-Week, Phase 2 Randomized, Placebo-Controlled, Double-Blind Study to Assess the 
Efficacy, Safety, and Tolerability of Gemcabene in Subjects with Hypercholesterolemia Not 
Adequately Controlled on High-Intensity or Moderate-Intensity Stable Statin Therapy (ROYAL-1) 
 
 
NCT ID: NCT02634151 
 
 
Approval Date: 05-Oct-2016 


 
CLINICAL STUDY PROTOCOL 
 
A 12-Week, Phase 2 Randomized, Placebo-Controlled, Double-Blind 
Study to Assess the Efficacy, Safety, and Tolerability of Gemcabene 
in Subjects with Hypercholesterolemia Not Adequately Controlled 
on High-Intensity or Moderate-Intensity Stable Statin Therapy 
(ROYAL-1) 
 
Investigational Product: Gemcabene calcium tablets (gemcabene) 
Protocol Number: GEM-301 
 
 
Sponsor: 
Gemphire Therapeutics Inc.  
17199 N. Laurel Park Drive, Suite 401 
Livonia, Michigan 48152 
United States 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
 
Original Protocol: 25 November 2015 
Amendment 1: 19 February 2016 
Amendment 2: 16 September 2016 
Amendment 3: 05 October 2016 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Gemphire Therapeutics Inc. except to the extent that disclosure would be required by 
law and for the purpose of evaluating and/or conducting a clinical study for Gemphire 
Therapeutics Inc. You are allowed to disclose the contents of this document only to your 
Institutional Review Board (IRB) and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Gemphire Therapeutics Inc. and that it may not be further 
disclosed to third parties. 




Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-301 
INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol in its entirety. I approve this document and I agree that it contains all 
necessary details for carrying out the study as described. I will conduct this study in accordance 
with the design and specific provision of this protocol and will make a reasonable effort to 
complete the study within the time designated. I will provide copies of this protocol and access 
to all information furnished by Gemphire Therapeutics Inc. to study personnel under my 
supervision. I will discuss this material with them to ensure they are fully informed about the 
study product and study procedures. I will let them know that this information is confidential and 
proprietary to Gemphire Therapeutics Inc. and that it may not be further disclosed to third 
parties. I understand that the study may be terminated or enrollment suspended at any time by 
Gemphire Therapeutics Inc. with or without cause, or by me if it becomes necessary to protect 
the best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Conference on 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Principal Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Principal Investigator’s Printed Name 
 
  
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< 500 mg/dL (5.65 mmol/L) at the Screening Visit, while on a stable, low-fat, low-cholesterol 
diet in combination with background high-intensity statin therapy (defined as atorvastatin 40 mg 
or 80 mg once daily [QD]; or rosuvastatin 20 mg or 40 mg QD) or background moderate-
intensity statin therapy (defined as atorvastatin 10 mg or 20 mg QD; or rosuvastatin 5 mg or 10 
mg QD; or simvastatin 20 or 40 mg QD) with or without ezetimibe 10 mg QD for at least 12 
weeks prior to the Screening Visit.  
STUDY DESIGN AND DURATION: 
This is a Phase 2, randomized, placebo-controlled, double-blind, multi-center study. Subjects are 
required to be on a high-intensity stable statin regimen (atorvastatin 40 mg or 80 mg QD or 
rosuvastatin 20 mg or 40 mg QD) or a moderate-intensity statin regimen (atorvastatin 10 mg or 
20 mg QD; rosuvastatin 5 mg or 10 mg QD; or simvastatin 20 or 40 mg QD) with or without 
ezetimibe 10 mg for at least 12 weeks prior to the Screening Visit.     
Approximately 104 subjects will be randomized into the study, including those with HeFH or 
ASCVD, with 52 (26 gemcabene 600 mg; 26 placebo) subjects on baseline high-intensity statins 
and 52 (26 gemcabene 600 mg; 26 placebo) subjects on baseline moderate-intensity statins. 
Total study duration will be up to 26 weeks with 12 weeks of study drug treatment. The study 
will consist of a Pre-Screening Visit (only for subjects requiring a wash-out period), a Screening 
Visit, a Treatment Period, and a Follow-up Visit.  
A wash-out period will be required for eligible subjects taking any lipid-regulating therapies or 
supplements, with the exception of atorvastatin 10 mg, 20 mg, 40 mg and 80 mg QD; 
rosuvastatin 5 mg, 10 mg, 20 mg and 40 mg QD; simvastatin 20 mg and 40 mg QD; and 
ezetimibe 10 mg QD. For subjects requiring a wash-out period, the Pre-Screening Visit will be 
their first study visit and will occur prior to the Screening Visit based on the duration of the 
wash-out period required. The duration of the wash-out period will be dependent upon the status 
of the subject’s current lipid-regulating therapy. Specifically, PCSK9 inhibitors will require an 
8-week wash-out period, fibrates will require a 6-week wash-out period, and niacins or other 
lipid-regulating therapies such as bile acid sequestrants will require a 4-week wash-out period 
prior to the Screening Visit.  
All eligible subjects will participate in the Screening Visit up to 14 days prior to Day 1. For 
eligible subjects taking the required moderate or high-intensity stable statin therapy for ≥ 12 
weeks and who do not require a wash-out period, the Screening Visit will be their first study 
visit.  
The duration of the Treatment Period will be 12 weeks. Eligible subjects will be randomized via 
an interactive web/voice response system (IWRS/IVRS) on Day 1 in a 1:1 ratio to the following 
treatment groups: placebo or gemcabene 600 mg. Subjects will be stratified by statin intensity 
(high-intensity or moderate-intensity as defined in Table 1) and diabetes (yes or no).  Subjects 
defined as diabetic will be those receiving concomitant anti-diabetic medication at screening. 
Randomization within a baseline statin intensity stratum will be capped at 52 subjects; once 52 
subjects are randomized into a baseline statin intensity stratum, no further subjects in that statin 
intensity stratum will be randomized (subjects in the other baseline statin intensity stratum will 
continue to be randomized until there are 52 randomized subjects in that stratum).  By also 
stratifying on diabetes status (yes, no) at baseline, diabetic subjects will be evenly distributed 
across the treatment groups and statin-intensity subgroups.  The first dose of study drug will be 
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administered at the site on Day 1.  
Post-randomization clinic visits will occur at Week 2, Week 4, Week 8 and Week 12.  The 
Follow-up Visit will occur 4 weeks (±3 days) after the last dose of study drug. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Study drug will be prepared as 7-day blister packages with each day’s segment containing 3 
tablets based on the treatment group: 
• 600 mg: two 300 mg gemcabene tablets and 1 placebo tablet, and 
• Placebo: 3 placebo tablets.  
On days with a scheduled office visit with blood sample collection, subject will remain fasted (at 
least 10 hours) and should not take gemcabene until after the blood samples are collected.  For 
days when the subject will self-dose, the subject will be instructed to take study drug at the same 
time in the morning with a full glass (8 ounces) of water either with or without food. 
STATISTICAL ANALYSIS: 
Sample Size 
The primary efficacy endpoint is the percent change from baseline to Week 12 in LDL-C, with 
the primary focus on the overall set of randomized subjects.  The efficacy within each baseline 
statin intensity (high-intensity; moderate-intensity) stratum is also of interest for this study; thus, 
the study is powered for the analyses within each baseline statin intensity stratum.  A sample 
size of 26 randomized subjects in the gemcabene 600 mg group and 26 randomized subjects in 
the placebo group within each baseline statin intensity stratum is expected to provide 80% power 
to detect a difference of 17% in the percent change from baseline to Week 12 in LDL-C between 
the gemcabene treatment group and the placebo group within each baseline statin intensity 
stratum.  This calculation is based on a 2-sided t-test at the 5% level of significance (α = 0.05), a 
common standard deviation of 20, and a drop-out rate of 10%.  The sample size of 26 
randomized subjects in each baseline statin intensity stratum in the gemcabene 600 mg group 
gives a total of 52 randomized subjects in the gemcabene 600 mg group.  Twenty-six 
randomized subjects in each baseline statin intensity stratum in the placebo group gives a total of 
52 randomized subjects in the placebo group.  Thus, the total study sample size is 104 
randomized subjects.   
There are no planned interim analyses for this study.  
Subject Population 
Full Analysis Set: The Full Analysis Set (FAS) will consist of all randomized subjects who 
receive at least 1 dose of study drug and have at least 1 post-baseline efficacy assessment. All 
efficacy analyses will be performed on the FAS. 
Per Protocol Set: The Per Protocol Set (PPS) will include all FAS subjects who complete the 12-
week Treatment Period without major protocol deviations. The PPS will be used to assess 
robustness of the analysis results. Protocol deviations will be reviewed and the PPS will be 
determined prior to database lock.  
Safety Analysis Set: The Safety Analysis Set (SAS) will include all randomized subjects who 
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receive at least 1 dose of study drug. All safety analyses will be conducted on the SAS. 
EFFICACY ENDPOINTS AND ANALYSIS 
The primary efficacy endpoint will be compared to a significance level of 0.05.  Each of the 
secondary and exploratory efficacy endpoints will also be compared to a significance level of 
0.05.  That is, analysis of secondary and exploratory endpoints will not be adjusted for 
multiplicity.  Given the large number of secondary and exploratory endpoints, p-values for these 
endpoints will be considered descriptive.   
Primary 
The primary efficacy endpoint is the percent change from baseline to Week 12 in fasting LDL-
C.  The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA) 
with percent change from baseline to Week 12 in LDL-C as the dependent variable; treatment, 
baseline statin intensity (high-intensity; moderate-intensity), and baseline diabetes (yes or no) as 
factors; and baseline fasting LDL-C as a covariate. Baseline will be defined as the average of the 
LDL-C values at Screening/Visit S1 and pre-dose Day 1/Visit T1.  The ANCOVA will be 
performed using the FAS, with subjects included in their randomized treatment group regardless 
of the treatment they actually received.  Missing values for Week 12 will be imputed using last 
observation carried forward (LOCF); only post-baseline values will be used for the imputation. 
The least-squares mean (LSM) and standard error (SE) will be provided for both treatment 
groups, along with the placebo-corrected LSM, its 95% confidence interval (CI), and associated 
p-value.  A 2-sided test with a significance level of 0.05 will be used for the comparison of 
gemcabene 600 mg to the placebo group.  If non-normality is detected, then either the data will 
be transformed so that it is normally distributed or a nonparametric test will be used.   
A confirmatory analysis of the primary efficacy endpoint will be performed using the PPS.   
Secondary 
Secondary efficacy endpoints include  
• Percent change from baseline to Week 12 in LDL-C within each statin intensity stratum 
(high-intensity; moderate-intensity);  
• Change from baseline to Week 2, Week 4, Week 8, and Week 12 in LDL-C;  
• Change and percent change from baseline to the average of Week 8 and Week 12 
measurements in LDL-C;  
• Change and percent change from baseline to Week 12 in LDL-C in subjects on and not on 
ezetimibe;  
• Change and percent change from baseline to Week 2, Week 4, Week 8, and Week 12 in non-
HDL-C, TC, TG, HDL-C and VLDL-C;  
• Percent of subjects achieving LDL-C reduction of ≥ 10%, ≥ 15%, and ≥ 20% at Week 4, 
Week 8, and Week 12;  
• Percent of subjects achieving an LDL-C value < 100 mg/dL (2.59 mmol/L) at Week 4, Week 
8, and Week 12;  
• Change and percent change from baseline to Week 4, Week 8 and Week 12 in ApoB, ApoA-
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will be analyzed in the same manner, with similar output provided for each endpoint. For all of 
these endpoints, the FAS will be used, with subjects included in their randomized treatment 
group regardless of the treatment they actually received. 
Framingham Risk scores and estimated 10-year risk will be summarized at baseline and Week 
12.  Additionally, the change from baseline to Week 12 in Framingham Risk scores and 
estimated 10-year risk will be summarized. The number and percent of subjects in each NCEP 
ATP-III Risk category will be summarized at baseline and Week 12.  Also, a shift table of 
NCEP ATP-III Risk categories from baseline and Week 12 will be provided.  The FAS, with 
subjects included in their randomized treatment group regardless of the treatment they actually 
received, will be used for all of these summarizations.  Finally, the percent of diabetic subjects 
in the FAS with a reduction in their anti-diabetic medications greater than 5% from baseline to 
Week 12 will be summarized by treatment group.  In addition, change from baseline [or first 
visit (Pre-Screening or Screening)] to Week 12 in fasting insulin, FPG, and HbA1c in diabetic 
subjects in the FAS will also be summarized by treatment group. 
Confirmatory analysis of the secondary and exploratory endpoints will be performed using the 
PPS. 
SAFETY ENDPOINTS AND ANALYSIS: 
The safety variables include adverse events, safety laboratory parameters (chemistry, 
hematology, coagulation, and urinalysis) with particular attention to hepatic (e.g., alanine 
aminotransferase/aspartate aminotransferase, bilirubin, alkaline phosphatase), renal (e.g., blood 
urea nitrogen, serum creatinine, protein:creatinine ratio,  albumin:creatinine  ratio, neutrophil 
gelatinase-associated lipocalin (NGAL), urinalysis sediments, pH, electrolytes), and skeletal 
muscle (i.e., creatine kinase) toxicities, 12-lead electrocardiograms (ECGs), physical 
examinations, and vital signs.  
No statistical analysis of safety data will be performed in this study.  Safety will be assessed 
using the SAS with subjects included in the treatment group they actually received, regardless of 
their randomized treatment. The assessment of safety will include adverse events, clinical 
laboratory assessments, ECGs, physical examinations, and vital signs.  Observed case data will 
be used. 
Adverse events (AEs) will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  The summarization of AEs will include only treatment-
emergent AEs (TEAEs), defined as AEs that begin or worsen after randomization and ingestion 
of the first dose of study drug. TEAEs and SAEs will be summarized by system organ class 
(SOC), severity, and relationship to study drug for each treatment group. Deaths, withdrawal 
from study treatment due to AEs, and withdrawal from the study due to AEs will each be 
summarized by treatment group.   
Safety laboratory data (including indicators of hepatic, renal, muscle, coagulation and 
hematologic effects) will be summarized by treatment group at baseline and at each post-
baseline time point.  Change from baseline to each time point, if appropriate, will also be 
summarized by treatment group. Baseline for safety laboratory data will be defined as the last 
pre-dose measurement (pre-dose Study Day 1/Visit T1 or prior).  Frequency counts of new or 
worsening abnormalities will also be provided. 
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Vital signs data (value and change from baseline, where appropriate) will be summarized by 
treatment group at baseline and at each post-baseline time point.  Baseline for vital signs data 
will be defined as the last pre-dose measurement (pre-dose Study Day 1/Visit T1 or prior). 
Abnormalities in ECGs and in PEs will be summarized. 
All safety data will be listed. 
SITES: Approximately 20 sites in the United States. 
SPONSOR: 
Gemphire Therapeutics Inc.  
17199 N. Laurel Park Drive, Suite 401 
Livonia, Michigan 48152 
United States 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
SYNOPSIS ...................................................................................................................................... 4 
TABLE OF CONTENTS .............................................................................................................. 11 
LIST OF TABLES ........................................................................................................................ 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 16 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 18 
1.1 
Background ................................................................................................................. 18 
1.2 
Dose Selection Rationale ............................................................................................ 18 
1.3 
Risk/Benefit ................................................................................................................ 19 
1.4 
Rationale ..................................................................................................................... 20 
2 
STUDY OBJECTIVES ..................................................................................................... 22 
2.1 
Primary Objective ....................................................................................................... 22 
2.2 
Secondary Objectives.................................................................................................. 22 
2.3 
Exploratory Objective ................................................................................................. 22 
3 
STUDY DESCRIPTION .................................................................................................. 23 
3.1 
Summary of Study Design .......................................................................................... 23 
3.2 
Study Indication(s) ...................................................................................................... 24 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................... 25 
4.1 
Inclusion Criteria ........................................................................................................ 25 
4.2 
Exclusion Criteria ....................................................................................................... 25 
4.3 
Withdrawal Criteria .................................................................................................... 27 
5 
STUDY TREATMENTS .................................................................................................. 28 
5.1 
Treatment Groups ....................................................................................................... 28 
5.2 
Dose Rationale ............................................................................................................ 28 
5.3 
Randomization and Blinding ...................................................................................... 28 
5.4 
Breaking the Blind ...................................................................................................... 29 
5.5 
Drug Supplies.............................................................................................................. 29 
5.5.1 Study Drug Identification ..................................................................................... 29 
5.5.2 Formulation and Packaging .................................................................................. 29 
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5.5.3 Study Drug Preparation and Dispensing ............................................................... 30 
5.5.4 Study Drug Administration ................................................................................... 30 
5.5.5 Treatment Compliance .......................................................................................... 30 
5.5.6 Storage and Accountability ................................................................................... 30 
5.6 
Prior and Concomitant Medications and/or Procedures ............................................. 31 
5.6.1 Permitted Medications and/or Procedures ............................................................ 31 
5.6.2 Excluded Medications and/or Procedures ............................................................. 31 
5.6.3 Restrictions and Dietary Guidelines ..................................................................... 31 
5.6.4 Documentation of Prior and Concomitant Medication Use .................................. 32 
6 
STUDY PROCEDURES .................................................................................................. 33 
6.1 
Informed Consent........................................................................................................ 33 
6.2 
Pre-Screening Visit ..................................................................................................... 33 
6.3 
Screening Visit (up to Day -14) .................................................................................. 34 
6.4 
Treatment Period (Visit T1 through Visit T5) ............................................................ 35 
6.4.1 Visit T1 (Day 1) .................................................................................................... 35 
6.4.2 Visit T2 (Week 2) ................................................................................................. 36 
6.4.3 Visit T3 (Week 4) ................................................................................................. 36 
6.4.4 Visit T4 (Week 8) ................................................................................................. 37 
6.4.5 Visit T5 (Week 12) ............................................................................................... 37 
6.5 
Follow-up Visit (Day 113) .......................................................................................... 38 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................. 38 
7 
EFFICACY ASSESSMENTS .......................................................................................... 40 
8 
SAFETY ASSESSMENTS ............................................................................................... 41 
8.1 
Adverse Events ........................................................................................................... 41 
8.1.1 Adverse (Drug) Reaction ...................................................................................... 42 
8.1.2 Unexpected Adverse Drug Reaction ..................................................................... 42 
8.1.3 Assessment of Adverse Events by the Investigator .............................................. 42 
8.1.4 Specific Safety Measures ...................................................................................... 43 
8.1.4.1 
Hemoglobin decrease ...................................................................................... 43 
8.1.4.2 
Creatinine increase .......................................................................................... 44 
8.1.4.3 
Possible muscle and liver injury ...................................................................... 44 
8.2 
Serious Adverse Events .............................................................................................. 44 
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8.3 
Serious Adverse Event Reporting ............................................................................... 45 
8.4 
Pregnancy Reporting ................................................................................................... 45 
8.5 
Expedited Reporting ................................................................................................... 46 
8.6 
Clinical Laboratory Evaluations ................................................................................. 46 
8.7 
Vital Signs ................................................................................................................... 47 
8.8 
Electrocardiograms ..................................................................................................... 48 
8.9 
Physical Examinations ................................................................................................ 48 
8.10 
Medical/Surgical History and Demographics ............................................................. 48 
8.11 
Reserve Samples ......................................................................................................... 48 
9 
STATISTICS .................................................................................................................... 49 
9.1 
Sample Size ................................................................................................................. 49 
9.2 
Analysis Populations ................................................................................................... 49 
9.2.1 Full Analysis Set ................................................................................................... 49 
9.2.2 Per Protocol Set..................................................................................................... 49 
9.2.3 Safety Analysis Set ............................................................................................... 49 
9.3 
Statistical Methods ...................................................................................................... 50 
9.3.1 Analysis of Efficacy .............................................................................................. 50 
9.3.1.1 
Primary efficacy analyses ................................................................................ 50 
9.3.1.2 
Secondary and exploratory efficacy analyses .................................................. 50 
9.3.2 Analysis of Safety ................................................................................................. 52 
10 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 53 
10.1 
Data Management ....................................................................................................... 53 
10.1.1 Data Handling ....................................................................................................... 53 
10.1.2 Computer Systems ................................................................................................ 53 
10.1.3 Data Entry ............................................................................................................. 53 
10.1.4 Medical Information Coding................................................................................. 53 
10.1.5 Data Validation ..................................................................................................... 53 
10.2 
Record Keeping .......................................................................................................... 53 
11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 54 
11.1 
Ethical Conduct of the Study ...................................................................................... 54 
11.2 
Institutional Review Board/Ethics Committee ........................................................... 54 
11.3 
Informed Consent........................................................................................................ 54 
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11.4 
Subject Card ................................................................................................................ 54 
11.5 
Study Monitoring Requirements ................................................................................. 55 
11.6 
Disclosure of Data....................................................................................................... 55 
11.7 
Retention of Records................................................................................................... 55 
11.8 
Publication Policy ....................................................................................................... 56 
11.9 
Financial Disclosure.................................................................................................... 56 
11.10 Insurance and Indemnity ............................................................................................. 56 
11.11 Legal Aspects .............................................................................................................. 56 
11.12 Definition of End of Study .......................................................................................... 56 
11.13 Sponsor Discontinuation Criteria ................................................................................ 56 
12 
STUDY ADMINISTRATIVE INFORMATION ............................................................. 57 
12.1 
Protocol Amendments ................................................................................................. 57 
12.2 
Address List ................................................................................................................ 57 
12.2.1 Sponsor ................................................................................................................. 57 
12.2.2 Contract Research Organization ........................................................................... 57 
12.2.3 Biological Specimens............................................................................................ 57 
13 
REFERENCES ................................................................................................................. 58 
APPENDIX A: SCHEDULE OF PROCEDURES ....................................................................... 59 
APPENDIX B: CLINICAL LABORATORY ANALYTES ........................................................ 63 
APPENDIX C: NEW YORK HEART ASSOCIATION CONGESTIVE HEART FAILURE 
CLASSIFICATION .......................................................................................................... 65 
APPENDIX D: CYTOCHROME P450 3A4 INHIBITORS: EXCLUSIONARY 
MEDICATIONS ............................................................................................................... 66 
APPENDIX E: MUSCLE INJURY AND HEPATIC MONITORING ....................................... 67 
 
 
 
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LIST OF TABLES 
Table 1. High-Intensity vs. Moderate-Intensity Classifications ................................................... 23 
Table 2. High-Intensity vs. Moderate-Intensity Classifications ................................................... 28 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance model 
Apo 
Apolipoprotein 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CK 
Creatine kinase 
CRA 
Clinical research associate 
CTA 
Clinical trial authorization 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
EC 
Ethic Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
Early Termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HbA1c 
Hemoglobin A1c 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
HIV 
Human immunodeficiency virus 
HoFH 
Homozygous familial hypercholesterolemia 
hsCRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IWRS/IVRS 
Interactive web/voice response system 
LDL-C 
Low-density lipoprotein cholesterol 
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Lp(a) 
Lipoprotein(a) 
LSM 
Least squares mean 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NCEP ATP-III 
National Cholesterol Education Program Adult Treatment Panel 
III 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NIMP 
Non-investigational medical product 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetics 
QD 
Once daily 
SAA 
Serum amyloid A 
SAE 
Serious adverse event 
SE 
Standard error 
SOP 
Standard Operating Procedure 
TC 
Total cholesterol 
TG 
Triglyceride 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Gemcabene calcium is the monocalcium salt of a dialkyl ether dicarboxylic acid having 2 
terminal gem dimethyl carboxylate moieties. Gemcabene is a novel lipid-regulating compound 
with a dual mechanism of action that involves: (1) blocking the hepatic production of triglyceride 
(TG) and cholesterol synthesis; and (2) enhancing the clearance of very low-density lipoprotein. 
Based on prior clinical studies, the combined effects for these mechanisms has been observed to 
result in a reduction of plasma very low-density lipoprotein cholesterol (VLDL-C), low-density 
lipoprotein cholesterol (LDL-C), triglycerides (TG), as well as an elevation in high-density 
lipoprotein cholesterol (HDL-C). Gemcabene has also been shown to markedly lower high 
sensitivity C-reactive protein (hsCRP). 
Gemphire Therapeutics Inc. (Gemphire) is developing gemcabene as an adjunct to diet and statin 
therapy for the treatment of subjects with dyslipidemia. 
1.2 
Dose Selection Rationale  
A Phase 1 PK/PD study (1027-003) of gemcabene administered across its dose range (50 mg 
through 900 mg once daily [QD]) for 2 weeks in healthy volunteers demonstrated clinically and 
statistically significant dose dependent lowering of LDL-C from 450 mg through 900 mg with a 
plateau of LDL-C lowering effects observed at 600 mg.  Plasma concentration data indicates that 
gemcabene LDL-C lowering exceeds 25% when AUC (0-24) values are greater than 2500 
hr*μg/mL (the range most broadly covered by 600 mg QD) with limited additional LDL-C 
lowering above 5000 hr*μg/mL.  This supported the Sponsor’s decision (in the original program 
conducted over 10 years ago) to test the 600 mg dose and its bordering doses in Phase 2 studies 
assessing gemcabene’s effects in dyslipidemia.  
To date, the effect of gemcabene on lipid parameters has been evaluated in three Phase 2 clinical 
studies involving over 500 subjects with hypercholesterolemia or dyslipidemia.  These studies 
individually demonstrated that the gemcabene LDL-C dose response curve spans the dose range 
of 150 mg through 900 mg, with a minimum effective dose at 150 mg and a plateau of LDL-C 
effects at 600 mg (with non-distinguishable additional LDL-C effects at 900 mg compared to 600 
mg).  
A retrospective integrated analysis of this Phase 2 data was recently performed by Gemphire to 
determine the LDL-C dose response in subjects with lipid values representative of the subject 
population included in the gemcabene hypercholesterolemic development program and GEM-
301 (LDL-C ≥ 100 mg/dL and TG < 500 mg/dL) (n=223).  
In an analysis of subjects who received gemcabene monotherapy (n=159), including study 1027-
004 (low HDL, dyslipidemic subjects) and the monotherapy arm of study 4141001 
(hypercholesterolemic subjects), the LDL-C mean % change difference from placebo for 
gemcabene 150 mg, 300 mg, 600 mg, and 900 mg was +2.0% (p=0.4359), -8.1% (p=0.0001), -
21.3% (p<0.0001), and -20.9% (p<0.0001), respectively.   The 1027-018 study tested gemcabene 
300 mg and 900 mg in hypercholesterolemic subjects on previously prescribed and stable statin 
therapy, a design similar to the current study and the way in which gemcabene is anticipated to 
be dosed in clinical practice. In this study the LDL-C mean % change difference from placebo 
for gemcabene 300 mg and 900 mg was -15.9% (p=0.005) and -20.4% (p<0.001), respectively.    
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to reach target LDL-C levels even with maximally tolerated statin treatment and their risk for 
cardiovascular disease (CVD) remains elevated. 
Other means of treatment, either in combination with statins or as stand-alone therapy, may 
include cholesterol absorption inhibitors, fibrates, bile acid sequestrants, or newly-approved 
proprotein convertase subtilkisin/kexin type 9 (PCSK9) inhibitors.  
The safety and efficacy profile of gemcabene has been demonstrated through 18 Phase 1 and 
Phase 2 clinical studies (17 completed and one Phase 1 study stopped due to a business 
decision), involving 1272 healthy adult subjects and subjects with various dyslipidemias. 
The clinical program conducted to date has demonstrated that gemcabene is well tolerated. A 
total of 895 healthy adult subjects and subjects with various underlying conditions (including 
dyslipidemia, osteoarthritis, and hypertension) have been exposed to a minimum of at least 1 
dose of gemcabene at doses ranging from 150 mg to 1500 mg either as a single dose or as 
multiple doses QD. This includes 837 subjects who received multiple doses of up to 900 mg for 
up to 12 weeks. Safety of these subjects was evaluated by adverse event monitoring, clinical 
laboratory assessments, electrocardiograms (ECGs), physical examinations, and vital sign 
assessments. 
Phase 1 pharmacokinetic (PK) studies have demonstrated that gemcabene is rapidly absorbed 
following oral administration, with exposure increasing approximately linearly with dose. No 
clinically meaningful drug-drug interactions have been observed with simvastatin (80 mg), 
atorvastatin (80 mg), or digoxin (0.25 mg). No clinically relevant effect on QTc or blood 
pressure has been observed.  
Across all clinical studies, the majority of treatment-emergent adverse events were mild to 
moderate in intensity. The most common adverse events reported included headache, asthenia 
(feeling of weakness), nausea, dizziness, dyspepsia (upset stomach), infection, abnormal bowel 
movements, myalgia, and abnormal kidney function tests. Ten healthy adult subjects reported a 
treatment-emergent serious adverse event (SAE) across all previous studies. None of these SAEs 
were considered treatment-related. There were no deaths. 
Small mean increases in serum creatinine and blood urea nitrogen (BUN) have been observed in 
some studies. These changes appeared within the first 2 to 4 weeks and did not appear to increase 
further over time. An iohexol clearance study showed that glomerular filtration rate (GFR) 
decreased slightly and was associated with a slight increase in serum creatinine. There was no 
indication of proteinuria or hematuria identified in any subject. There were no significant 
changes observed in urine protein, which seems to indicate that gemcabene does not cause 
tubular or glomerular injury. And, the increase was reversible with all creatinine values returning 
to baseline within approximately 2 weeks of cessation of gemcabene, suggesting a vascular 
effect and not renal injury. 
1.4 
Rationale  
Gemcabene dose response analysis on LDL-C in individual studies as well as across Phase 2 
studies indicate gemcabene 600 mg is the optimal dose to move forward for testing in Phase 3. 
What is not known is the ability of gemcabene at its optimal dose (600 mg) to provide clinically 
and statistically meaningful LDL-C lowering in subjects not at goal (LDL-C ≥100 mg/dL) while 
receiving their maximum statin therapy, including high-intensity and moderate-intensity. In the 
real world clinical setting, high-risk patients are treated with both high-intensity as well as 
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moderate-intensity statins. Reasons subjects may remain on moderate-intensity statins although 
not at LDL-C goal include intolerability on high-intensity statins; LDL-C is close to goal at the 
lower regimen; or perceived intolerance issues, drug interactions and/or safety concerns with 
high-intensity statins. In order to obtain meaningful data in this small Phase 2 study, subjects on 
moderate-intensity statins will be included regardless of their reason.  
Therefore, the current study will assess the effect of gemcabene 600 mg on LDL-C and other 
lipids and lipoproteins and hsCRP in subjects with LDL-C ≥ 100 mg while on stable statin 
therapy, of which 50% will be high-intensity and 50% will be moderate-intensity.   Efficacy and 
safety data from this study will be used along with the integrated analysis work from previously 
completed studies to inform the dose for Phase 3 in subjects with homozygous familial 
hypercholesterolemia (HoFH), and to confirm gemcabene 600 mg for use in Phase 3 studies in 
heterozygous FH (HeFH), and atherosclerotic cardiovascular disease (ASCVD).  
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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 2, randomized, placebo-controlled, double-blind, multi-center study. Subjects are 
required to be on either a high-intensity stable statin regimen (atorvastatin 40 mg or 80 mg QD; 
or rosuvastatin 20 mg or 40 mg QD) or a moderate-intensity statin regimen (atorvastatin 10 mg 
or 20 mg QD; rosuvastatin 5 mg or 10 mg QD; or simvastatin 20 or 40 mg QD) with or without 
ezetimibe 10 mg QD for at least 12 weeks prior to the Screening Visit. 
Table 1. High-Intensity vs. Moderate-Intensity Classifications 
High-Intensity Dosage (QD) 
      Moderate-Intensity Dosage (QD) 
Atorvastatin 40 mg, 80 mg 
Atorvastatin 10 mg, 20 mg 
Rosuvastatin   20 mg, 40 mg 
Rosuvastatin 5 mg, 10 mg 
 
Simvastatin   20 mg, 40 mg 
Approximately 104 subjects, including those with HeFH and ASCVD will be randomized into 
the study, with 52 (26 gemcabene 600 mg; 26 placebo) subjects on baseline high-intensity statins 
and 52 (26 gemcabene 600 mg; 26 placebo) subjects on baseline moderate-intensity statins. Total 
study duration will be up to 26 weeks with 12 weeks of study drug treatment. The study will 
consist of a Pre-Screening Visit (only for subjects requiring a wash-out period), a Screening 
Visit, a Treatment Period, and a Follow-up Visit.  
A wash-out period will be required for eligible subjects taking any lipid-regulating therapies or 
supplements, with the exception of atorvastatin (10 mg, 20 mg, 40 mg or 80 mg QD), 
rosuvastatin (5 mg, 10 mg, 20 mg or 40 mg QD) or simvastatin (20 mg or 40 mg QD), or 
ezetimibe 10 mg QD. For subjects requiring a wash-out period, the Pre-Screening Visit will be 
their first study visit and will occur prior to the Screening Visit based on the duration of the 
wash-out period required. The duration of the wash-out period will be dependent upon the status 
of the subject’s current lipid-regulating therapy. Specifically, PCSK9 inhibitors will require an 8-
week wash-out period, fibrates will require a 6-week wash-out period, and niacin or other lipid-
regulating therapies such as bile acid sequestrants will require a 4-week wash-out period prior to 
the Screening Visit.  
All eligible subjects will participate in the Screening Visit up to 14 days prior to Day 1. For 
eligible subjects taking the required stable statin therapy for ≥12 weeks and who do not require a 
wash-out period, the Screening Visit will be their first study visit.  
The duration of the Treatment Period will be 12 weeks. Eligible subjects will be randomized via 
an interactive web/voice response system (IWRS/IVRS) on Day 1 in a 1:1 ratio to the following 
treatment groups: placebo or gemcabene 600 mg.  Subjects will be stratified by statin intensity 
(as defined in Table 1) and Type 2 diabetes (yes or no).  Subjects defined as diabetic will be 
those receiving concomitant anti-diabetic medication at screening.  Randomization within a 
baseline statin intensity stratum will be capped at 52 subjects; once 52 subjects are randomized 
into a baseline statin intensity stratum, no further subjects in that statin intensity will be 
randomized (subjects in the other baseline statin intensity stratum will continue to be randomized 
until there are 52 randomized subjects in that stratum).  By also stratifying on baseline diabetes 
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(yes, no), diabetic subjects will be evenly distributed across the treatment groups and statin-
intensity subgroups.  The first dose of study drug will be administered at the site on Day 1. On 
days with a scheduled office visit with blood sample collection, subjects will remain fasted (at 
least 10 hours) and should not take gemcabene until after the blood samples are collected.  For 
days when the subject will self-dose, subjects will be instructed to take study drug at the same 
time in the morning with a full glass (8 ounces) of water either with or without food. 
Post-randomization clinic visits will occur at Week 2, Week 4, Week 8 and Week 12.  The 
Follow-up Visit will occur 4 weeks (±3 days) after the last dose of study drug. 
3.2 
Study Indication(s) 
The indication for this study is for the treatment of hypercholesterolemia, including subjects, 
with or without Type 2 diabetes, with heterozygous familial hypercholesterolemia (HeFH) and 
subjects with atherosclerotic cardiovascular disease (ASCVD) not adequately controlled on 
stable statin therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Provision of written and signed informed consent (by subject or legal guardian) prior to any 
study-specific procedure; 
2. Male or female (neither pregnant or lactating) ≥18 years of age at time of consent;  
a. Female subjects must not be pregnant or lactating. Women of child-bearing potential 
must have a negative serum pregnancy test at the Screening Visit and negative urine 
dipstick on Day 1 prior to dosing in order to qualify for the study. Women who are 
surgically sterile or are clinically confirmed to be post-menopausal (i.e., documented 
amenorrhea for ≥1 year in the absence of other biological or physiological causes) are 
not considered to be of child-bearing potential;  
b. Women of child-bearing potential must agree to use acceptable methods of 
contraception throughout the duration of the study and for 30 days after the last dose 
of study drug. Double-barrier contraception is required; and 
c. Male subjects must agree to use contraception by means of a condom throughout the 
duration of the study and for 8 days after the last dose of study drug. 
3. Currently on a stable, low-fat, low-cholesterol diet in combination with allowed statin doses 
as described in Table 1, with or without ezetimibe 10 mg QD for at least 12 weeks prior to 
the Screening Visit;   
4. Fasting LDL-C value ≥100 mg/dL (2.59 mmol/L) at the Screening Visit; 
5. Physical examination, including vital signs, that is within normal limits or clinically 
acceptable to the Investigator; 
6. Weight ≥50 kg; with a body mass index (BMI) ≤ 45 kg/m²; 
7. Subjects with Type 2 diabetes who take anti-hyperglycemic agents must be on a stable a 
regimen for at least 3 months, with no planned changes in medications for the study duration. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Abnormal liver function test at the Pre-Screening Visit or the Screening Visit (aspartate 
aminotransferase or alanine aminotransferase >2 × the upper limit of normal [ULN], total 
bilirubin >1.5 × ULN, or alkaline phosphatase >2 × ULN based on appropriate age and 
gender normal values). Subjects with bilirubin >1.5 × ULN and history of Gilbert’s 
syndrome may be included; reflexive direct bilirubin testing will be used to confirm Gilbert’s 
syndrome; 
2. Moderate (Grade B) or severe (Grade C) chronic hepatic impairment according to the 
Child-Pugh classification; 
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3. Active liver disease (e.g., cirrhosis, alcoholic liver disease, hepatitis B [HBV], hepatitis C 
[HCV], autoimmune hepatitis, liver failure, liver cancer), history of liver transplant, known 
diagnosis of human immunodeficiency virus (HIV), or acquired immune deficiency virus;  
4. Triglyceride value ≥500 mg/dL (5.65 mmol/L) at the Pre-Screening Visit or the Screening 
Visit; 
5. Moderate to severe renal insufficiency defined as an estimated GFR <60 mL/min/1.73m2 
(calculated using The Chronic Kidney Disease Epidemiology Collaboration equation) at the 
Pre-Screening Visit or the Screening Visit;  
6. Abnormal urinalysis (proteinuria greater than trace or any male or non-menstruating female 
with greater than trace hematuria), confirmed by reflexive urine protein:creatinine ratio 
testing;  
7. Uncontrolled thyroid disease: hyperthyroidism or hypothyroidism as defined by 
thyroid-stimulating hormone (TSH) below the lower limit of normal or >1.5 × ULN, 
respectively, based on results from the Pre-Screening Visit or the Screening Visit. If 
controlled, treatment should be stable for at least 3 months prior to the Screening Visit; 
8. Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c]) 
value >8.5% based on results from the Pre-Screening Visit or the Screening Visit, or taking a 
thiazolidinedione (ie, pioglitazone or rosiglitazone);  
9. New York Heart Association Class III or IV heart failure (see Appendix C);  
10. Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, coronary 
artery bypass graft, or other major cardiovascular events resulting in hospitalization within 3 
months of the Screening Visit. Subjects with adequately treated stable angina, per 
Investigator assessment, may be included; 
11. Uncontrolled cardiac arrhythmia or prolonged QT on the Screening Visit or Day 1 prior to 
dosing ECG (QTcF >450 msec for men and >470 msec for women) or known family history 
of prolonged QT or unexplained sudden cardiac death; 
12. Uncontrolled hypertension, defined as sitting systolic blood pressure >180 mmHg or diastolic 
blood pressure >110 mmHg, and confirmed by repeat measurement; 
13. Currently receiving cancer treatments or, in the Investigator’s opinion, at risk of relapse for 
recent cancer; 
14. Inadequate wash-out of a PCSK9 inhibitor (8 weeks prior to the Screening Visit), a fibrate 
lipid-regulating agent (6 weeks prior to the Screening Visit), niacins (4 weeks prior to the 
Screening Visit), or other lipid-regulating therapies such as bile acid sequestrants (4 weeks 
prior to the Screening Visit);  
15. Hypersensitivity to or a history of significant adverse reactions to any fibrate lipid-regulating 
agent; 
16. Use of any excluded medications or supplements (e.g., potent cytochrome P450 [CYP] 3A4 
inhibitors, see Appendix D);  
17. History of drug or alcohol abuse within the past year or inability to comply with protocol 
requirements, including subject restrictions (see Section 5.6.3); 
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18. Previously treated with gemcabene (CI-1027), participation in another clinical study of an 
investigational agent or device concurrently or within 1 month prior to the Screening Visit, or 
use of an investigational agent within 1 month or 5 half-lives (if known), whichever is 
longer, prior to the Screening Visit; or 
19. Any other finding which, in the opinion of the Investigator, would compromise the subject’s 
safety or participation in the study. 
4.3 
Withdrawal Criteria 
Participation of a subject in this clinical study may be discontinued for any of the following 
reasons: 
• The subject withdraws consent or requests discontinuation from the study for any reason; 
• Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol; 
• Any SAE, clinically significant adverse event, severe laboratory abnormality, concomitant 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the subject; 
• Pregnancy; 
• Requirement of prohibited concomitant medication which is prohibited by the protocol; 
• Subject failure to comply with protocol requirements or study-related procedures; or  
• Termination of the study by the Sponsor or the regulatory authority. 
If a subject withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
Early Termination (ET) Visit. The reason for subject withdrawal must be documented in the 
electronic Case Report Form (eCRF). 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records. 
Withdrawn subjects will not be replaced. The sample size calculation accounts for a 10% 
dropout rate in the study.  
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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Subjects will be randomized on Day 1 in a 1:1 ratio to the following treatment groups: placebo or 
gemcabene 600 mg. Subjects are required to be on either a high-intensity statin therapy as 
defined in Table 2 (atorvastatin 40 mg or 80 mg QD; or rosuvastatin 20 mg or 40 mg QD) or a 
moderate-intensity statin therapy (atorvastatin 10 mg or 20 mg QD; rosuvastatin 5 mg or 10 mg 
QD; or simvastatin 20 or 40 mg QD) with or without ezetimibe 10 mg QD for at least 12 weeks 
prior to the Screening Visit. Subjects will be stratified by baseline statin intensity (high-intensity; 
moderate-intensity) and diabetes (yes or no).   
Table 2. High-Intensity vs. Moderate-Intensity Classifications 
High-Intensity Dosage (QD) 
      Moderate-Intensity Dosage (QD) 
Atorvastatin 40 mg, 80 mg 
Atorvastatin 10 mg, 20 mg 
Rosuvastatin   20 mg, 40 mg 
Rosuvastatin 5 mg, 10 mg 
 
Simvastatin   20 mg, 40 mg 
5.2 
Dose Rationale  
Gemcabene was observed to be well tolerated at single doses up to 1500 mg and multiple doses 
up to 900 mg. This included 837 healthy subjects and subjects with varying underlying 
conditions who received multiple doses of up to 900 mg for up to 12 weeks. Adverse events were 
generally mild to moderate in intensity with no treatment-related SAEs reported.  
Gemcabene dose response analysis on LDL-C in individual studies as well as across Phase 2 
studies indicate gemcabene 600 mg is the optimal dose to move forward for testing in Phase 3. 
What is not known is the ability of gemcabene at its optimal dose (600 mg) to provide clinically 
and statistically meaningful LDL-C lowering in subjects not at goal (LDL-C ≥100 mg/dL) while 
receiving maximum statin therapy, including high-intensity statin and moderate-intensity statin 
therapy. Therefore, the current study will assess the effect of gemcabene 600 mg on LDL-C and 
other lipids and hsCRP in subjects whose LDL-C ≥ 100 mg while on stable statin therapy, of 
which 50% will be high-intensity and 50% will be moderate- intensity.   Efficacy and safety data 
from this study will be used along with the integrated analysis work from previously completed 
studies to evaluate and confirm gemcabene 600 mg for use in Phase 3 studies.   
5.3 
Randomization and Blinding 
Subjects who have completed the Screening Visit and meet all of the inclusion and none of 
exclusion criteria will be randomized into the study on Day 1. Randomized treatment assignment 
and randomization numbers will be assigned via IWRS/IVRS. Following randomization, study 
drug will be dispensed in a double-blind manner. The Sponsor and all clinical site personnel 
(Investigator, pharmacist, etc.) will be blinded to the treatment group for each subject. Subjects 
also will be blinded to the treatment they receive.  
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Study drug will be prepared as 7-day blister packages with each day’s segment containing 3 
tablets based on the treatment group: 
• 600 mg: two 300 mg gemcabene tablets and 1 placebo tablet, 
• Placebo: 3 placebo tablets.  
5.5.3 
Study Drug Preparation and Dispensing 
Study drug will be administered at the site on Day 1 and on other clinic visit days. Subjects will 
self-dose at all other times during the Treatment Period. The Investigator or designee will 
provide subjects with sufficient study drug until the next scheduled study visit. 
5.5.4 
Study Drug Administration 
The first dose of study drug will be administered at the site on Study Day 1. On days with a 
scheduled office visit with blood sample collection, subject will remain fasted and should not 
take gemcabene until after the blood samples are collected at the site.  On all other days, the 
subject will self-dose: taking study drug at the same time in the morning with a full glass (8 
ounces) of water either with or without food.  If a subject misses a dose but remembers within 6 
hours, then the subject should take their dose.  However, if past 6:00 PM, the subject should not 
dose and then count the dose as a “missed dose.”  The subject will resume normal dosing the 
next day (i.e., do not take two doses the following day).  
5.5.5 
Treatment Compliance 
Subjects will be instructed to take study drug daily according to the protocol and return used and 
unused packaging to the site at each subsequent study visit.  
Compliance with administration of study drug will be assessed at each study visit 
post-randomization during the Treatment Period and at the Early Termination Visit, if applicable, 
and recorded on the appropriate eCRF and the drug accountability log.  
The Investigator or designee will remind subjects at each visit of the importance of following the 
protocol-defined schedule for taking study drug. Reasons for not following the study drug 
administration schedule as described in the protocol will be clearly recorded in the source 
documents. 
Plasma samples collected for potential pharmacokinetic analysis may be assayed to assess 
compliance.    
5.5.6 
Storage and Accountability 
The study drug will be stored at room temperature (20 ±5°C) in a secured location (locked) with 
access restricted to authorized personnel only. Storage temperature will be monitored and 
recorded.  
Upon receipt of study drug, the Investigator or designee will conduct a complete inventory of all 
study drug and ensure no damage occurred during shipment.  
The Investigator will maintain adequate records documenting the receipt, use, loss, or other 
disposition of study drug. Drug accountability logs will identify the study drug code number and 
account for the disposition on a subject-by-subject basis, including specific dates and quantities. 
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The drug accountability logs will be signed by the individual who dispenses the study drug and 
copies will be provided to the Sponsor.  
All used and unused supplies will be appropriately inventoried and verified by the clinical 
research associate (CRA). 
Unused study drug may be destroyed at the sites according to their Standard Operating 
Procedures (SOPs). If a site does not have appropriate SOPs for compliance, the study drug will 
be returned to the Sponsor at the end of the study. 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Permitted Medications and/or Procedures 
Subjects are required to be on a stable, low-fat, low-cholesterol diet in combination with the 
allowed statins and doses as described in Table 1 for at least 12 weeks prior to the Screening 
Visit and through the duration of the study. Subjects may be on ezetemibe 10 mg QD, but are not 
required to be. Subjects with Type 2 diabetes who receive pharmacologic treatment must be on a 
stable regimen for 3 months prior to signing informed consent and not expected to change 
throughout the duration of study participation.  It is strongly recommended that subjects with 
Type 2 diabetes be under routine care for management and monitoring of their diabetes. 
5.6.2 
Excluded Medications and/or Procedures 
Subjects are not permitted to receive treatment with a PCSK9 inhibitor (8 weeks prior to the 
Screening Visit), a fibrate lipid-regulating agent (6 weeks prior to the Screening Visit), niacin 
(4 weeks prior to the Screening Visit), or other lipid-regulating therapies such as bile acid 
sequestrants (4 weeks prior to the Screening Visit). Subjects are not permitted to use strong 
CYP3A4 inhibitors while on the study drug. See Appendix D for a specific list of CYP3A4 
inhibitors.  
5.6.3 
Restrictions and Dietary Guidelines 
It is important that subjects are instructed to not undertake any form of strenuous physical 
activity for at least 24 hours prior to repeat blood testing.  
Subjects are restricted from using alcohol within 48 hours prior to study visits.  
Assessments that require a subject fast will be defined as no food or caloric beverage for at least 
10 hours prior to sample collection. Subjects will be permitted to have water. On days with a 
scheduled office visit with blood sample collection, subject will remain fasted and should not 
take gemcabene until after the blood samples are collected.  For days when the subject will self-
dose, the subject will be instructed to take study drug at the same time in the morning with a full 
glass (8 ounces) of water either with or without food. 
Subjects will be counseled on maintaining a low-fat, low-cholesterol diet (National Cholesterol 
Education Program Adult Treatment Panel III [NCEP ATP-III] or equivalent) throughout the 
study. 
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5.6.4 
Documentation of Prior and Concomitant Medication Use 
A concomitant medication is any treatment including nutritional supplements, vitamins, or 
over-the-counter medications received by or prescribed to the subject concomitantly to the study, 
from the time of informed consent to the Follow-up Visit or the ET Visit, if applicable. 
The Investigator should record the use of all concomitant medications taken during the study, 
both prescribed and over the counter, in the eCRF and the source document. This includes drugs 
used on a chronic and as needed basis. Subjects should be discouraged from starting any new 
medication, both prescribed and over the counter, without consulting the Investigator, unless the 
new medication is required for an emergency. 
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6 
STUDY PROCEDURES 
A tabular listing of the Schedule of Procedures can be found in Appendix A. Assessments that 
require that a subject fast will be defined as no food or caloric beverage for at least 10 hours 
prior to sample collection. Subjects will be permitted to have water ad lib.  
6.1 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before any 
protocol-specific procedures are performed. See Section 11.3 for details on informed consent.  
6.2 
Pre-Screening Visit 
Only subjects requiring a wash-out period will participate in the Pre-Screening Visit.  
A wash-out period will be required for eligible subjects taking any lipid-regulating therapies or 
supplements, with the exception of atorvastatin (10 mg, 20 mg, 40 mg or 80 mg QD), 
rosuvastatin (5 mg, 10 mg, 20 mg or 40 mg QD), simvastatin (20 mg or 40 mg QD) or ezetimibe 
10 mg QD. For subjects requiring a wash-out period, the Pre-Screening Visit will be their first 
study visit and will occur prior to the Screening Visit based on the duration of the wash-out 
period required. The duration of the wash-out period will be dependent upon the status of the 
subject’s current lipid-regulating therapy. Specifically, PCSK9 inhibitors will require an 8-week 
wash-out period, fibrates will require a 6-week wash-out period, and niacin or other lipid-
regulating therapies such as bile acid sequestrants will require a 4-week wash-out period prior to 
the Screening Visit.  
The following procedures will be performed at the Pre-Screening Visit: 
• Obtain informed consent; 
• Conduct eligibility assessment based on inclusion/exclusion criteria; 
• Obtain medical/surgical history and demographics; 
• Obtain concomitant medications; including all diabetes pharmacologic therapy for subjects 
with Type 2 diabetes; 
• Perform full physical examination; 
• Record vital signs, height, weight and calculate BMI; 
• Collect urine sample for urinalysis; 
• Perform urine pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o TSH, HbA1c, and serology (HBV, HCV, and HIV); and 
o Fasting LDL-C (LDL-C ultracentrifugation in subjects with TG ≥ 400 mg/dL) and TG; 
• Initiate wash-out; 
• Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
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• Assess adverse events (SAEs that occur prior to the first dose of study drug [Day 1] should 
be reported as an update to medical history as well as be reported on the appropriate adverse 
event eCRF) and concomitant medications. 
6.3 
Screening Visit (up to Day -14) 
All eligible subjects will participate in the Screening Visit up to 14 days prior to Day 1. 
Subjects must fast (at least 10 hours) prior to this visit. 
For subjects taking the required stable statin therapy for >12 weeks at the Screening Visit and do 
not require a wash-out period, the Screening Visit will be their first study visit.  
For subjects who required a wash-out period and completed the Pre-Screening Visit, the 
following Screening Visit procedures will not be repeated: informed consent, full physical 
examination, height, TSH, HbA1c, and serology (HBV, HCV, and HIV) screening. Updates, as 
needed, will be made to medical/surgical history, demographics, and concomitant medications.   
The following procedures will be performed at the Screening Visit (up to Day -14): 
• Obtain informed consent; 
• Confirm eligibility based on inclusion/exclusion criteria;  
• Obtain medical/surgical history and demographics;  
• If applicable, document diagnosis of HeFH as: 
- 
Clinical diagnosis; per Simon Broome criteria for definite FH or the WHO/Dutch Lipid 
Network criteria with a score >8 points or; 
- 
Genotyping; 
• If applicable, document diagnosis of ASCVD for those subjects with: 
-  A history of myocardial infarction, prior coronary angiography showing ≥ 75% stenosis 
of at least one epicardial coronary vessel, or prior coronary revascularization procedures 
(either percutaneous coronary intervention or coronary artery bypass graph); 
• Obtain concomitant medications; including all anti-hyperglycemic agents for subjects with 
Type 2 diabetes; 
• Perform full physical examination; 
• Perform symptom-directed physical examination (only for subjects who required a wash-out 
period and completed the full physical examination at the Pre-Screening Visit); 
• Record vital signs, height, weight and BMI; 
• Collect urine sample for urinalysis including urine protein:creatinine ratio and 
albumin:creatinine ratio; 
• Perform serum pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o TSH, HbA1c, and serology (HBV, HCV, and HIV); and 
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o Fasting lipid panel (including LDL-C ultracentrifugation, for subjects with TGs ≥ 400 
mg/dL); 
• Perform 12-lead ECG; 
• Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
• Assess adverse events (SAEs that occur prior to the first dose of study drug [Day 1] should 
be reported as an update to medical history as well as be reported on the appropriate adverse 
event eCRF) and concomitant medications. 
6.4 
Treatment Period (Visit T1 through Visit T5) 
Subjects must fast (at least 10 hours) prior to each visit. 
6.4.1 
Visit T1 (Day 1)  
The following procedures will be performed pre-dose at Visit T1 (Day 1): 
• Perform symptom-directed physical examination; 
• Determine if there have been any changes in the subject’s health affecting eligibility; 
• Record vital signs and weight; 
• Collect 
urine 
sample 
for 
urinalysis 
including 
urine 
protein:creatinine 
ratio, 
albumin:creatinine ratio and neutrophil gelatinase-associated lipocalin (NGAL); 
• Perform urine pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel (including LDL-C ultracentrifugation, for subjects with TGs ≥ 400 
mg/dL) and apolipoproteins; 
o Fasting insulin and FPG;  
o 
  
o hsCRP, serum amyloid A (SAA), adiponectin, and fibrinogen; and 
o Reserve samples; 
• Perform 12-lead ECG; 
• Randomize subjects via IVRS/IWRS; 
• Dispense study drug and instructions; 
• Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent);  
• Assess adverse events and update concomitant medications; and 
• Administer study drug (study drug will be administered at the site on Day 1).  
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6.4.2 
Visit T2 (Week 2) 
The following procedures will be performed at Visit T2 (Week 2; Day 15 ±3 days): 
• Perform symptom-directed physical examination; 
• Record vital signs and weight; 
• Perform urine pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology; 
o Fasting lipid panel; and 
o Reserve samples; 
• Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Dispense study drug and instructions; 
• Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); 
• Assess adverse events and update concomitant medications; and 
• Administer study drug (subjects will self-dose). 
6.4.3 
Visit T3 (Week 4) 
The following procedures will be performed at Visit T3 (Week 4; Day 29 ±3 days): 
• Perform symptom-directed physical examination; 
• Record vital signs and weight; 
• Collect 
urine 
sample 
for 
urinalysis 
including 
urine 
protein:creatinine 
ratio, 
albumin:creatinine ratio and NGAL; 
• Perform urine pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology; 
o Fasting lipid panel, LDL-C ultracentrafugation (in subjects with TG ≥ 400 mg/dL) and 
apolipoproteins; and  
o Reserve samples; 
•  Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Dispense study drug and instructions; 
• Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent);  
• Assess adverse events and update concomitant medications; and 
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• Administer study drug (subjects will self-dose). 
6.4.4 
Visit T4 (Week 8)  
The following procedures will be performed at Visit T4 (Week 8; Day 57 ±3 days): 
• Perform symptom-directed physical examination; 
• Record vital signs and weight; 
• Collect urine sample for urinalysis; 
• Perform urine pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology; 
o Fasting lipid panel, LDL-C ultracentrifugation (in subjects with TG ≥ 400 mg/dL) and 
apolipoproteins;  
o Reserve samples; 
• Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Dispense study drug and instructions; 
• Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); 
• Assess adverse events and update concomitant medications; and 
• Administer study drug (subjects will self-dose). 
6.4.5 
Visit T5 (Week 12)  
The following procedures will be performed at Visit T5 (Week 12; Day 85 [can be performed up 
to 3 days prior to Day 85, but not after Day 85]): 
• Perform full physical examination; 
• Record vital signs and weight; 
• Collect 
urine 
sample 
for 
urinalysis 
including 
urine 
protein:creatinine 
ratio, 
albumin:creatinine ratio and NGAL; 
• Perform serum pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel (clinically significant abnormal creatinine results at Week 12/Day 
85 will also be followed-up 2 weeks (±3 days) after the last dose of study drug in addition 
to the Week 4 (±3 days) Follow-up Visit), coagulation, and hematology;  
o Fasting lipid panel, LDL-C ultracentrifugation (in subjects with TGs ≥ 400 mg/dL) and 
apolipoproteins;  
o Fasting insulin and FPG 
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o 
  
o HbA1c; 
o hsCRP, SAA, adiponectin and fibrinogen; and 
o Reserve samples; 
• Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Assess adverse events and update concomitant medications; and 
• Administer study drug (subjects will self-dose). 
6.5 
Follow-up Visit (Day 113) 
The Follow-up Visit will be conducted as a telephone call 4 weeks (±3 days) after the last dose 
of study drug, unless the subject requires a site visit due to an abnormal result at Week 12 (or the 
ET Visit, if applicable) or an ongoing treatment-related adverse event.  
The following procedures will be performed at the Follow-up Visit (Day 113 ±3 days): 
• Perform symptom-directed physical examination (only for subjects who had an abnormal 
result at Week 12/Day 85 [or the ET Visit, if applicable] or an ongoing treatment-related 
adverse event); 
• Collect 
urine 
sample 
for 
urinalysis 
including 
urine 
protein:creatinine 
ratio, 
albumin:creatinine ratio and NGAL (only for subjects who had an abnormal result at Week 
12/Day 85 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event);  
• Obtain blood sample for safety chemistry panel, coagulation, and hematology (only for 
subjects who had an abnormal result at Week 12/Day 85 [or the ET Visit, if applicable] or an 
ongoing treatment-related adverse event); and 
• Assess adverse events and update concomitant medications. 
6.6 
Early Termination Visit and Withdrawal Procedures 
Subjects must fast (at least 10 hours) prior to this visit.  
For subjects who are withdrawn from the study prior to completion, the following procedures 
will be performed at the ET Visit:  
• Perform full physical examination; 
• Record vital signs and weight; 
• Collect 
urine 
sample 
for 
urinalysis 
including 
urine 
protein:creatinine 
ratio, 
albumin:creatinine ratio and NGAL; 
• Perform serum pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
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o Fasting lipid panel, LDL-C ultracentrifugation (in subjects with TG ≥ 400 mg/dL) and 
apolipoproteins;  
o Fasting insulin and FPG 
o 
  
o HbA1c; 
o hsCRP, SAA, adiponectin and fibrinogen; and 
o Reserve samples; 
• Perform 12-lead ECG; 
• Assess and document study drug compliance; and 
• Assess adverse events and update concomitant medications. 
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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. All adverse events, including observed or volunteered 
problems, complaints, or symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include abnormal and clinically significant clinical laboratory test 
variables, will be monitored and documented from the time of first dose of study drug (Day 1) 
until study participation is complete (the Follow-up Visit). Subjects should be instructed to report 
any adverse event that they experience to the Investigator. Beginning with the signing of the 
informed consent until the time of the first dose of study drug (Day 1), investigators should make 
updates to medical history and record any pre-existing medical condition or signs or symptoms 
that changes in severity, frequency, or seriousness in the medical history. Serious adverse events 
that occur prior to the first dose of study drug (Day 1) should be reported as an update to medical 
history as well as be reported on the appropriate adverse event eCRF. Beginning with the first 
dose of study drug (Day 1), investigators should make an assessment for adverse events at each 
visit and record all adverse events, non-serious and serious, on the appropriate adverse event 
eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure. 
Concomitant procedures should be recorded as such on the appropriate eCRF.  
Any medical condition already present prior to the subject taking the first dose of study drug 
(Day 1) should be reported in the medical history. Any SAEs occurring prior to the first dose of 
study drug (Day 1) should be reported as an update to medical history as well as an adverse 
event. Any pre-existing medical condition or signs or symptoms that changes in severity, 
frequency, or seriousness after the subject takes the first dose of study drug (Day 1) and through 
the Follow-up Visit should be reported as an adverse event. 
Clinically significant abnormal laboratory values or other examinations (e.g., ECG) that are 
detected at the time of the first dose of study drug (Day 1) and worsen during the study should be 
reported as adverse events. An abnormal laboratory result that is not verified by repeat testing 
does not necessitate reporting as an adverse event. The Investigator will exercise his or her 
medical, scientific, and clinical judgment in deciding whether an abnormal laboratory finding or 
other abnormal assessment is clinically significant. Clinically significant abnormal laboratory 
values occurring during the clinical study will be followed until repeat tests return to normal, 
stabilize, or are no longer clinically significant. Any abnormal test that is determined to be an 
error does not require reporting as an adverse event. 
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An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol and higher than known therapeutic doses. Overdoses with associated 
symptoms are always handled as AEs and reported as such. Overdoses without associated 
symptoms are not reported as AEs but are documented in EDC in order to collate information for 
the IB regarding the level of excess dosage taken or administered without adverse effects. An 
overdose will be reported irrespective of outcome even if toxic effects were not observed. 
8.1.1 
Adverse (Drug) Reaction 
For adverse events with a causal relationship to study drug, follow-up by the Investigator will be 
required until the event or its sequelae resolve or stabilize to a level acceptable to the 
Investigator. 
8.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (see Investigator’s Brochure). 
For gemcabene, the reference safety information is included in Sections 8.4 and 10 of the 
Investigator’s Brochure currently in force. The reference safety information will be reviewed 
yearly and the periodicity of the review will be harmonized with the reporting period of the 
Development Safety Update Report. 
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of Yes or No, as defined below. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality Assessment: 
The investigator’s assessment of causality must be provided for all AEs. The causality is the 
determination of whether there exists a reasonable possibility that the study drug itself (eg, 
gemcabene or placebo) caused or contributed to an AE.  
If the final determination of causality is unknown and the investigator does not know whether the 
study drug caused the event, then the event will be handled as “related to study drug” for 
reporting purposes. If the investigator’s causality is “unknown, but not related to study drug”, 
this should be clearly documented on study records. 
The relationship of an adverse event to the administration of the study drug will be assessed 
according to the following definitions: 
No (unlikely related, unrelated, not related, no relation) – The time course between the 
administration of study drug and the occurrence or worsening of the adverse event rules out a 
causal relationship and another cause (e.g., medical history, concomitant drugs, therapies, and 
complications) is suspected. 
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Yes (possibly related, related) – The time course between the administration of study drug and 
the occurrence or worsening of the adverse event is consistent with a causal relationship and no 
other cause (e.g., medical history, concomitant drugs, therapies, and complications) can be 
identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
The following factors should also be considered: 
• The temporal sequence from study drug administration - 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant diseases (medical history) - 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
• Concomitant drug - 
o The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
• Known response pattern for this class of study drug - 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be 
a class effect. 
• Exposure to physical and/or mental stresses - 
o The exposure to stress might induce adverse changes in the recipient and provide a 
logical and better explanation for the event. 
• The pharmacology and PKs of the study drug - 
o The known pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of the study drug should be considered. 
8.1.4 
Specific Safety Measures 
8.1.4.1 
Hemoglobin decrease 
For a hemoglobin decrease of >1.5 g/dL from baseline during the study, repeat hematology 
studies and reflexive evaluation of reticulocyte count will be performed. The subject’s past 
medical history, concomitant medications (including over the counter drugs and herbal 
supplements), and any recent symptoms (e.g., bleeding, shortness of breath, fatigue) will be 
reviewed to determine a potential etiology and make a clinical assessment of the significance of 
the finding. 
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8.1.4.2 
Creatinine increase 
If, at any visit, a creatinine increase >0.3 mg/dL (27 µmol/L) from baseline or a GFR decrease of 
>15 mL/min from baseline is observed, a repeat chemistry will be performed. The subject’s past 
medical history, concomitant medications (including over the counter drugs and herbal 
supplements), and any recent symptoms (e.g., fatigue, malaise, polyuria/oliguria, or palpitations) 
will be reviewed to determine a potential etiology and make a clinical assessment of the 
significance of the finding.  
During the study, clinically significant abnormal results in NGAL will be used as a means of 
identifying subjects who have unremarkable creatinine/BUN values at the time of assessment but 
may require additional or closer/follow-up monitoring of renal studies. 
8.1.4.3 
Possible muscle and liver injury 
For muscle injury, CK, hepatic, and renal function laboratory data will be integrated with 
myopathy signs and symptoms. For management of CK elevations >3 × ULN, refer to 
Appendix E. For liver injury, laboratory data will be integrated with hepatic signs and symptoms. 
Alanine aminotransferase increases >2 × ULN with symptoms of hepatitis or >3 × ULN with or 
without symptoms of hepatitis will be evaluated and managed according to guidelines.  
8.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 
o NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view 
of either the Investigator or Sponsor, its occurrence places the subject at immediate risk 
of death. It does not include an event that, had it occurred in a more severe form, might 
have caused death. 
• Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least one overnight stay will be considered an 
insubject hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent. However, unexpected complications 
and/or prolongation of hospitalization that occur during elective surgery should be 
recorded as adverse events and assessed for seriousness. Admission to the hospital for 
social or situational reasons (i.e., no place to stay, live too far away to come for hospital 
visits) will not be considered inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
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o NOTE: Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency or drug abuse. 
8.3 
Serious Adverse Event Reporting  
All observed or volunteered SAEs regardless of treatment group or suspected causal relationship 
to the study drug will be reported as described below. If a SAE occurs, the sponsor or designee is 
to be notified within 24 hours of awareness of the event by the investigator or designee.  
All SAEs and follow-up information must be reported to the sponsor or designee within 1 
business day or 24 hours of awareness of the event as required by your local requirements by 
emailing or faxing a completed SAE report form to the following:  
Safety Contact Information: 
 
Facsimile: 
 
E-mail: 
   
In particular, if the SAE if fatal or life-threatening, notification to the sponsor or designee must 
be made immediately, irrespective of the extent of available AE information. 
This timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE reports, initial and follow-up reporting of exposure in utero (EIU) cases, and any SAEs that 
the Investigator considers related to study drug occurring after the 30-day follow-up period. 
The Investigator must continue to follow the patient as medically necessary until the SAE has 
subsided or until the condition becomes chronic in nature, stabilizes (in the case of persistent 
impairment), or the patient dies. 
In the rare event that the investigator does not become aware of the occurrence of a SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
their first awareness of the SAE. 
8.4 
Pregnancy Reporting 
For investigational products within clinical studies, an Exposure In Utero occurs if: 
• A female becomes, or is found to be pregnant after receiving the study drug (eg, after Study 
Day 1). 
If a patient participating in the study becomes pregnant during their participation in the study or 
within 30 days of discontinuing study drug, the Investigator must report the pregnancy to 
 
 within 24 hours of awareness on the Exposure In Utero form.  
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
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The Investigator will follow the subject until completion of the pregnancy or until pregnancy 
termination (ie, induced abortion) and notify 
 of the pregnancy outcome. The 
investigator will provide this information as a follow up to the initial EIU form. The reason(s) for 
an induced abortion should be specified. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures 
for reporting SAE(s). 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth (ie, 
no minimum follow-up period of a presumably normal infant is required before an EIU form can 
be completed). The “normality” of an aborted fetus can be assessed by gross visual inspection, 
unless pre-abortion findings are suggestive of a congenital anomaly. 
8.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the Food and Drug 
Administration (FDA), applicable competent authorities in all the Member States concerned, and 
to the Central Ethics Committee, and in any case no later than 7 days after knowledge by the 
Sponsor of such a case, and that relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA, applicable 
competent authorities concerned, and to the Central Ethics Committee concerned as soon as 
possible, but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all investigators as required.  
Expedited reporting of suspected unexpected serious adverse reactions related to 
non-investigational medical products (NIMPs) used in this study (e.g., simvastatin, atorvastatin, 
rosuvastatin, and/or ezetimibe) will not be necessary. Listings of cases related to these NIMPs 
will be included in the Development Safety Update Report. 
8.6 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be collected at the visits shown in the Schedule of 
Procedures (Appendix A) and the data captured will be forwarded to the central laboratory for 
evaluation. Assessments that require a subject to fast will be defined as no food or caloric 
beverage for at least 10 hours prior to sample collection. Subjects will be permitted to have water 
ad lib.  
Central laboratory results will be provided to the sites, with the exception of the post-
randomization lipid values. Laboratory results that appear potentially spurious based on the 
Investigator’s clinical assessment and review of the subject’s medical history may be repeated 
for confirmation of the finding. Reassessments of non-qualifying screening labs must be 
reviewed and approved by the Medical Monitor prior to obtaining the new specimen. The 
clinical rationale for performing repeat testing of screening assessments should be thoroughly 
documented. 
Standard clinical laboratory evaluations for safety chemistry, coagulation, and hematology will 
be conducted at all study visits and the Follow-up Visit (only for subjects who had an abnormal 
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result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event). 
Clinically significant abnormal creatinine results at Week 12 (or the ET Visit, if applicable) will 
also be followed-up 2 weeks (±3 days) after the last dose of study drug in addition to the 4 week 
(±3 days) Follow-up Visit. See Appendix B for a list of clinical laboratory analytes. 
At the Pre-Screening Visit, if applicable, fasting LDL-C and TG will be measured. A full fasting 
lipid panel will be assessed at all other study visits, excluding the Follow-up Visit. Fasting 
apolipoproteins will be assessed at Day 1, Week 4, Week 8, Week 12, and the ET Visit, if 
applicable. In addition to these lipid parameters, 
 hsCRP, SAA, adiponectin, FPG, 
fasting insulin, and fibrinogen will also be measured at Day 1, Week 12, and the ET Visit, if 
applicable. 
A urine sample for urinalysis will be collected at the Pre-Screening Visit, if applicable, the 
Screening Visit, Day 1, Week 4, Week 8, Week 12, the Follow-up Visit (only for subjects who 
had an abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-
related adverse event), and the ET Visit, if applicable. A urine microscopic examination will be 
performed when the dipstick result is abnormal (positive for blood, leukocyte esterase, or 
nitrites). Urine protein:creatinine ratio and albumin:creatinine ratio will be performed at the 
Screening Visit, Day 1, Week 4, Week 12, the Follow-up Visit (only for subjects who had an 
abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-related 
adverse event), and the ET Visit, if applicable. Urinary NGAL will be measured at Day 1, Week 
4, Week 12, the Follow-up Visit (only for subjects who had an abnormal result at Week 12 [or 
the ET Visit, if applicable] or an ongoing treatment-related adverse event), and the ET Visit, if 
applicable. 
Tests for HBV, HCV, and HIV will be conducted at the subject’s first study visit, either at the 
Pre-Screening Visit, if applicable, or the Screening Visit. 
For women of child-bearing potential only, a serum pregnancy test will be conducted at the 
Screening Visit, Week 12, and the ET Visit, if applicable. A urine pregnancy test will be 
conducted at the Pre-Screening Visit, Day 1, Week 2, Week 4, and Week 8.  
Thyroid-stimulating hormone will be measured at the subject’s first study visit, either at the 
Pre-Screening Visit, if applicable, or the Screening Visit. 
HbA1c will be measured at the subject’s first study visit, either at the Pre-Screening Visit, if 
applicable, or the Screening Visit, Week 12, and the ET visit, if applicable.  
8.7 
Vital Signs 
Measurement of vital signs will include an assessment of pulse rate, blood pressure, respiration 
rate, and temperature. Vital signs will be measured at all study visits, excluding the Follow-up 
Visit. Blood pressure should be obtained in the seated position, after the subject has rested 
comfortably for at least 5 minutes. Blood pressure at the Screening Visit should be obtained in 
both arms and the arm with the highest value should be used for ongoing monitoring throughout 
the rest of the study. If an automated assessment is performed, the same machine should be used 
for the subject throughout the study when possible. Care should be taken to ensure an appropriate 
cuff size is utilized.   
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8.8 
Electrocardiograms 
Electrocardiograms will be performed in triplicate and sent to a central reviewer. Subjects should 
be lying quietly in a fully supine position for at least 10 minutes prior to each 12-lead ECG. A 
12-lead ECG will be performed at the Screening Visit, Day 1, Week 2, Week 4, Week 8, Week 
12, and the ET Visit, if applicable.  
The Investigator will assess ECG data as normal, abnormal not clinically significant, or 
abnormal clinically significant. Any clinically significant abnormalities should be documented as 
medical history/adverse event/SAE as applicable. All ECG traces will be kept as source data. 
8.9 
Physical Examinations 
A full physical examination will be performed at the subject’s first study visit, either at the 
Pre-Screening Visit, if applicable, or the Screening Visit, Week 12, and the ET Visit, if 
applicable. A full physical examination includes genitourinary examination per the Investigator’s 
discretion and does not include a rectal examination.  
A symptom-directed physical examination will be conducted at the Screening Visit (only for 
subjects who required a wash-out period and completed the full physical examination at the 
Pre-Screening Visit), Day 1, Week 2, Week 4, Week 8, and the Follow-up Visit (only for 
subjects who had an abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing 
treatment-related adverse event). 
Height will be measured at the subject’s first study visit, either at the Pre-Screening Visit, if 
applicable, or the Screening Visit and weight will be measured at all study visits, excluding the 
Follow-up Visit. BMI will be calculated at the Screening Visit. 
8.10 
Medical/Surgical History and Demographics 
Medical and surgical history and demographics will be recorded at the Pre-Screening Visit, if 
applicable, and/or the Screening Visit. Subject eligibility will be evaluated to determine all 
inclusion and none of the exclusion criteria are met. The Investigator will inquire with the 
subject at Day 1 to determine if there have been any changes in the subject’s health affecting 
eligibility or requiring an update to their medical and surgical history.  
8.11 
Reserve Samples 
Reserve samples will be collected for the optional assay of exploratory biomarkers or 
pharmacokinetic assessments.  Reserve blood samples will be collected at all study visits during 
the Treatment Period and the ET Visit, if applicable, to be available for analysis of exploratory 
biomarkers associated with lipid metabolism, repeat lipid testing, and/or repeat or additional 
clinical laboratory and urine testing in the event of a safety issue.  The reserve samples collected 
on Visits 3 and 5 may be used for assay of plasma drug concentrations (PK Analysis).  The PK 
concentration values be used to confirm subject compliance, summarize of observed plasma 
concentrations, or a model based population pharmacokinetic analysis.  
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9 
STATISTICS 
9.1 
Sample Size 
The primary efficacy endpoint is the percent change from baseline to Week 12 in LDL-C, with 
the primary focus on the overall set of randomized subjects.  The efficacy within each baseline 
statin intensity (high-intensity; moderate-intensity) stratum is also of interest for this study; thus, 
the study is powered for the analyses within each baseline statin intensity stratum.  A sample size 
of 26 randomized subjects in the gemcabene 600 mg group and 26 randomized subjects in the 
placebo group within each baseline statin intensity stratum is expected to provide 80% power to 
detect a difference of 17% in the percent change from baseline to Week 12 in LDL-C between 
the gemcabene treatment group and the placebo group within each baseline statin intensity 
stratum.  This calculation is based on a 2-sided t-test at the 5% level of significance (α = 0.05), a 
common standard deviation of 20, and a drop-out rate of 10%.  The sample size of 26 
randomized subjects in each baseline statin intensity stratum in the gemcabene 600 mg group 
gives a total of 52 randomized subjects in the gemcabene 600 mg group.  Twenty-six randomized 
subjects in each baseline statin intensity stratum in the placebo group gives a total of 52 
randomized subjects in the placebo group.  Thus, the total study sample size is 104 randomized 
subjects.   
There are no planned interim analyses in the study. 
9.2 
Analysis Populations 
9.2.1 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized subjects who receive at least 1 dose 
of study drug and have at least 1 post-baseline efficacy assessment. All efficacy analyses will be 
performed on the FAS. 
9.2.2 
Per Protocol Set 
The Per Protocol Set (PPS) will include all FAS subjects who complete the 12-week Treatment 
Period without major protocol deviations. The PPS will be used to assess robustness of the 
analysis results. Protocol deviations will be reviewed and the PPS will be determined prior to 
treatment unblinding at the end of the study. 
9.2.3 
Safety Analysis Set 
The Safety Analysis Set (SAS) will include all randomized subjects who receive at least 1 dose 
of study drug. All safety analyses will be conducted on the SAS.  
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9.3 
Statistical Methods 
9.3.1 
Analysis of Efficacy 
9.3.1.1 
Primary efficacy analyses 
The primary efficacy endpoint is the percent change in fasting LDL-C from baseline to Week 12.  
The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA) with 
percent change from baseline to Week 12 in LDL-C as the dependent variable; treatment, 
baseline statin intensity (high-intensity; moderate-intensity), and baseline diabetes (yes or no) as 
factors; and baseline fasting LDL-C as a covariate. Baseline will be defined as the average of the 
LDL-C values at Screening/Visit S1 and pre-dose Day 1/Visit T1.  The ANCOVA will be 
performed using the FAS, with subjects included in their randomized treatment group regardless 
of the treatment they actually received.  Missing values for Week 12 will be imputed using last 
observation carried forward (LOCF); only post-baseline values will be used for the imputation.  
The least-squares mean (LSM) and standard error (SE) will be provided for both treatment 
groups, along with the placebo-corrected LSM, its 95% confidence interval (CI), and associated 
p-value.  A 2-sided test with a significance level of 0.05 will be used for the comparison of 
gemcabene 600 mg to the placebo group.  If non-normality is detected, then either the data will 
be transformed so that it is normally distributed or a nonparametric test will be used.   
A confirmatory analysis of the primary efficacy endpoint will be performed using the PPS.   
9.3.1.2 
Secondary and exploratory efficacy analyses 
Secondary efficacy endpoints include: 
• Percent change from baseline to Week 12 in LDL-C for each statin intensity stratum 
(high-intensity; moderate-intensity);  
• Change from baseline to Week 2, Week 4, Week 8, and Week 12 in LDL-C;  
• Change and percent change from baseline to the average of Week 8 and Week 12 
measurements in LDL-C;  
• Change and percent change from baseline to Week 12 in LDL-C in subjects on and not 
on ezetimibe;  
• Change and percent change from baseline to Week 2, Week 4, Week 8, and Week 12 in 
non-HDL-C, TC, TG, HDL-C and VLDL-C;  
• Percent of subjects achieving LDL-C reduction of ≥ 10%, ≥ 15%, and 20% at Week 4, 
Week 8, and Week 12;  
• Percent of subjects achieving an LDL-C value < 100 mg/dL (2.59 mmol/L) at Week 4, 
Week 8, and Week 12;  
• Change and percent change from baseline to Week 4, Week 8 and Week 12 in Apo B, 
ApoA-I, ApoA-II, ApoA-V, ApoC-II, ApoC-III, ApoE and Lp(a);  
• Change and percent change from baseline to Week 4, Week 8 and Week 12 in hsCRP, 
SAA, adiponectin, and fibrinogen;  
• Change from baseline to Week 12 in Framingham Risk score; and  
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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. 
The CRAs will verify data recorded in the EDC system with source documents. All corrections 
or changes made to any study data must be appropriately tracked in an audit trail in the EDC 
system. An eCRF will be considered complete when all missing, incorrect, and/or inconsistent 
data has been accounted for. 
10.1.2 
Computer Systems 
Data will be collected and processed using a validated EDC system. The system and procedures 
are designed in compliance with Title 21 of the Code of Federal Regulations (21 CFR Part 11). 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or 
correct study data. These procedures must comply with 21 CFR Part 11 and other appropriate 
international regulations. All passwords will be strictly confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA for medical history and adverse events, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data 
are contained in source documents (original records or certified copies). These records will be 
retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records.  
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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki, and that the clinical study data are credible. 
11.2 
Institutional Review Board/Ethics Committee 
Federal regulations and the International Conference on Harmonisation (ICH) require that 
approval be obtained from an Institutional Review Board (IRB)/Ethics Committee (EC) prior to 
participation of subjects in research studies. The IRB/EC will review all appropriate study 
documentation in order to safeguard the rights, safety, and well-being of subjects. The study will 
only be conducted at sites where IRB/EC approval has been obtained. The protocol, 
Investigator’s Brochure, Informed Consent Form (ICF), advertisements (if applicable), written 
information given to the subjects, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/EC by the Investigator. 
Prior to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for 
subject recruitment, and any other written information regarding this study being provided to a 
subject or subject’s legal guardian must be approved by the IRB/EC. 
No drug will be released to the site for dosing until written IRB/EC authorization has been 
received by the Sponsor, or designee. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by 
the Sponsor or designee and the IRB/EC prior to its use and must be in compliance with all ICH 
GCP, local regulatory requirements, and legal requirements.  
The Investigator, or a person delegated the responsibility by the Investigator, must ensure that 
each study subject (or legally acceptable representative) is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator or delegate will allow the 
subject adequate opportunity to read the written informed consent and ask any questions. The 
Investigator will obtain written informed consent from each subject before any study-specific 
activity is performed and should document in the source documentation that consent was 
obtained prior to any study-specific activity. The original signed copy of the ICF must be 
maintained by the Investigator and is subject to inspection by a representative of the Sponsor, 
their representatives, auditors, the IRB/EC and/or regulatory agencies. A copy of the signed ICF 
will be given to the subject. 
11.4 
Subject Card 
On enrollment in the study, the subject will receive a subject card to be carried at all times. The 
subject card will state that the subject is participating in a clinical research study, type of 
treatment, number of treatment packs received, and contact details in case of an SAE. 
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11.5 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki (Seoul 2008) and that valid data are entered into the eCRFs. 
The role of the study monitor is to verify the rights and well-being of the subjects are protected, 
the data is accurate, complete, and verifiable from source documents, and the conduct of the 
study is in compliance with the protocol, Declaration of Helsinki, ICH GCP, and applicable 
regulatory requirements. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, 
the Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, management of 
investigational product, and the procedure for reporting adverse events such as SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. 
During the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to 
help monitor the clinical study. If necessary, requests for clarification or correction will be sent 
to investigators. The Investigator and his/her staff will be expected to cooperate with the monitor 
and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log 
and findings documented in a follow-up letter. 
11.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB/EC as appropriate. Subjects or their 
legal representatives may request their medical information be given to their personal physician 
or other appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
11.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to 
link records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, 
SAE forms, source documents, and detailed records of treatment disposition. The records should 
be retained by the Investigator according to specifications in the ICH guidelines, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer. The 
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Investigator must obtain written permission from Gemphire before disposing of any 
records, even if retention requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to the Sponsor.  
11.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication 
rights until mutual agreement on the content, format, interpretation of data in the manuscript, and 
journal selected for publication are achieved. 
11.9 
Financial Disclosure 
Clinical Investigators are required to provide financial disclosure information to the Sponsor to 
permit the Sponsor to fulfill its obligations under 21 CFR §54. In addition, investigators must 
commit to promptly updating this information if any relevant changes occur during the study and 
for a period of 1 year after the completion of the study. 
11.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out clinical trial 
insurance. This insurance provides coverage to the Sponsor in the event of physical injury or 
death related to the study drug or any procedure related to the protocol. 
11.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (i.e., initiation of study centers) when the CTA and favorable Ethics 
opinion have been received.  
11.12 
Definition of End of Study 
The End of Study is defined as the completion of the Follow-up Visit or the ET Visit, if 
applicable. 
11.13 
Sponsor Discontinuation Criteria 
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the IRB/EC, drug safety problems, or at the discretion of Gemphire. In addition, 
Gemphire retains the right to discontinue development of gemcabene at any time.  
If a study is prematurely terminated or discontinued, Gemphire will promptly notify the 
Investigator. After notification, the Investigator must contact all participating subjects within 
2 weeks. As directed by Gemphire, all study materials must be collected and all eCRFs 
completed to the greatest extent possible.  
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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the investigators by 
 
 or the Sponsor. All protocol amendments will undergo the same review and 
approval process as the original protocol. A protocol amendment may be implemented only after 
it has been approved by the IRB, unless immediate implementation of the change is necessary for 
subject safety. In this case, the situation must be documented and reported to the IRB within 5 
working days. 
12.2 
Address List 
12.2.1 
Sponsor 
Gemphire Therapeutics Inc.  
17199 N. Laurel Park Drive, Suite 401 
Livonia, Michigan 48152 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
12.2.2 
Contract Research Organization 
12 2 3 
Biological Specimens 
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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Pre-Screeninga 
Screeningb 
Treatment Periodc 
Follow-
upd 
ET 
 
up to Day -14 
Day 1e  
Week 2 
(Day 15± 3 
days) 
Week 4 
(Day 29± 3 
days) 
Week 8 
(Day 57± 3 
days) 
Week 12 (Day 
85, or up to 3 
days earlier)  
Day 113 
± 3 days 
 
 
Visit S1 
Visit T1 
Visit T2 
Visit T3 
Visit T4 
Visit T5 
 
 
Informed consent 
X 
Xf 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical/surgical history and demographics 
X 
Xf 
 
 
 
 
 
 
 
Full physical examinationg 
X 
Xf 
 
 
 
 
X 
 
X 
Symptom-directed physical examination 
 
Xh 
X 
X 
X 
X 
 
Xi 
 
Vital signsj, heightk, and weight 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body Mass Index (BMI) 
X 
X 
 
 
 
 
 
 
 
Urinalysisl 
X 
X 
X 
 
X 
X 
X 
Xi 
X 
Serum/urine pregnancy testm 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety chemistry panel, coagulation, and 
hematologyn 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
TSH, HbA1c, and serologyo 
X 
Xf 
 
 
 
 
X 
 
X 
Fasting lipid panelp; LDL-C 
ultracentrifugation when necessary 
Xq 
X 
X 
X 
X 
X 
X 
 
X 
Fasting apolipoproteinsr 
 
 
X 
 
X 
X 
X 
 
X 
  
 
 
X 
 
 
 
X 
 
X 
hsCRP, SAA,fibrinogen, and adiponectin 
 
 
X 
 
 
 
X 
 
X 
Fasting plasma glucose, insulin 
 
 
X 
 
 
 
X 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
Study drug administrations 
 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug and instructions 
 
 
X 
X 
X 
X 
 
 
 
Compliance check 
 
 
 
X 
X 
X 
X 
 
X 
Dietary instructionst 
X 
X 
X 
X 
X 
X 
 
 
 
12-lead ECGu 
 
X 
X 
X 
X 
X 
X 
 
X 
Initiate wash-out 
X 
 
 
 
 
 
 
 
 
Adverse events 
Xv 
Xv 
X 
X 
X 
X 
X 
X 
X 
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Footnotes appear on the following page
Concomitant medications 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Reserve samples  
 
 
X 
X 
X 
X 
X 
 
X 
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a. 
Only subjects requiring a wash-out period will participate in the Pre-Screening Visit. Specifically, PCSK9 inhibitors will require an 8-week wash-out period, fibrates will 
require a 6-week wash-out period, and niacins or other lipid-regulating therapies such as bile acid sequestrants will require a 4-week wash-out period, prior to the 
Screening Visit. 
b. 
All eligible subjects will participate in the Screening Visit up to 14 days prior to Day 1. For subjects taking the required stable statin therapy for >4 weeks at the 
Screening Visit and do not require a wash-out period, the Screening Visit will be their first study visit.  
c. 
Study assessments will be completed ±3 days of given time point for all study visits from Day 1 through Week 8. Week 12 assessments can be performed up to 3 days 
prior to Week 12, but not after Week 12. 
d. 
The Follow-up Visit will be conducted as a telephone call 4 weeks (±3 days) after the last dose of study drug, unless the subject requires a site visit due to an abnormal 
result at Week 12 (or the ET Visit, if applicable) or an ongoing treatment-related adverse event. 
e. 
Procedures will be performed pre-dose. The Investigator will inquire with the subject at Day 1 to determine if there have been any changes in the subject’s health 
affecting eligibility or requiring an update to their medical and surgical history. 
f. 
For subjects who required a wash-out period and completed the Pre-Screening Visit, the following Screening Visit procedures will not be repeated: informed consent, 
full physical examination, height, TSH, HbA1c, and serology (HBV, HCV, and HIV) screening. Updates, as needed, will be made to medical/surgical history, 
demographics, and concomitant medications.   
g. 
A full physical examination includes genitourinary examination per the Investigator’s discretion and does not include a rectal examination. 
h. 
Only for subjects who required a wash-out period and completed the full physical examination at the Pre-Screening Visit. 
i. 
Only for subjects who had an abnormal result at Week 12 (or the ET Visit, if applicable) or an ongoing treatment-related adverse event.  
j. 
Vital signs include pulse rate, blood pressure, respiration rate, and temperature. Blood pressure should be obtained in the seated position, after the subject has rested 
comfortably for at least 5 minutes. Blood pressure at the Screening Visit should be obtained in both arms and the arm with the highest value should be used for ongoing 
monitoring throughout the rest of the study. If an automated assessment is performed, the same machine should be used for the subject throughout the study when 
possible. Care should be taken to ensure an appropriate cuff size is utilized. 
k. 
Height will be measured only at the subject’s first study visit, either at the Pre-Screening Visit or the Screening Visit. 
l. 
A urine microscopic examination will be performed when the dipstick result is abnormal (positive for blood, leukocyte esterase, or nitrites). Urine protein:creatinine ratio 
(albumin:creatinine) will be performed at the Screening Visit, Day 1, Week 4, Week 12, the Follow-up Visit (only for subjects who had an abnormal result at Week 12 
[or the ET Visit, if applicable] or an ongoing treatment-related adverse event), and the ET Visit, if applicable. Urinary NGAL will be measured at Day 1, Week 4, Week 
12, the Follow-up Visit (only for subjects who had an abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event), and the 
ET Visit, if applicable. 
m. For women of child-bearing potential only, a serum pregnancy test will be conducted at the Screening Visit, Week 12, and the ET Visit, if applicable. A urine pregnancy 
test will be conducted at the Pre-Screening Visit, Day 1, Week 2, Week 4, and Week 8.  
n. 
Clinically significant abnormal creatinine results at Week 12 (or the ET Visit, if applicable) will also be followed-up 2 weeks (±3 days) after the last dose of study drug 
in addition to the Week 4 (±3 days) Follow-up Visit. See Appendix B for a list of analytes and description of when repeat or reflexive testing will be required.  
o. 
Thyroid-stimulating hormone, HbA1c, and serology (HBV, HCV, and HIV) will be measured at the subject’s first study visit, either at the Pre-Screening Visit, if 
applicable, or the Screening Visit. Only HbA1c will be measured at Week 12, and the ET Visit, if applicable.  
p. 
Includes LDL-C, non-HDL-C, TC, TG, HDL-C, and VLDL-C. Fasting will be defined as no food or caloric beverage for at least 10 hours prior to sample collection. 
Subjects will be permitted to have water.  
q. 
Includes LDL-C and TG only. Fasting will be defined as no food or caloric beverage for at least 10 hours prior to sample collection. Subjects will be permitted to have 
water. 
r. 
Includes ApoB, ApoA-I, ApoA-II, ApoA-V, ApoC-II, ApoC-III, ApoE, and Lp(a). Fasting will be defined as no food or caloric beverage for at least 10 hours prior to 
sample collection. Subjects will be permitted to have water.  
s. 
Study drug will be administered at the site on Day 1. Subjects will self-dose at all other times during the Treatment Period.  
t. 
Subjects will be counseled on a low-fat, low-cholesterol diet (NCEP ATP-III guidelines or equivalent). 
u. 
Subjects should be lying quietly in a fully supine position for at least 10 minutes prior to each 12-lead ECG. 
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v. 
Serious adverse events that occur prior to the first dose of study drug (Day 1) should be reported as an update to medical history as well as be reported on the appropriate 
adverse event eCRF. 
Apo = apolipoprotein; ECG = electrocardiogram; eCRF = electronic case report form; ET = Early Termination; HBV = hepatitis B virus; HbA1c = hemoglobin A1c; 
HCV = hepatitis C virus; HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; HoFH = homozygous familial hypercholesterolemia; 
hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); NCEP ATP-III = National Cholesterol Education Program Adult 
Treatment Panel III; NGAL = neutrophil gelatinase-associated lipocalin; non-HDL-C = non-high-density lipoprotein cholesterol; 
 
 TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone; VLDL-C = very low-density lipoprotein cholesterol.
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CI


Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-301 
APPENDIX B: CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel  
Alanine aminotransferase  
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase  
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase  
Creatinine [1] 
Gamma-glutamyl transferase 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Total bilirubin [2] 
Total protein 
Estimated glomerular filtration rate (GFR) [3] 
 
1. 
For a creatinine increase of >0.3 mg/dL (27 µmol/L) from baseline during the study, repeat chemistry will be performed. 
2. 
If total bilirubin is elevated, reflexive direct bilirubin testing will be performed. 
3. 
For an estimated GFR decrease of >15 mL/min from baseline during the study, repeat chemistry will be performed. 
 
Additional Chemistry Parameter 
Glycosylated hemoglobin (HbA1c) 
Fasting plasma glucose  
Fasting insulin 
 
 
Endocrinology 
Thyroid-stimulating hormone 
 
 
Hematology  
Hematocrit 
Hemoglobin [1] 
Platelet count 
Red blood cell count 
Mean corpuscular hemoglobin concentration 
Mean corpuscular hemoglobin 
White blood cell count and differential 
(basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils) [2] 
Mean corpuscular volume 
1. 
For a hemoglobin decrease of >1.5 g/dL from baseline during the study, repeat hematology studies and reflexive 
evaluation of reticulocyte count will be performed. 
2. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-301 
Urinalysis [1] 
pH 
Proteinuria [2] 
Ketones 
Blood 
Leukocyte esterase 
Specific Gravity 
Glucose 
Bilirubin  
Nitrite 
Albumin 
 
Neutrophil gelatinase-associated lipocalin 
(NGAL) [3] 
 
 
1. 
A urine microscopic examination will be performed when dipstick results are abnormal (positive for blood, leukocyte 
esterase, or nitrites).  
2. 
Urine protein:creatinine ratio (and albumin:creatinine ratio) will be performed at the Screening Visit, Day 1, Week 4, 
Week 12, the Follow-up Visit (only for subjects who had an abnormal result at Week 12 [or the ET Visit, if applicable] 
or an ongoing treatment-related adverse event), and the ET Visit, if applicable.  
3. 
Urinary NGAL will be measured at Day 1, Week 4, Week 12, the Follow-up Visit (only for subjects who had an 
abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event), and the ET 
Visit, if applicable. 
 
Pregnancy Test  
Serum and urine pregnancy tests will be administered to all female subjects of child-bearing 
potential. 
Serology 
Hepatitis B 
Hepatitis C  
Human Immunodeficiency Virus 
 
Coagulation  
Prothrombin time 
Activated partial thromboplastin time 
International normalized ratio 
 
 
Efficacy Parameters  
The following efficacy parameters will be assessed in this study: 
Apolipoprotein (Apo) A-I 
ApoA-II 
ApoB 
ApoA-V 
ApoC-III 
ApoE 
ApoC-II 
Lipoprotein (a) 
High-density lipoprotein cholesterol  
Low-density lipoprotein cholesterol  
Non-high-density lipoprotein cholesterol 
Very low-density lipoprotein cholesterol 
Triglycerides 
Total cholesterol 
High-sensitivity C-reactive protein 
Serum amyloid A 
 
Fibrinogen 
Adiponectin 
 
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-301 
APPENDIX C: NEW YORK HEART ASSOCIATION CONGESTIVE 
HEART FAILURE CLASSIFICATION  
• Class I: subjects with cardiac disease but without resulting limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain. 
• Class II: subjects with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
• Class III: subjects with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, 
or anginal pain. 
• Class IV: subjects with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is increased. 
Source: The Criteria of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-
256.  
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-301 
APPENDIX D: CYTOCHROME P450 3A4 INHIBITORS: 
EXCLUSIONARY MEDICATIONS  
Amiodarone 
Amprenavir 
Atazanavir 
Cimetidine 
Clarithromycin 
Conivaptan 
Darunavir 
Delavirdine 
Diltiazem 
Erythromycin 
Fluconazole 
Fluvoxamine 
Fosamprenavir 
Grapefruit juice 
Imatinib 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir 
Miconazole 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telithromycin 
Tipranavir 
Troleandomycin 
Verapamil 
Voriconazole 
 
 
 
 
 
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-301 
APPENDIX E: MUSCLE INJURY AND HEPATIC MONITORING 
Muscle Injury 
Muscle injury will be assessed using a combination of clinical signs and symptoms and 
laboratory data (creatine kinase [CK], hepatic, and renal function). 
All subjects with suspected or confirmed muscle injury should be managed according to the 
standard of care at the discretion of the Investigator. 
• Subjects with new or unexplained muscle symptoms should have an unscheduled visit 
scheduled within 7 days of site notification. At this visit, samples should be sent for a full 
chemistry panel, including CK, liver, and renal function. 
• Subjects with CK elevations of >3 × upper limit of normal (ULN) who are asymptomatic 
should be considered for an unscheduled visit (+ isozymes), based upon medical 
judgment. 
• All subjects with CK elevations >10 × ULN should have an unscheduled visit (+ 
isozymes). Study drug should be temporarily discontinued, pending the results of an 
investigation into the cause of muscle injury and/or CK elevation is complete. 
It is important that subjects are instructed to not undertake any form of strenuous physical 
activity for at least 24 hours prior to repeat blood testing. 
Hepatic Monitoring 
Subjects with hepatic enzyme elevations should be managed according to the standard of care, at 
the discretion of the Investigator. For subjects with signs or symptoms suggestive of hepatitis, an 
unscheduled visit and a chemistry panel should be performed. Subjects with an alanine 
aminotransferase (ALT) >2 × ULN with symptoms suggestive of hepatitis should have an 
unscheduled visit. Subjects with ALT >3 × ULN with or without symptoms should also have an 
unscheduled visit. A repeat assessment should be performed as soon as possible to confirm the 
finding. A clinical evaluation should be performed, including assessment of past medical history 
(including non-alcoholic fatty liver disease/steatohepatitis and alcohol use) and concomitant 
medications (including over the counter drugs and herbal supplements). Risk factors for hepatitis 
infection should be reviewed and hepatitis studies should be performed.  
Study drug should be temporarily discontinued during this evaluation if the subject has signs or 
symptoms of hepatitis or an ALT >5 × ULN. The possible dosing re-initiation (re-challenge) or 
follow-up schedule for any events meeting these criteria will be determined by the Investigator in 
consultation with the Medical Monitor. 
Recommended Hepatic Discontinuation Criteria 
Study drug should be discontinued permanently if one of the following occurs (as confirmed by 
repeat assessment) and if the event is without an alternative explanation: 
• ALT or aspartate aminotransferase (AST) >8 × ULN; 
• ALT or AST >5 × ULN for more than 2 weeks; 
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-301 
• ALT or AST >3 × ULN and either total bilirubin >2 × ULN or international normalized 
ratio >1.5; and/or 
• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
It is also recommended that statin regimen is discontinued. Abnormal values should be followed 
until they return within normal range or to a level deemed acceptable by the Investigator, or until 
the abnormality is explained by an appropriate diagnosis. 
 
 
Confidential & Proprietary 
Page 68 of 68 
Version 4.0, 05 October 2016 

SAP_000.pdf: 
Title: A 12-Week, Phase 2 Randomized, Placebo-Controlled, Double-Blind Study to Assess the 
Efficacy, Safety, and Tolerability of Gemcabene in Subjects with Hypercholesterolemia Not 
Adequately Controlled on High-Intensity or Moderate-Intensity Stable Statin Therapy (ROYAL-1) 
 
NCT ID: NCT02634151 
 
Approval Date: 10-Jul-2017 


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Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 2 of 43 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
LIST OF TABLES .....................................................................................................................3 
LIST OF APPENDICES ............................................................................................................3 
2 
SIGNATURE PAGE .........................................................................................................4 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................6 
4 
INTRODUCTION .............................................................................................................9 
5 
TRIAL OBJECTIVES .....................................................................................................10 
5.1 
Primary Objectives.................................................................................................10 
5.2 
Secondary Objectives.............................................................................................10 
5.3 
Exploratory Objectives ..........................................................................................10 
6 
STUDY DESIGN CONSIDERATIONS .........................................................................11 
6.1 
Study Design ..........................................................................................................11 
6.2 
Efficacy Measures ..................................................................................................12 
6.3 
Safety Measures .....................................................................................................13 
7 
STUDY POPULATIONS ................................................................................................14 
7.1 
Analysis Populations ..............................................................................................14 
7.1.1 
Full Analysis Set ..........................................................................................14 
7.1.2 
Per-Protocol Set ...........................................................................................14 
7.1.3 
Safety Analysis Set ......................................................................................14 
8 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ..15 
9 
OVERALL STATISTICAL CONSIDERATIONS .........................................................16 
9.1 
Sample Size Computation ......................................................................................16 
9.2 
General Conventions ..............................................................................................16 
9.3 
Baseline Definitions ...............................................................................................17 
9.4 
Handling of Missing Data ......................................................................................18 
9.5 
Interim Analysis .....................................................................................................18 
9.6 
Visit Windows .......................................................................................................18 
10 STATISTICAL ANALYSIS METHODS .......................................................................20 
10.1 
Subject Disposition ................................................................................................20 
10.2 
Demographics and Baseline Characteristics ..........................................................20 
10.3 
Treatment Compliance and Exposure ....................................................................21 
10.3.1 
Treatment Compliance .................................................................................21 
10.3.2 
Treatment Exposure .....................................................................................22 
11 EFFICACY PARAMETERS ...........................................................................................23 
11.1 
Primary Analysis ....................................................................................................23 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 3 of 43 
11.2 
Secondary Analysis ................................................................................................23 
11.3 
Exploratory Analysis .............................................................................................25 
11.4 
Manuscript Analysis ..............................................................................................26 
12 SAFETY AND TOLERABILITY ...................................................................................27 
12.1 
Adverse Events ......................................................................................................27 
12.2 
Clinical Laboratory Assessments ...........................................................................28 
12.3 
ECGs ......................................................................................................................30 
12.4 
Vital Signs and Weight ..........................................................................................31 
12.5 
Physical Examinations ...........................................................................................31 
13 OTHER RELEVANT DATA ANALYSES/SUMMARIES ...........................................32 
13.1 
Medical History .....................................................................................................32 
13.2 
Prior and Concomitant Medications ......................................................................32 
13.3 
Concomitant Procedures ........................................................................................32 
14 REFERENCES ................................................................................................................33 
15 APPENDICES .................................................................................................................34 
 
LIST OF TABLES 
Table 1. Overview of Study Periods .....................................................................................11 
Table 2. Visit Windows for Assessments Done at Day 1, Weeks 2, 4, 8, and 12a ...............19 
Table 3. Lab PCS Criteria .....................................................................................................29 
Table 4. ECG PCS Criteria ...................................................................................................30 
 
LIST OF APPENDICES 
Appendix 1. Schedule of Assessments and Procedures ..........................................................34 
Appendix 2. Prior and Concomitant Medications and Smoking Status Date Imputation .......37 
Appendix 3. ATC Categories and Descriptions of Hypertensive Treatments ........................38 
Appendix 4. Sex-specific Framingham Risk Score algorithms ..............................................42 
Appendix 5. Manuscript Analyses ..........................................................................................43 
 
 


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Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 5 of 43 
Document History – Major changes compared to previous versions of the analysis plan 
Version 
Date 
Changes 
Final 1.0 
17-Apr-17 
N/A 
Amendment 1.0 
10-Jul-17 
Added that potentially clinically significant laboratory 
values, single occurrences, will also be summarized by 
statin-intensity stratum. 
Added information on imputing drug interruptions with 
partial start/stop dates to be 1 day in length along with 
technical comments regarding assignment.  
Added that we are summarizing days on treatment and days 
drug was interrupted for.  
Added 2 urinalysis parameters to PCS criteria.  
Updated PPS section. 
Edited text to reflect hsCRP and TG being analyzed using 
ranked ANCOVA. 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 6 of 43 
3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance  
Apo 
apolipoprotein  
AST 
aspartate aminotransferase  
ATC 
anatomical therapeutic chemical  
BMI 
body mass index  
BUN 
blood urea nitrogen  
CFBL 
change from baseline  
CI 
confidence interval  
CRF 
case report form  
CVD 
cardiovascular disease  
DBP 
diastolic blood pressure  
DPP 
dipeptidyl peptidase 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination  
FAS 
Full Analysis Set  
FPG 
fasting plasma glucose  
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase  
HbA1c 
hemoglobin A1c  
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL-C 
high-density lipoprotein cholesterol  
HIV 
human immunodeficiency virus 
HoFH  
homozygous familial hypercholesterolemia 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 7 of 43 
hsCRP 
high-sensitivity C-reactive protein  
LDH 
lactate dehydrogenase  
LDL-C 
low-density lipoprotein cholesterol  
LOCF 
last observation carried forward  
Lp(a) 
Lipoprotein(a) 
LSM 
least-squares mean  
MAO 
monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities  
NCEP ATP-III 
National Cholesterol Education Program Adult Treatment Panel III  
NGAL 
neutrophil gelatinase-associated lipocalin  
OR 
odds ratio  
PCS 
potentially clinically significant  
PCSK9 
proprotein convertase subtilisin/kexin type 9  
PPS 
Per-Protocol Set  
PT 
preferred term  
QD 
once daily  
QTcB 
QT interval corrected for heart rate with Bazett’s formula 
QTcF 
QT interval corrected for heart rate with Fridericia’s formula  
SAA 
serum amyloid A  
SAE 
serious adverse event  
SAS 
Safety Analysis Set  
SBP 
systolic blood pressure  
SD 
standard deviation  
SE 
standard error  
SOC 
system organ class  
TC 
total cholesterol  
TEAE 
treatment-emergent adverse event  
TG 
triglyceride  
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 8 of 43 
VLDL-C 
very low-density lipoprotein cholesterol  
WHO 
World Health Organization  


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 9 of 43 
4 INTRODUCTION 
The purpose of this statistical analysis plan is to describe the framework for the reporting, 
summarization, and statistical analysis methodology of the safety and efficacy parameters 
measured throughout the study. It is based on Protocol GEM-301 (Amendment 3) dated 
05 Oct 2016. 


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Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 11 of 43 
6 STUDY DESIGN CONSIDERATIONS 
6.1 
Study Design 
This is a Phase 2, randomized, placebo-controlled, double-blind, multicenter study with a 
duration of up to 26 weeks with 12 weeks of study drug treatment. The study will consist of a 
Pre-Screening Visit (only for subjects requiring a wash-out period), a Screening Visit, a 
Treatment Period, and a Follow-up Visit. 
Table 1. Overview of Study Periods 
 
Wash-out Period (for 
subjects requiring wash-out) 
Screening Visit 
Treatment Period 
Study Days 
Day -70 to -15, inclusive 
Day -14 to -1, inclusive 
Day 1 to 85, inclusive 
Approximately 104 subjects will participate in the study at up to 20 sites in the United States. 
Subjects are required to be on either a high-intensity stable statin regimen (atorvastatin at 40 or 
80 mg QD, or rosuvastatin at 20 or 40 mg QD) or a moderate-intensity stable statin regimen 
(atorvastatin at 10 or 20 mg QD, rosuvastatin at 5 or 10 mg QD, or simvastatin at 20 or 
40 mg QD) with or without ezetimibe 10 mg QD for at least 12 weeks prior to the Screening 
Visit. Further, subjects must have a fasting LDL-C value ≥ 100 mg/dL (2.59 mmol/L) and a TG 
value < 500 mg/dL (5.65 mmol/L) at the Screening Visit, while on a stable, low-fat, low-
cholesterol diet.  
A wash-out period will be required for eligible subjects taking any lipid-regulating therapies or 
supplements except for atorvastatin at 10, 20, 40, or 80 mg QD, rosuvastatin at 5, 10, 20, or 
40 mg QD, simvastatin at 20 or 40 mg QD, and/or ezetimibe at 10 mg QD. For subjects requiring 
a wash-out period, the Pre-Screening Visit will be their first study visit and will occur prior to the 
Screening Visit. The time between the Pre-Screening Visit and Screening Visit will depend on 
the required wash-out period duration which varies according to the status of a given subject’s 
current lipid-regulating therapy. Specifically, PCSK9 inhibitors require an 8-week wash-out 
period, fibrates require a 6-week wash-out period, and niacins along with other lipid-regulating 
therapies including bile acid sequestrants require a 4-week wash-out period. For eligible subjects 
that do not require a wash-out period, the Screening Visit will be their first study visit. 
Subjects will be randomized on Day 1 in a 1:1 ratio (gemcabene 600 mg to placebo). 
Randomization will be stratified by baseline statin-intensity regimen (moderate or high) and 
diabetes status (yes or no), both of which are recorded on the Medical History form at the 
subject’s first visit (Pre-Screening or Screening Visit) and updated, when appropriate, at the 
Screening Visit. Subjects defined as diabetic are those receiving concomitant anti-diabetic 
medication at screening. Randomization within a baseline statin-intensity stratum will be capped 
at 52 subjects. By further stratifying on diabetes status at baseline, diabetic subjects will be 
evenly distributed across treatment groups within each statin-intensity stratum. 
Post-randomization clinic visits will occur at Weeks 2, 4, 8 and 12. The Follow-up Visit will 
occur 4 weeks (± 3 days) after the last dose of the study drug.  


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Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 14 of 43 
7 STUDY POPULATIONS 
7.1 
Analysis Populations 
A summary table containing the number of subjects in each of the populations defined below 
will be provided. 
7.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all randomized subjects who receive at least 1 dose of the 
study drug and have at least 1 post-baseline efficacy assessment. Subjects will be classified 
according to the treatment they were randomized to. Efficacy analyses will be conducted using 
the FAS. 
7.1.2 
Per-Protocol Set 
The Per-Protocol Set (PPS) includes all FAS subjects who complete the 12-week Treatment 
Period without major protocol deviations. Subjects will be classified according to the treatment 
they were randomized to. The PPS will be determined by the sponsor prior to treatment 
unblinding at the end of the study. The PPS will be used to assess the robustness of analysis 
results. Subjects excluded from the PPS and the reason for exclusion will be provided in the 
listings. 
 
7.1.3 
Safety Analysis Set 
The Safety Analysis Set (SAS) consists of all randomized subjects who receive at least 1 dose of 
the study drug. Subjects will be classified according to the treatment they actually received. 
Safety analyses will be conducted using the SAS. 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 15 of 43 
8 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL 
Although the National Cholesterol Education Program Adult Treatment Panel III 
(NCEP ATP-III) Risk Category was specified in the protocol as a secondary endpoint, this was 
not computed because the CRFs did not collect all of the necessary information (family history 
of premature coronary heart disease).  
Additionally, although the percent of diabetic subjects with > 5% decrease in dosage of anti-
diabetes pharmacologic therapy from baseline to Week 12 was cited in the protocol as an 
exploratory endpoint, this analysis will not be conducted.  
Although the protocol indicates that secondary analyses will be performed on subjects on and not 
on ezetimibe, these will not be done due to an insufficient number of subjects on ezetimibe. 
Even though confirmatory analyses for secondary and exploratory analyses were detailed in the 
protocol, these will not be conducted.  
Additionally, although percent CFBL to Weeks 2, 4, and 8 in LDL-C was not specified in the 
protocol, these analyses will be performed for completeness.  


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 16 of 43 
9 OVERALL STATISTICAL CONSIDERATIONS 
9.1 
Sample Size Computation 
The primary efficacy endpoint is the percent CFBL to Week 12 in LDL-C, with the primary 
focus on the overall set of randomized subjects. The efficacy within each baseline stable 
statin-intensity (high and moderate) stratum is also of interest for this study; thus, the study is 
powered for analysis within each baseline statin-intensity stratum. A sample size of 
26 randomized subjects in the gemcabene 600 mg group and 26 randomized subjects in the 
placebo group within each baseline statin-intensity stratum is expected to provide 80% power to 
detect a difference of 17% in the percent CFBL to Week 12 in LDL-C between the gemcabene 
treatment group and the placebo group within each baseline statin-intensity stratum. This 
calculation is based on a 2-sided t-test at the 5% level of significance (alpha = 0.05), a common 
standard deviation (SD) of 20, and a drop-out rate of 10%. The sample size of 26 randomized 
subjects in each baseline statin-intensity stratum in the gemcabene 600 mg group gives a total of 
52 randomized subjects in the gemcabene 600 mg group. Twenty-six randomized subjects in 
each baseline statin-intensity stratum in the placebo group gives a total of 52 randomized 
subjects in the placebo group. Thus, the total study sample size is 104 randomized subjects. 
9.2 
General Conventions 
In general, variables will be summarized using summary statistics. Frequency and percentages 
will be used for categorical variables whereas mean, SD, median, minimum, and maximum will 
be used to summarize continuous variables. Decimal precision for continuous variables will be 
based on the mean value; the median will contain the same number of decimal places as the 
mean, the SD will contain one more decimal place than the mean, and the minimum and 
maximum will contain one less decimal place than the mean. Typically, the mean will contain 
one more decimal place than actual values but decimal precision may vary in order to obtain an 
organized and understandable table or listing. 
The first day of administration of randomized study medication (first dose) is defined as 
Study Day 1 or Day 1. All other study days will be computed relative to Day 1. For events on or 
after Day 1, study day for a particular event will be calculated as: 
ܦܽݐ݁௘௩௘௡௧െܦܽݐ݁௙௜௥௦௧ௗ௢௦௘൅ͳ. For events before Day 1, study day for a particular event will be 
calculated as: ܦܽݐ݁௘௩௘௡௧െܦܽݐ݁௙௜௥௦௧ௗ௢௦௘. Day 0 will not be used.  
All statistical testing will be 2-sided and performed at the alpha = 0.05 level. No multiplicity 
adjustments will be made for testing multiple secondary and exploratory efficacy outcomes. 
Given the large number of secondary and exploratory efficacy outcomes, p-values associated 
with such outcomes will be considered descriptive. As it is possible that some significant results 
could occur due to chance alone, undue consideration will not be given to isolated significant 
differences; rather, interpretation will be made based on patterns of significant differences and 
consistency with the primary outcome.  
For a given parameter (eg, y) CFBL will be calculated as ݕ௧െݕ௕, where ݕ௧ is a given subject’s 
value t weeks post-baseline and ݕ௕ is a given subject’s value at baseline. CFBL will be computed 


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CI


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 19 of 43 
Table 2. 
Visit Windows for Assessments Done at Day 1, Weeks 2, 4, 8, and 12a 
Visit 
Target Study Day 
Visit Window 
Day 1 
1 
(1) 
Week 2 
15 
(2, 22) 
Week 4 
29 
(23, 43) 
Week 8 
57 
(44, 71) 
Week 12 
85 
> 71 
a. As Apo and select urinalysis parameters are not measured at Week 2, the Visit Window for 
Week 4 for Apo and urinalysis parameters is (2, 43). Remaining urinalysis parameters are not 
measured at Week 2 or Week 8; thus, the Visit Windows for Week 4 and Week 12 are (2, 57) 
and > 57, respectively. 
 


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CI


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 21 of 43 
each baseline statin-intensity stratum (moderate, high). Additionally, the number and percentage 
of diabetic subjects and subjects on and not on ezetimibe in each of the previously mentioned 
groups will be summarized for the FAS. A subject on ezetimibe is defined as a subject with 
ezetimibe recorded on the Concomitant Medications CRF with a start date on or before first dose 
(ie, medication start date ≤ day of first dose) and a stop date on or after first dose (ie, medication 
stop date ≥ day of first dose). Partial and missing dates will be imputed using rules in Appendix 
2.  
Further, for the subgroup of diabetic subjects within the FAS, baseline fasting insulin, FPG, 
HbA1c, lipids, apolipoproteins, and inflammatory biomarkers will be summarized by 
randomized treatment group and overall.  
Lastly, for the subgroup of subjects with mixed dyslipidemia at baseline within the FAS, baseline 
lipids, apolipoproteins, and inflammatory biomarkers will be summarized by randomized 
treatment group and overall. This table will then be repeated for the subgroup of subjects without 
mixed dyslipidemia at baseline within the FAS.  
For categorical parameters, denominators for percentages will be the number of subjects in the 
corresponding group (eg, gemcabene 600 mg) with non-missing data for the parameter of 
interest. 
10.3 Treatment Compliance and Exposure 
10.3.1 
Treatment Compliance  
Compliance with administration of study drug will be assessed at each study visit 
post-randomization during the Treatment Period and at the ET Visit, if applicable, and recorded 
on the appropriate CRF and the drug accountability log. Compliance will be computed using 
information collected on the Study Drug Interruption CRF. Specifically, compliance will be 
calculated for each subject at each scheduled post-randomization visit during the treatment 
period (and the ET visit, if applicable), where treatment period is defined as the time period 
bounded by the first dose date and last dose date, as (number of tablets taken since last 
visit/number of tablets that should have been taken since last visit)*100. As each subject is 
instructed to take 3 tablets per day during the treatment period, the number of tablets that should 
have been taken since the last visit will be computed as 3 tablets per day*number of days since 
last visit, where the number of days since the last visit will be computed as (day of visit - day of 
last visit + 1). Compliance will be summarized by visit and actual treatment group for the SAS.  
For each subject, overall compliance will be computed as (number of tablets taken during 
treatment period/number of tablets that should have been taken during treatment period)*100. 
The number of tablets that should have been taken during the treatment period will be computed 
as 3 tablets per day* number of days during the treatment period, where the number of days 
during the treatment period will be computed as (last dose date – first dose date + 1). Subjects 
will then be grouped into categories of overall compliance (< 80%, 80% to 100%) according to 
their overall estimate of compliance. Overall compliance and categories of compliance will be 
summarized using descriptive statistics by actual treatment group for the SAS.  


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 22 of 43 
10.3.2 
Treatment Exposure 
Duration of exposure will be calculated for each subject as (last dose date – first dose date + 1) 
and will be summarized using descriptive statistics. The number of subjects who receive ≥ 1 day, 
≥ 7 days, ≥ 14 days, ≥ 28 days, ≥ 42 days, ≥ 56 days, ≥ 70 days, and ≥ 84 days of the study 
medication will be presented by actual treatment group for the SAS. 
Days on treatment will be computed as the number of days that the study medication was taken 
(ie, treatment exposure excluding days when the study medication was interrupted). Number of 
days on treatment and number of days study medication was interrupted for will be summarized 
for the SAS.  


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 23 of 43 
11 EFFICACY PARAMETERS 
11.1 Primary Analysis  
The primary efficacy endpoint (percent CFBL to Week 12 in LDL-C) will be analyzed using 
ANCOVA and the FAS population. The null hypothesis to be tested is that there is no difference 
in the expected percent CFBL to Week 12 in LDL-C between the active treatment (subjects 
treated with gemcabene 600 mg) and placebo (subjects treated with placebo) groups after 
adjusting for baseline statin-intensity stratum, baseline diabetes status, and baseline LDL-C. 
Explicitly, in the ANCOVA, percent CFBL to Week 12 in LDL-C will be the dependent variable 
whereas randomized treatment group (gemcabene 600 mg or placebo), baseline statin-intensity 
stratum (moderate or high), and baseline diabetes status (yes or no) will be included as factors, 
and baseline LDL-C will be included as a covariate. LOCF will be used to impute missing values 
for Week 12; only post-baseline values will be used for imputation. The least-squares mean 
(LSM) and standard error (SE) for percent CFBL to Week 12 in LDL-C for each treatment group 
and the least-squares mean and 95% confidence interval (CI) of the treatment difference will be 
produced from the model using type III sums of squares to estimate the magnitude of the 
treatment effect. The following SAS code will be used to conduct the ANCOVA: 
proc glm data=data; 
    class Drug(ref=”Placebo”) Diabetes StatinStrat; 
    model pctCFBL = Drug Diabetes StatinStrat Base / solution; 
    lsmeans Drug / stderr pdiff out=adjmeans; 
run; 
The following additional analyses will be performed to assess assumptions of ANCOVA. The 
assumptions of normality and homoscedasticity (equal variance) will be assessed using residuals 
from the ANCOVA. Explicitly, normality will be assessed by visually inspecting 
quantile-quantile plots and conducting the Shapiro-Wilk test. If normality is clearly violated, 
ranked ANCOVA will be conducted. Further, Levene’s test will be conducted and residual plots 
will be visually assessed to determine if the assumption of homoscedasticity is met. Lastly, we 
will investigate the assumption of homogeneity of regression slopes across treatment groups 
(parallel slopes) by including the interaction between baseline LDL-C and treatment group in the 
model explicated previously. If results indicate that the interaction between baseline LDL-C and 
treatment group is not significant, we will assume that the assumption of parallel slopes is met. If 
the assumption of homoscedasticity or parallel slopes is clearly violated, the final model may be 
adjusted.  
Confirmatory analysis will be conducted by performing the primary analysis using the PPS 
population.  
11.2 Secondary Analysis 
All secondary analyses will be conducted using the FAS population (or the specific subgroup 
within the FAS population, eg, diabetic subjects) with subjects included in their randomized 
treatment group regardless of the treatment they actually received.  


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 24 of 43 
Similar analysis of ANCOVA as specified for the primary analysis in the above section will be 
conducted for the secondary efficacy endpoints. Note that the covariate included in the 
ANCOVA will be the baseline value of the parameter of interest (eg, if the parameter of interest 
is HDL-C, the covariate in the ANCOVA will be HDL-C at baseline). 
As previous research suggests that hsCRP and TG are non-normally distributed, 3, 4, 5, hsCRP and 
TG will be analyzed using ranked ANCOVA. 6 Results of parametric ANCOVA will also be 
provided for these parameters as supportive results. Ranked ANCOVA will be conducted by first 
ranking the outcome and covariate at a given timepoint (eg, Week 12) prior to conducting 
ANCOVA. The p-value corresponding to the difference in ranked outcome between treatment 
groups will be output, and results will be interpreted in the context of the median change from 
baseline for each treatment group. The SAS code for conducting ranked ANCOVA is provided 
below (this can be extended to percent change from baseline): 
proc rank data=data out=data_rank ties=mean;  
 
var base chg;  
 
ranks r_base r_chg;  
run; 
 
proc glm data=data_rank; 
 
class Drug(ref=”Placebo”) Diabetes StatinStrat; 
 
model r_chg = Drug Diabetes StatinStrat r_base / solution;   
 
lsmeans Drug / stderr pdiff cl out=adjmeans; 
quit; 
 
 The secondary efficacy endpoints that are binary will be analyzed using logistic regression. The 
output from each logistic regression model will include the odds ratio (OR), 95% CI, and the 
associated p-value. The SAS code for conducting a logistic regression model is provided below: 
 
proc logistic data=data; 
class Drug(ref=”Placebo”) Diabetes StatinStrat; 
model Outcome(event=”event”)= Drug Diabetes StatinStrat Base / expb; 
run; 
The secondary efficacy analyses are: 
• 
percent CFBL to Week 12 in LDL-C within each statin-intensity stratum (moderate, high); 
• 
CFBL to Weeks 2, 4, 8, and 12 in LDL-C; 
• 
percent CFBL to Weeks 2, 4, and 8 in LDL-C; 
• 
CFBL and percent CFBL to the average of Weeks 8 and 12 in LDL-C; 
• 
CFBL and percent CFBL to Weeks 2, 4, 8, and 12 in non-HDL-C, TC, TG, HDL-C, and 
VLDL-C; 
• 
percent of subjects achieving a LDL-C reduction of ≥ 10%, ≥ 15%, and ≥ 20% at Weeks 4, 8, 
and 12 (separately); 
• 
percent of subjects achieving a LDL-C value < 100 mg/dL (2.59 mmol/L) at Weeks 4, 8, and 
12 (separately); 


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CI


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 27 of 43 
12 SAFETY AND TOLERABILITY 
Safety will be assessed through analysis of AEs, clinical laboratory assessments, ECGs, vital 
signs, and physical examinations for the SAS using descriptive statistics. Observed case data will 
be used. Additionally, summaries of safety data will be displayed by treatment group. Treatment 
group will be based on the treatment each subject actually received regardless of the treatment 
group they were randomized to. All safety data will be presented in listings. 
12.1 Adverse Events 
AEs will be coded using MedDRA version 19.1. Except for the AE overview table and 
summaries of serious adverse events (SAEs) and AEs resulting in death (both of which will 
include all AEs), AE tables will only include summaries of treatment-emergent adverse events 
(TEAEs). A TEAE is defined as an AE with a start date on or after the first dose date and less 
than 30 days after the last dose date. If the AE start date is missing, the AE is assumed to be a 
TEAE. An AE overview table containing the frequency and percent of the following will be 
summarized by treatment group, treatment group within each stratum, and treatment group 
within each statin type (atorvastatin, rosuvastatin, simvastatin): 
• 
Number of subjects with at least one TEAE, drug-related TEAE, SAE, and drug-related SAE; 
• 
Number of subjects who discontinued study treatment due to a TEAE, drug-related TEAE, 
SAE, and drug-related SAE;  
• 
Number of subjects who had a study treatment interruption due to a TEAE; 
• 
Number of subjects who discontinued the study due to a TEAE; and  
• 
Number of deaths and deaths due to a drug-related TEAE.  
Additionally, the following will be summarized by treatment group, and treatment group within 
each stratum: 
• 
TEAEs by system organ class (SOC) and preferred term (PT); 
• 
TEAEs by PT (decreasing frequency in the gemcabene group); 
• 
TEAEs by SOC, PT, and maximum severity; 
• 
Related TEAEs by SOC and PT; 
• 
Related TEAEs by PT (decreasing frequency in the gemcabene group); 
• 
SAEs by SOC and PT; 
• 
Related SAEs by SOC and PT; 
• 
Discontinuation of study treatment due to TEAEs by SOC and PT; 
• 
Discontinuation of study treatment due to related TEAEs by SOC and PT; and 
• 
AEs that resulted in death by SOC and PT. 
Summaries of SOC and PT will be sorted alphabetically by SOC and by decreasing frequency of 
PT in the gemcabene group. 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 28 of 43 
If a subject has more than 1 TEAE at a given level (eg, SOC and PT), the subject will only be 
counted once within that level. When summarizing TEAEs by maximum severity or causality, at 
each level of summarization, subjects who report 1 or more TEAEs within that level are only 
counted once at that level using the event of greatest severity (in severity tables) or strongest 
relationship to study drug (in causality tables). All tables will show the number and percent of 
subjects with at least 1 TEAE (or SAE, per the criteria on the table). For example, the table of 
related SAEs will include a row for number and percent of subjects with at least one related 
SAE. Additionally, a drug-related TEAE is defined as a TEAE with an assigned relationship of 
“related.” A listing containing all AEs (pre-treatment and TEAEs) will be created; AEs that are 
not treatment-emergent will be flagged as non-treatment-emergent. Additionally, a listing 
containing AEs missing severity or relationship to the study drug will be provided; AEs that are 
not treatment-emergent will be flagged as non-treatment-emergent. 
12.2 Clinical Laboratory Assessments 
Standard clinical laboratory evaluations for safety chemistry, coagulation, and hematology will 
be conducted at all study visits and the Follow-up Visit (only for subjects who had an abnormal 
result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-related AE). Clinically 
significant abnormal creatinine results at Week 12 (or the ET Visit, if applicable) will also be 
followed-up 2 weeks (± 3 days) after the last dose of study drug in addition to the 4 week 
(± 3 days) Follow-up Visit.  
Additionally, a urine sample for urinalysis will be collected at the Pre-Screening Visit, if 
applicable, the Screening Visit, Day 1, Week 4, Week 8, Week 12, the Follow-up Visit (only for 
subjects who had an abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing 
treatment-related AE), and the ET Visit, if applicable. A urine microscopic examination will be 
performed when the dipstick result is abnormal (positive for blood, leukocyte esterase, or 
nitrites). Urine protein/creatinine ratio and albumin/creatinine ratio will be performed at the 
Screening Visit, Day 1, Week 4, Week 12, the Follow-up Visit (only for subjects who had an 
abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-related AE), 
and the ET Visit, if applicable. Urinary NGAL will be measured at Day 1, Week 4, Week 12, the 
Follow-up Visit (only for subjects who had an abnormal result at Week 12 [or the ET Visit, if 
applicable] or an ongoing treatment-related AE), and the ET Visit, if applicable. 
The following laboratory parameters will be summarized at baseline and at each post-baseline 
time point by treatment group. Additionally, CFBL to each time point (including end of 
treatment), if appropriate, for each of the following laboratory parameters will also be 
summarized by treatment group. If, for a given subject at a given visit, the absolute count of 
neutrophils are not provided but segmented and band neutrophils are, segmented and band 
neutrophils are summed to determine the absolute count of neutrophils. If only segmented 
neutrophils are provided, they are used as the absolute count of neutrophils. Similarly, if 
neutrophils/leukocytes are not provided at a given visit but neutrophils (segmented)/leukocytes 
are, neutrophils (segmented)/leukocytes are used as neutrophils/leukocytes. If a laboratory value 
is lower or higher than the detection limit, the value will not contribute to summary statistics but 
will be included in the listings.  


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 29 of 43 
• 
Chemistry: ALT, albumin, ALP, AST, bicarbonate, BUN, calcium, chloride, 
creatine kinase (CK), creatinine, gamma-glutamyl transferase (GGT), glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium, sodium, (total) bilirubin, (total) protein, 
estimated glomerular filtration rate (GFR) 
• 
Coagulation: prothrombin time, activated partial thromboplastin time, international 
normalized ratio 
• 
Hematology: hemoglobin, hematocrit, leukocytes, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, platelets, red blood cell count, mean corpuscular hemoglobin 
concentration, mean corpuscular hemoglobin, mean corpuscular volume 
• 
Urinalysis: pH, specific gravity, NGAL, creatinine, protein, protein/creatinine ratio, albumin, 
albumin/creatinine ratio 
Out-of-range values will be assessed using shift tables. Laboratory values will be identified as 
low, normal, or high based on the normal ranges provided by the central laboratory. Shift tables 
for each parameter will display, for each treatment group, the number of subjects with low, 
normal, and high values at baseline and end of treatment. Additionally, a summary will be 
provided of the number of subjects who shifted to high or low during the study. The 
denominators will be the number of subjects at risk for shifting, ie, the subjects at risk for 
shifting to low are those with high or normal values at baseline, and the subjects at risk for 
shifting to high are those with low or normal values at baseline.  
Potentially clinically significant (PCS) tables will also be used to summarize out-of-range values 
for safety laboratory parameters. The PCS values are found in Table 3. The number and percent 
of subjects meeting the criteria below for single occurrences and consecutive (multiple) 
occurrences will be summarized by treatment group. The number and percent of subjects 
meeting the criteria below for single occurrences will be repeated for each statin-intensity 
stratum. Summaries will be given for any time post-baseline. The denominator for a given 
percentage will be the number of subjects who had a post-baseline assessment for the 
corresponding parameter. Additionally, for subjects with at least 1 post-baseline laboratory value 
meeting the PCS criteria, all laboratory values will be provided in a listing.  
Table 3. Lab PCS Criteria 
Laboratory Parameter 
Unit 
PCS Criteria 
ALT 
U/L 
> 2 × ULN 
AST 
U/L 
> 2 × ULN 
BUN 
mg/dL 
> 2 × ULN 
Creatine kinase 
U/L 
> 3 × ULN 
Creatinine 
mg/dL 
> 0.3 increase from baseline 
Estimated GFR 
mL/min 
Decrease > 15 from baseline 
Hemoglobin 
g/dL 
Decrease > 1.5 from baseline 
Urinalysis Parameter 
Unit 
PCS Criteria 
Blood 
- 
present 
Protein (qualitative) 
- 
present 
Protein (quantitative) 
- 
> ULN 
Protein/creatinine ratio 
mg/mmol 
> ULN 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 30 of 43 
Albumin/creatinine ratio 
mg/mmol 
> ULN 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, GFR = glomerular 
filtration rate, PCS = potentially clinically significant, ULN = upper limit of normal. 
Urinalysis parameters that are not fully numeric (ie, blood, bilirubin, glucose, ketones, leukocyte 
esterase, protein [dipstick results], and nitrite) will be included in a listing.  
Over the course of the study, there may be lab tests performed that were not specified in the 
protocol. These tests will not be summarized but will be included in the listings and flagged as 
non-protocol tests. 
12.3 ECGs 
ECGs will be performed in triplicate at the Screening Visit, Day 1, Week 2, Week 4, Week 8, 
Week 12, and the ET Visit, if applicable. The following ECG parameters will be reported by the 
central reader: heart rate, PR interval, QRS duration, QT interval (uncorrected), QT interval 
corrected for heart rate using Bazett’s formula (QTcB) and using Fridericia’s formula (QTcF), 
and T-wave amplitude. The average of the 3 values for a given ECG parameter (eg, heart rate) 
will be used for analysis. In cases where an ECG is performed in duplicate, the average will be 
used, and in cases where only one ECG is performed, the result of the single ECG will be used. 
CFBL and percent CFBL will be calculated for each parameter at each time point (including end 
of treatment) and summarized by treatment group.  
Further, QTcB and QTcF will also be investigated through PCS tables (see Table 4 below for the 
criteria). The number and percent of subjects meeting the criteria below will be summarized by 
treatment group. Summaries will be given for both overall (ie, any time post-baseline) and by 
visit. Subjects will be included in all categories for which they qualify. For criteria on the 
“Actual” values, the denominator for the percentages is the number of subjects who had a 
post-baseline assessment for each parameter. For criteria on the change, the denominator is the 
number of subjects who had a baseline and post-baseline assessment. 
Table 4. ECG PCS Criteria 
ECG Parameter 
Actual or Change 
PCS Criteria 
QTcB (msec) 
Actual 
> 450 
Actual 
> 480 
Actual 
> 500 
CFBL (increase) 
> 30 
CFBL (increase) 
> 60 
QTcF (msec) 
Actual 
> 450 
Actual 
> 480 
Actual 
> 500 
CFBL (increase) 
> 30 
CFBL (increase) 
> 60 
CFBL = change from baseline, ECG = electrocardiogram, PCS = potentially clinically significant, QTcB = QT 
interval corrected for heart rate with Bazett’s formula, QTcF = QT interval corrected for heart rate with Fridericia’s 
formula. 
All interpretations along with the corresponding details will be provided in a listing. 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 31 of 43 
12.4 Vital Signs and Weight 
Vital signs comprise pulse rate, diastolic blood pressure (DBP), SBP, respiration rate, and 
temperature. Except for the Follow-up Visit, vital signs and weight will be measured at all study 
visits. CFBL and percent CFBL will be calculated for each vital sign and weight parameter at 
each time point (including end of treatment) and summarized by treatment group. Additionally, 
for DBP and SBP, the previous table will be presented by baseline hypertensive treatment status 
(yes or no) and treatment group. 
Vital signs and weight will also be presented in a listing. 
12.5 Physical Examinations 
A full physical examination will be performed at each subject’s first study visit (either at the 
Pre-Screening Visit or the Screening Visit) and last study visit (either at the Week 12 Visit or the 
ET Visit). At all other Study Visits (eg, Week 2) where a full physical examination was not 
conducted except the Follow-up Visit, a symptom-directed physical examination will be 
performed. Additionally, a symptom-directed physical examination will only be conducted at the 
Follow-up Visit for subjects who had an abnormal result at Week 12 (or the ET visit) or had an 
ongoing treatment-related AE. 
For each assessment (general appearance, respiratory, etc.), the number and percentage of normal 
and abnormal findings will be provided by actual treatment group and visit for the SAS. The 
denominator used to calculate the percentage will be the number of subjects that underwent a 
physical examination at the corresponding visit. 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 32 of 43 
13 OTHER RELEVANT DATA ANALYSES/SUMMARIES 
13.1 Medical History  
Medical history will be coded using MedDRA version 19.1. Medical history will be summarized 
by SOC and PT by actual treatment group for the SAS and will be presented in the listings. At 
each level of summarization, subjects who report one or more medical history events within a 
given level (SOC/PT) will only be counted once at that level. The table will be sorted by SOC 
(alphabetically) and then by PT (decreasing frequency in the gemcabene column within each 
SOC). 
13.2 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary version 01 Mar 2016. A prior medication is defined as a medication with a stop 
date prior to the date of the subject’s first dose (ie, medication stop date < date of first dose). A 
concomitant medication is defined as a medication with a start date on or before the date of the 
subject’s last dose (ie, medication start date ≤ date of last dose) and a stop date on or after the 
date of the subject’s first dose (ie, medication stop date ≥ date of first dose); thus, a medication 
that is ongoing at the time of the subject’s first dose is considered concomitant. Partial and 
missing dates will be imputed using rules in Appendix 2.  
Prior and concomitant medications will be summarized in separate tables and listings. 
Medications will be summarized by ATC level 3 (level 3 indicates the therapeutic/pharmacologic 
subgroup) alphabetically and preferred name (decreasing frequency in the Gemcabene column 
within each ATC) by actual treatment group for the SAS. At each level of summarization, 
subjects who report one or more medications within a given level (eg, ATC and preferred name) 
will only be counted once at that level. Excluded medications will be flagged in the concomitant 
medications listing.  
13.3 Concomitant Procedures 
Concomitant procedures will be recorded on the concomitant medications CRF. A concomitant 
procedure is defined as a procedure with a start date on or before the date of the subject’s last 
dose (ie, procedure start date ≤ date of last dose) and a stop date on or after the date of the 
subject’s first dose (ie, procedure stop date ≥ date of first dose). Concomitant procedures will be 
presented in a listing containing verbatim terms for the SAS. 
 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 July 2017 
 
 
 
Confidential 
Page 33 of 43 
14 REFERENCES 
1. D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General 
cardiovascular risk profile for use in primary care the Framingham Heart Study. Circulation. 
2008 Feb 12;117(6):743-53. 
2. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction 
of coronary heart disease using risk factor categories. Circulation. 
1998 May 1;97(18):1837-47. 
3. Stein E, Bays H, Koren M, Bakker-Arkema R, Bisgaier C. Efficacy and safety of gemcabene 
as add-on to stable statin therapy in hypercholesterolemic patients. Journal of Clinical 
Lipidology. 2016 Oct 31;10(5):1212-22. 
4. Meyer JM, Davis VG, McEvoy JP, Goff DC, Nasrallah HA, Davis SM, Daumit GL, Hsiao J, 
Swartz MS, Stroup TS, Lieberman JA. Impact of antipsychotic treatment on nonfasting 
triglycerides in the CATIE Schizophrenia Trial phase 1. Schizophrenia research. 2008 Aug 
31;103(1):104-9. 
5. Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in 
patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-
based therapy. Archives of Internal Medicine. 2008 Jul 28;168(14):1531-40. 
6. Conover WJ, Iman RL. Analysis of covariance using the rank transformation. Biometrics. 
1982 Sep 1:715-24. 


Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 Jul 2017 
 
 
 
Confidential 
Page 34 of 43 
15 APPENDICES 
Appendix 1. 
Schedule of Assessments and Procedures 
 
Pre-
Screening
a 
Screening
b 
Treatment Periodc 
Follow-
upd 
ET 
up to 
Day-14 
Day 1e 
Week 2 
(Day 15 ± 3 
days) 
Week 4 (Day 
29 ± 3 days) 
Week 8 
(Day 57 ± 3 
days) 
Week 12 (Day 
85, or up to 3 
days earlier) 
Day 113 ± 
3 days 
Visit S1 
Visit T1 
Visit T2 
Visit T3 
Visit T4 
Visit T5 
 
Informed consent 
X 
Xf 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical/surgical history and 
demographics 
X 
Xf 
 
 
 
 
 
 
 
Full physical examinationg 
X 
Xf 
 
 
 
 
X 
 
X 
Symptom-directed physical 
examination 
 
Xh 
X 
X 
X 
X 
 
Xi 
 
Vital signsj, heightk, and weight 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body Mass Index (BMI) 
X 
X 
 
 
 
 
 
 
 
Urinalysisl 
X 
X 
X 
 
X 
X 
X 
Xi 
X 
Serum/urine pregnancy testm 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety chemistry panel, 
coagulation, and hematologyn 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
TSH, HbA1c, and serologyo 
X 
Xf 
 
 
 
 
X 
 
X 
Fasting lipid panelp; LDL-C 
ultracentrifugation when 
necessary 
Xq 
X 
X 
X 
X 
X 
X 
 
X 
Fasting apolipoproteinsr 
 
 
X 
 
X 
X 
X 
 
X 
PCSK9  
 
 
X 
 
 
 
X 
 
X 
hsCRP, SAA, fibrinogen, and 
adiponectin 
 
 
X 
 
 
 
X 
 
X 
Fasting plasma glucose, insulin 
 
 
X 
 
 
 
X 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
Study drug administrations 
 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug and 
instructions 
 
 
X 
X 
X 
X 
 
 
 


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Pre-
Screening
a 
Screening
b 
Treatment Periodc 
Follow-
upd 
ET 
up to 
Day-14 
Day 1e 
Week 2 
(Day 15 ± 3 
days) 
Week 4 (Day 
29 ± 3 days) 
Week 8 
(Day 57 ± 3 
days) 
Week 12 (Day 
85, or up to 3 
days earlier) 
Day 113 ± 
3 days 
Visit S1 
Visit T1 
Visit T2 
Visit T3 
Visit T4 
Visit T5 
 
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Gemcabene 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan: GEM-301 
10 Jul 2017 
 
 
 
Confidential 
Page 36 of 43 
 
Pre-
Screening
a 
Screening
b 
Treatment Periodc 
Follow-
upd 
ET 
up to 
Day-14 
Day 1e 
Week 2 
(Day 15 ± 3 
days) 
Week 4 (Day 
29 ± 3 days) 
Week 8 
(Day 57 ± 3 
days) 
Week 12 (Day 
85, or up to 3 
days earlier) 
Day 113 ± 
3 days 
Visit S1 
Visit T1 
Visit T2 
Visit T3 
Visit T4 
Visit T5 
 
monitoring throughout the rest of the study. If an automated assessment is performed, the same machine should be used for the subject throughout the study when possible. 
Care should be taken to ensure an appropriate cuff size is utilized. 
k 
Height will be measured only at the subject’s first study visit, either at the Pre-Screening Visit or the Screening Visit. 
l 
A urine microscopic examination will be performed when the dipstick result is abnormal (positive for blood, leukocyte esterase, or nitrites). Urine protein:creatinine ratio 
(albumin:creatinine) will be performed at the Screening Visit, Day 1, Week 4, Week 12, the Follow-up Visit (only for subjects who had an abnormal result at Week 12 [or the 
ET Visit, if applicable] or an ongoing treatment-related adverse event), and the ET Visit, if applicable. Urinary NGAL will be measured at Day 1, Week 4, Week 12, the 
Follow-up Visit (only for subjects who had an abnormal result at Week 12 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event), and the ET Visit, if 
applicable. 
m 
For women of child-bearing potential only, a serum pregnancy test will be conducted at the Screening Visit, Week 12, and the ET Visit, if applicable. A urine pregnancy test 
will be conducted at the Pre-Screening Visit, Day 1, Week 2, Week 4, and Week 8.  
n 
Clinically significant abnormal creatinine results at Week 12 (or the ET Visit, if applicable) will also be followed-up 2 weeks (± 3 days) after the last dose of study drug in 
addition to the Week 4 (± 3 days) Follow-up Visit. See Appendix B in the protocol for a list of analytes and description of when repeat or reflexive testing will be required.  
o 
Thyroid-stimulating hormone, HbA1c, and serology (HBV, HCV, and HIV) will be measured at the subject’s first study visit, either at the Pre-Screening Visit, if applicable, 
or the Screening Visit. Only HbA1c will be measured at Week 12, and the ET Visit, if applicable.  
p 
Includes LDL-C, non-HDL-C, TC, TG, HDL-C, and VLDL-C. Fasting will be defined as no food or caloric beverage for at least 10 hours prior to sample collection. Subjects 
will be permitted to have water.  
q 
Includes LDL-C and TG only. Fasting will be defined as no food or caloric beverage for at least 10 hours prior to sample collection. Subjects will be permitted to have water. 
r 
Includes ApoB, ApoA-I, ApoA-II, ApoA-V, ApoC-II, ApoC-III, ApoE, and Lp(a). Fasting will be defined as no food or caloric beverage for at least 10 hours prior to sample 
collection. Subjects will be permitted to have water.  
s 
Study drug will be administered at the site on Day 1. Subjects will self-dose at all other times during the Treatment Period.  
t 
Subjects will be counseled on a low-fat, low-cholesterol diet (NCEP ATP-III guidelines or equivalent). 
u 
Subjects should be lying quietly in a fully supine position for at least 10 minutes prior to each 12-lead ECG. 
v 
Serious adverse events that occur prior to the first dose of study drug (Day 1) should be reported as an update to medical history as well as be reported on the appropriate 
adverse event eCRF. 


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Appendix 2. 
Prior and Concomitant Medications and Smoking Status 
Date Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date  
D only 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
M and D 
Y same as Y of first dose of study drug 
Date of first dose of study drug 
Y not same as Y of first dose of study 
drug 
Use Jan 01 of Y 
M, D, and Y 
None - date completely missing 
Day prior to date of first dose 
of study drug 
Stop date  
D only 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study drug 
M and/or Y not same as date of last 
dose of study drug 
Last day of month 
M and D 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study 
drug 
Use Dec 31 of Y 
M, D, and Y 
None - date completely missing and 
NOT ongoing 
Date of last dose of study drug 
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date 
month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
 


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Appendix 3. 
ATC Categories and Descriptions of Hypertensive 
Treatments 
The WHO Drug Dictionary version 01 Mar 2016 was used to identify the following ATC 
categories and descriptions which will be used to identify hypertensive treatment.  
ATC2/ATC2 Description1 
ATC3/ATC3 Description 
ATC4/ATC4 Description 
C02/ANTIHYPERTENSIVES 
C02A/ ANTIADRENERGIC AGENTS, 
CENTRALLY ACTING 
C02AA/ Rauwolfia alkaloids 
C02/ANTIHYPERTENSIVES 
C02A/ ANTIADRENERGIC AGENTS, 
CENTRALLY ACTING 
C02AB/Methyldopa 
C02/ANTIHYPERTENSIVES 
C02A/ ANTIADRENERGIC AGENTS, 
CENTRALLY ACTING 
C02AC/Imidazoline receptor 
agonists 
C02/ANTIHYPERTENSIVES 
C02B/ANTIADRENERGIC AGENTS, 
GANGLION-BLOCKING 
C02BA/Sulfonium derivatives 
C02/ANTIHYPERTENSIVES 
C02B/ANTIADRENERGIC AGENTS, 
GANGLION-BLOCKING 
C02BB/Secondary and tertiary 
amines 
C02/ANTIHYPERTENSIVES 
C02B/ANTIADRENERGIC AGENTS, 
GANGLION-BLOCKING 
C02BC/Bisquaternary ammonium 
compounds 
C02/ANTIHYPERTENSIVES 
C02C/ANTIADRENERGIC AGENTS, 
PERIPHERALLY ACTING 
C02CA/Alpha-adrenoreceptor 
antagonists 
C02/ANTIHYPERTENSIVES 
C02C/ANTIADRENERGIC AGENTS, 
PERIPHERALLY ACTING 
C02CC/Guanidine derivatives 
C02/ANTIHYPERTENSIVES 
C02D/ARTERIOLAR SMOOTH 
MUSCLE, AGENTS ACTING ON 
C02DA/Thiazide derivatives 
C02/ANTIHYPERTENSIVES 
C02D/ARTERIOLAR SMOOTH 
MUSCLE, AGENTS ACTING ON 
C02DB/Hydrazinophthalazine 
derivatives 
C02/ANTIHYPERTENSIVES 
C02D/ARTERIOLAR SMOOTH 
MUSCLE, AGENTS ACTING ON 
C02DC/Pyrimidine derivatives 
C02/ANTIHYPERTENSIVES 
C02D/ARTERIOLAR SMOOTH 
MUSCLE, AGENTS ACTING ON 
C02DD/Nitroferricyanide 
derivatives 
C02/ANTIHYPERTENSIVES 
C02D/ARTERIOLAR SMOOTH 
MUSCLE, AGENTS ACTING ON 
C02DG/Guanidine derivatives 
C02/ANTIHYPERTENSIVES 
C02K/OTHER ANTIHYPERTENSIVES 
C02KA/Alkaloids, excl. 
rauwolfia 
C02/ANTIHYPERTENSIVES 
C02K/OTHER ANTIHYPERTENSIVES 
C02KB/Tyrosine hydroxylase 
inhibitors 
C02/ANTIHYPERTENSIVES 
C02K/OTHER ANTIHYPERTENSIVES 
C02KC/MAO inhibitors 
C02/ANTIHYPERTENSIVES 
C02K/OTHER ANTIHYPERTENSIVES 
C02KD/Serotonin antagonists 
C02/ANTIHYPERTENSIVES 
C02K/OTHER ANTIHYPERTENSIVES 
C02KW/Herbal 
antihypertensives, other 
C02/ANTIHYPERTENSIVES 
C02K/OTHER ANTIHYPERTENSIVES 
C02KX/Antihypertensives for 
pulmonary arterial hypertension 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LA/Rauwolfia alkaloids and 
diuretics in combination 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LB/Methyldopa and diuretics 
in combination 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LC/Imidazoline receptor 
agonists in combination with 
diuretics 


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C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LE/Alpha-adrenoreceptor 
antagonists and diuretics 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LF/Guanidine derivatives and 
diuretics 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LG/Hydrazinophthalazine 
derivatives and diuretics 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LK/Alkaloids, excl. 
rauwolfia, in combination with 
diuretics 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LL/MAO inhibitors and 
diuretics 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LN/Serotonin antagonists and 
diuretics 
C02/ANTIHYPERTENSIVES 
C02L/ANTIHYPERTENSIVES AND 
DIURETICS IN COMBINATION 
C02LX/Other antihypertensives 
and diuretics 
C02/ANTIHYPERTENSIVES 
C02N/COMBINATIONS OF 
ANTIHYPERTENSIVES IN ATC-GR. 
C02 
- 
C03/DIURETICS 
C03A/LOW-CEILING DIURETICS, 
THIAZIDES 
C03AA/Thiazides, plain 
C03/DIURETICS 
C03A/LOW-CEILING DIURETICS, 
THIAZIDES 
C03AB/Thiazides and potassium 
in combination 
C03/DIURETICS 
C03A/LOW-CEILING DIURETICS, 
THIAZIDES 
C03AH/Thiazides, combinations 
with psycholeptics and/or 
analgesics 
C03/DIURETICS 
C03A/LOW-CEILING DIURETICS, 
THIAZIDES 
C03AX/Thiazides, combinations 
with other drugs 
C03/DIURETICS 
C03B/LOW-CEILING DIURETICS, 
EXCL. THIAZIDES 
C03BA/Sulfonamides, plain 
C03/DIURETICS 
C03B/LOW-CEILING DIURETICS, 
EXCL. THIAZIDES 
C03BB/Sulfonamides and 
potassium in combination 
C03/DIURETICS 
C03B/LOW-CEILING DIURETICS, 
EXCL. THIAZIDES 
C03BC/Mercurial diuretics 
C03/DIURETICS 
C03B/LOW-CEILING DIURETICS, 
EXCL. THIAZIDES 
C03BD/Xanthine derivatives 
C03/DIURETICS 
C03B/LOW-CEILING DIURETICS, 
EXCL. THIAZIDES 
C03BK/Sulfonamides, 
combinations with other drugs 
C03/DIURETICS 
C03B/LOW-CEILING DIURETICS, 
EXCL. THIAZIDES 
C03BX/Other low-ceiling 
diuretics 
C03/DIURETICS 
C03C/HIGH-CEILING DIURETICS 
C03CA/Sulfonamides, plain 
C03/DIURETICS 
C03C/HIGH-CEILING DIURETICS 
C03CB/Sulfonamides and 
potassium in combination 
C03/DIURETICS 
C03C/HIGH-CEILING DIURETICS 
C03CC/Aryloxyacetic acid 
derivatives 
C03/DIURETICS 
C03C/HIGH-CEILING DIURETICS 
C03CD/Pyrazolone derivatives 
C03/DIURETICS 
C03C/HIGH-CEILING DIURETICS 
C03CX/Other high-ceiling 
diuretics 
C03/DIURETICS 
C03D/POTASSIUM-SPARING 
AGENTS 
C03DA/Aldosterone antagonists 
C03/DIURETICS 
C03D/POTASSIUM-SPARING 
AGENTS 
C03DB/Other potassium-sparing 
agents 


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C03/DIURETICS 
C03E/DIURETICS AND POTASSIUM-
SPARING AGENTS IN 
COMBINATION 
C03EA/Low-ceiling diuretics and 
potassium-sparing agents 
C03/DIURETICS 
C03E/DIURETICS AND POTASSIUM-
SPARING AGENTS IN 
COMBINATION 
C03EB/High-ceiling diuretics and 
potassium-sparing agents 
C03/DIURETICS 
C03X/OTHER DIURETICS 
C03XA/Vasopressin antagonists 
C03/DIURETICS 
C03X/OTHER DIURETICS 
C03XW/Herbal diuretics, other 
C07/BETA BLOCKING 
AGENTS 
C07A/BETA BLOCKING AGENTS 
C07AA/Beta blocking agents, 
non-selective 
C07/BETA BLOCKING 
AGENTS 
C07A/BETA BLOCKING AGENTS 
C07AB/Beta blocking agents, 
selective 
C07/BETA BLOCKING 
AGENTS 
C07A/BETA BLOCKING AGENTS 
C07AG/Alpha and beta blocking 
agents 
C07/BETA BLOCKING 
AGENTS 
C07B/BETA BLOCKING AGENTS 
AND THIAZIDES 
C07BA/Beta blocking agents, 
non-selective, and thiazides 
C07/BETA BLOCKING 
AGENTS 
C07B/BETA BLOCKING AGENTS 
AND THIAZIDES 
C07BB/Beta blocking agents, 
selective, and thiazides 
C07/BETA BLOCKING 
AGENTS 
C07B/BETA BLOCKING AGENTS 
AND THIAZIDES 
C07BG/Alpha and beta blocking 
agents and thiazides 
C07/BETA BLOCKING 
AGENTS 
C07C/BETA BLOCKING AGENTS 
AND OTHER DIURETICS 
C07CA/Beta blocking agents, 
non-selective, and other diuretics 
C07/BETA BLOCKING 
AGENTS 
C07C/BETA BLOCKING AGENTS 
AND OTHER DIURETICS 
C07CB/Beta blocking agents, 
selective, and other diuretics 
C07/BETA BLOCKING 
AGENTS 
C07C/BETA BLOCKING AGENTS 
AND OTHER DIURETICS 
C07CG/Alpha and beta blocking 
agents and other diuretics 
C07/BETA BLOCKING 
AGENTS 
C07D/BETA BLOCKING AGENTS, 
THIAZIDES AND OTHER 
DIURETICS 
C07DA/Beta blocking agents, 
non-selective, thiazides and other 
diuretics 
C07/BETA BLOCKING 
AGENTS 
C07D/BETA BLOCKING AGENTS, 
THIAZIDES AND OTHER 
DIURETICS 
C07DB/Beta blocking agents, 
selective, thiazides and other 
diuretics 
C07/BETA BLOCKING 
AGENTS 
C07E/BETA BLOCKING AGENTS 
AND VASODILATORS 
C07EA/Beta blocking agents, 
non-selective, and vasodilators 
C07/BETA BLOCKING 
AGENTS 
C07E/BETA BLOCKING AGENTS 
AND VASODILATORS 
C07EB/Beta blocking agents, 
selective, and vasodilators 
C07/BETA BLOCKING 
AGENTS 
C07F/BETA BLOCKING AGENTS 
AND OTHER ANTIHYPERTENSIVES 
C07FA/Beta blocking agents, 
non-selective, and other 
antihypertensives 
C07/BETA BLOCKING 
AGENTS 
C07F/BETA BLOCKING AGENTS 
AND OTHER ANTIHYPERTENSIVES 
C07FB/Beta blocking agents, 
selective, and other 
antihypertensives 
C08/CALCIUM CHANNEL 
BLOCKERS 
C08C/SELECTIVE CALCIUM 
CHANNEL BLOCKERS WITH 
MAINLY VASCULAR EFFECTS 
C08CA/Dihydropyridine 
derivatives 
C08/CALCIUM CHANNEL 
BLOCKERS 
C08C/SELECTIVE CALCIUM 
CHANNEL BLOCKERS WITH 
MAINLY VASCULAR EFFECTS 
C08CX/Other selective calcium 
channel blockers with mainly 
vascular effects 
C08/CALCIUM CHANNEL 
BLOCKERS 
C08D/SELECTIVE CALCIUM 
CHANNEL BLOCKERS WITH 
DIRECT CARDIAC EFFECTS 
C08DA/Phenylalkylamine 
derivatives 


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C08/CALCIUM CHANNEL 
BLOCKERS 
C08D/SELECTIVE CALCIUM 
CHANNEL BLOCKERS WITH 
DIRECT CARDIAC EFFECTS 
C08DB/Benzothiazepine 
derivatives 
C08/CALCIUM CHANNEL 
BLOCKERS 
C08E/NON-SELECTIVE CALCIUM 
CHANNEL BLOCKERS 
C08EA/Phenylalkylamine 
derivatives 
C08/CALCIUM CHANNEL 
BLOCKERS 
C08E/NON-SELECTIVE CALCIUM 
CHANNEL BLOCKERS 
C08EX/Other non-selective 
calcium channel blockers 
C08/CALCIUM CHANNEL 
BLOCKERS 
C08G/CALCIUM CHANNEL 
BLOCKERS AND DIURETICS 
C08GA/Calcium channel 
blockers and diuretics 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09A/ACE INHIBITORS, PLAIN 
C09AA/ACE inhibitors, plain 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09B/ACE INHIBITORS, 
COMBINATIONS 
C09BA/ACE inhibitors and 
diuretics 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09B/ACE INHIBITORS, 
COMBINATIONS 
C09BB/ACE inhibitors and 
calcium channel blockers 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09B/ACE INHIBITORS, 
COMBINATIONS 
C09BX/ACE inhibitors, other 
combinations 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09C/ANGIOTENSIN II 
ANTAGONISTS, PLAIN 
C09CA/Angiotensin II 
antagonists, plain 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09D/ANGIOTENSIN II 
ANTAGONISTS, COMBINATIONS 
C09DA/Angiotensin II 
antagonists and diuretics 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09D/ANGIOTENSIN II 
ANTAGONISTS, COMBINATIONS 
C09DB/Angiotensin II 
antagonists and calcium channel 
blockers 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09D/ANGIOTENSIN II 
ANTAGONISTS, COMBINATIONS 
C09DX/Angiotensin II 
antagonists, other combinations 
C09/AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN 
SYSTEM 
C09X/OTHER AGENTS ACTING ON 
THE RENIN-ANGIOTENSIN SYSTEM 
C09XA/Renin-inhibitors 
ATC = anatomical therapeutic chemical, MAO = monoamine oxidase, ACE = angiotensin-converting enzyme 
1 
All medications listed have ATC1/ATC1 Description=C/CARDIOVASCULAR SYSTEM. 
 
 
 


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Appendix 4. 
Sex-specific Framingham Risk Score algorithms 
Framingham Risk Score (10-year CVD risk) for each subject is based on sex-specific Cox 
proportional hazard models. 1 Explicitly, the algorithm to compute Framingham Risk Score 
for each subject is:  
݌Ƹ ൌͳ െܵ଴ሺݐሻୣ୶୮ሺσ
ఉ೔௑೔ିσ
ఉ೔௑ത೔
೛
೔సభ
ሻ
೛
೔సభ
, 
 
where ܵ଴ሺݐሻ is baseline survival at follow-up time ݐ (10 years), ߚ௜ is the estimated regression 
coefficient (log hazard ratio), ܺ௜ is the log-transformed value of the i-th risk factor if 
continuous, ܺത௜ is the corresponding mean, and ݌ denotes the number of risk factors. For 
women, baseline 10-year survival is 0.95012. For men, the baseline 10-year survival is 
0.88936.  
 
 
 


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Appendix 5. 
Manuscript Analyses 
The following additional analyses will be performed for possible inclusion in a manuscript 
using the FAS. These results will not be included in the CSR. For analyses within a given 
baseline statin-intensity stratum, baseline statin-intensity stratum will not be included in the 
model (where appropriate).  
• 
In addition to percent CFBL to Week 12 in LDL-C, all other secondary efficacy analyses 
will be conducted within each baseline statin-intensity stratum.