A 12-Week, Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy Safety and Tolerability of Gemcabene in Subjects With Severe Hypertriglyceridemia (INDIGO-1)
Phase: PHASE2
Conditions: Severe Hypertriglyceridemia, Mixed Dyslipidaemia
Sponsor: NeuroBo Pharmaceuticals Inc.

Title: A 12-Week, Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy Safety and Tolerability of Gemcabene in Subjects with Severe Hypertriglyceridemia (INDIGO-
1) 
 
NCT ID: NCT02944383 
 
Approval Date: 17-Mar-2017 

 
CLINICAL STUDY PROTOCOL 
 
A 12-Week, Phase 2 Randomized, Double-Blind, Placebo-Controlled 
Study to Assess the Efficacy Safety and Tolerability of Gemcabene 
in Subjects with Severe Hypertriglyceridemia (INDIGO-1) 
 
 
Investigational Product: Gemcabene calcium tablets (gemcabene) 
Protocol Number: GEM-401 
 
 
Sponsor: 
Gemphire Therapeutics Inc.  
17199 N. Laurel Park Drive, Suite 401 
Livonia, MI 48152 
United States 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
 
 
Version Number: 1.0; September 26, 2016 
Amendment #1; Version Number: 2.0; November 11, 2016 
Amendment #2; Version Number: 3.0; December 22, 2016 
Amendment #3; Version Number: 4.0; March 17, 2017  
 
 
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. 
Page 230 of 307

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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
3 
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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Version 4.0, 17 March 2017 
5 
Period, while on a self-reported stable, heart-healthy diet. 
STUDY DESIGN: 
Pre-Screening (Wash-Out Period): A Wash-Out Period will be required for potential subjects 
taking any lipid-regulating therapies or supplements, with the exception of statins 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 anywhere from 4 to 8 weeks prior to the Screening Visit (S1, Week -4) 
based on the type of lipid-regulating therapy and its associated duration of wash-out required.  
Subjects currently taking lipid-altering medications such as: niacin > 200 mg/day, fibrates, 
prescription or over-the-counter fish oil or other products containing omega-3 fatty acids (OMG-
3), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants, or 
other herbal products or dietary supplements with potential lipid-altering effects, must be able to 
safely discontinue therapy at the Pre-Screening Visit. 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, OMG-3 compounds, bile acid sequestrants or other lipid-regulating 
therapies will require a 4-week Wash-Out Period prior to the Screening Visit.  If the subject 
needs to be washed off more than one lipid-altering medication; the medication that requires the 
longest Wash-Out Period will be the default.  For example, if a subject is taking OMG-3 and 
fibrates, then the subject would undergo a six-week Was-Out Period.  Exception: if a potential 
subject is statin-naïve, or dosing only on a statin or ezetimibe (for at least 12 weeks) and not 
currently dosing on other lipid-altering medications, there is no requirement for a Pre-Screening 
Visit. 
The Wash-Out Period will only be initiated after inclusionary lab values are received and 
reviewed.  During this Wash-Out Period, potential subjects will be counseled on the importance 
of maintaining a heart-healthy diet and limiting alcohol intake. 
Screening Period: This is the TG qualifying period. All potential subjects will participate in the 
Screening Period, including Screening Visit 1 (S1), Screening Visit 2 (S2) and, if necessary as 
outlined below, optional Screening Visit 3 (S3) up to 28 days prior to Study Day 1 (Visit T1). 
For potential subjects on stable statin and/or ezetimibe therapy for ≥ 12 weeks and who do not 
require a Wash-Out Period, S1 will be their first study visit.  For other subjects who have been 
washing out their other lipid medications, S1 occurs after the full required washout has been 
completed. 
During this Screening Period, potential subjects must meet the TG qualifying values to be 
eligible for randomization on Day 1 (Visit T1). 
The screening visits can be completed up to 28 days but not less than 14 days prior to T1 (Day 
1).  The visits are provided with recommended timepoints; however the minimum time between 
visits can be as short as 1 week with the Screening Period as short as 14 days for qualification 
with S1 and S2 visits or 21 days for qualification with S2 and S3. At the end of this 2-4-week 
diet and lifestyle stabilization and TG qualifying period, eligible subjects must have an average 
fasting TG level ≥ 500 mg/dL to < 1500 mg/dL to qualify for randomization into the 12-week 
double-blind treatment period. The TG level for qualification will be based on the average 
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
6 
(arithmetic mean) of the Visit S1 and Visit S2 values. If a subject's average TG level from Visit 
S1 and Visit S2 falls outside the required range for entry into the study, one additional sample 
for fasting TG value can be collected 1 week later (at the Optional Visit S3), and the arithmetic 
mean from Visits S2 and S3 will then be used to determine eligibility.   
Double-Blind Treatment Period: After confirmation of qualifying fasting TG values and all 
other inclusion and exclusion criteria, eligible subjects will be randomized and enter a 12-week, 
double-blind treatment period. At Visit T1, 90 eligible subjects will be randomized via an 
interactive web/voice response system (IWRS/IVRS) on Study Day 1 in a 1:1:1 ratio (30 
subjects per group) to one of the following treatment groups:  
• Gemcabene 300 mg QD, or 
• Gemcabene 600 mg QD, or  
• Placebo 
Subjects will be stratified by baseline statin therapy (yes or no) and qualifying TG value (< 880 
mg/dL or ≥ 880 mg/dL) to ensure background therapies and baseline TG values are balanced 
across all treatment groups.   
The primary evaluation of efficacy will be at End of Study (EOS) (using the average of Week 10 
[T4] and Week 12 [T5]).  The Follow-up Visit (telephone call) will occur 4 weeks (± 3 days) 
after the last dose of study drug. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Study drug will be double-blinded and prepared in bottles with 30 days of dosing contained 
within each bottle.  The subjects will be asked to take one tablet from each of the 2 bottles for a 
total of 2 tablets per day as outlined below: 
• 300 mg: 30 gemcabene tablets in one bottle + 30 matching placebo tablet in a second bottle  
• 600 mg: 2 bottles each containing 30 300 mg gemcabene tablets 
• Placebo: 2 bottles each containing 30 placebo tablets.  
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 
(approximately 8 ounces) of water either with or without food. 
STATISTICAL ANALYSIS: 
Sample Size 
Approximately 90 subjects (30 subjects per treatment group) will be randomized into 1 of 3 
treatment groups: gemcabene 300 mg, gemcabene 600 mg or placebo. 
A sample size of 30 randomized subjects in the gemcabene 300 mg group, 30 randomized 
subjects in the 600 mg group and 30 randomized subjects in the placebo group is expected to 
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7 
provide 80% power to detect a difference of 35% in the percent change in TG from baseline to 
End of Study (EOS) between either of the gemcabene treatment groups and the placebo group. 
This calculation is based on a 2-sided t-test at the 5% level of significance (α = 0.05), a common 
standard deviation of 43, and a drop-out rate of 15%.   
Subject Populations 
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. The 
FAS population will be the primary analysis population. All efficacy analyses will be performed 
on the FAS population. 
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 
receive at least 1 dose of study drug. All safety analyses will be conducted on SAS. 
EFFICACY ENDPOINTS AND ANALYSIS: 
Primary Efficacy 
The primary efficacy endpoint is the percent change in fasting serum TG from baseline to EOS. 
Baseline will be defined as the average of the (Screening Visits [S1 and S2] or [S2 and S3] 
occurring up to 28 days prior to Study Day 1) and Study Day 1 [pre-dose]) values.  EOS will be 
defined as the average of Week 10 and Week 12.  If either the Week 10 or Week 12 value is 
missing, then the single value (Week 10 or Week 12) will be used.  Completely missing values 
(both Week 10 and Week 12) will be imputed using last observation carried forward (LOCF), 
with the last on-treatment value carried forward as the EOS value.    
The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA) with 
percent change from baseline to EOS in TG as the dependent variable; treatment and baseline 
statin (yes or no) as factors; and baseline fasting serum TG as a covariate. The ANCOVA will be 
performed using the FAS, with subjects included in their randomized treatment group regardless 
of the treatment they actually received.  The least-squares mean (LSM) and standard error (SE) 
will be provided for each treatment group, along with the placebo-corrected LSM, its 95% 
confidence interval (CI), and associated p-value for both gemcabene groups.  A 2-sided test with 
a significance level of 0.05 will be used for the comparison of the gemcabene 300 mg and 600 
mg groups separately 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 Efficacy 
Secondary efficacy endpoints include: 
• Change and percent change from baseline to Weeks 2, 6, 10 and 12 in fasting serum TG, and 
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Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
8 
change from baseline to EOS in fasting serum TG;  
• Change and percent change from baseline to Weeks 2, 6, 10, 12 and EOS in total cholesterol 
(TC), non-HDL-C, HDL-C, and VLDL-C;  
• Change and percent change from baseline to Weeks 10, 12 and EOS in Apo B, ApoA-I, 
ApoA-II, ApoA-V, ApoC-II, ApoC-III, and ApoE;  
• Change and percent change from baseline to Weeks 10, 12 and EOS in LDL-C 
(ultracentrifugation), LDL-TG, VLDL-TG, HDL-TG;  
• Change and percent change from baseline to Week 12 in lipoprotein size and particle number 
(NMR);  
• Change and percent change from baseline to Week 12 in hsCRP, IL-6, SAA, ANGPTL4, 
adiponectin and fibrinogen; and  
• Percent of subjects achieving a TG value < 500 mg/dL (5.65 mmol/L) at EOS.   
For continuous secondary efficacy endpoints, the same ANCOVA model outlined above for the 
primary efficacy endpoint will be used, with the respective baseline included as the covariate. 
Baseline for TC, non-HDL-C, HDL-C, and VLDL-C will be defined as the average of the last 
two pre-dose values (generally will be the average of Visit S2 and pre-dose Study Day 1/Visit 
T1).  Baseline for fasting apolipoproteins, LDL-C (ultracentrifugation), LDL-TG, VLDL-TG, 
HDL-TG, hsCRP, IL-6, SAA, adiponectin, fibrinogen, and ANGPTL4 is defined as the value 
from pre-dose Study Day 1/Visit T1.  For the EOS time point, EOS will be defined as the 
average of Week 10 and Week 12.  If either the Week 10 or Week 12 value is missing, then the 
single value (Week 10 or Week 12) will be used.  Completely missing values (both Week 10 and 
Week 12) will be imputed using LOCF, with the last on-treatment value carried forward as the 
EOS value.  For all other time points, missing values will be imputed using LOCF, with the last 
on-treatment value carried forward to that time point. 
Each ANCOVA will be performed using the FAS, with subjects included in their randomized 
treatment group regardless of the treatment they actually received.  The output from each 
ANCOVA will include the LSM and SE for each treatment group, along with the placebo-
corrected LSM, its 95% confidence interval (CI) and associated p-value for both gemcabene 
groups.  For every continuous endpoint (each parameter, each time point), 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.   
The percent of subjects achieving a TG value < 500 mg/dL (5.65 mmol/L) will be analyzed 
using a logistic regression with treatment, baseline statin use (yes or no) and baseline TG value 
as independent factors.  The percent of subjects in each treatment group achieving a TG value < 
500 mg/dL, and the odds ratios with 95% confidence intervals and p-values will be presented to 
compare gemcabene 300 mg and gemcabene 600 mg separately with the placebo group.   
The secondary efficacy analyses will be repeated using the PPS. 
Exploratory Efficacy 
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
10 
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 will be summarized by treatment group at baseline, and at each post-
baseline time point, if applicable, and change from baseline to End of Treatment (Week 12) or 
the ET Visit, if applicable. Baseline for safety laboratory data will be defined as the last pre-dose 
value (pre-dose Study Day 1/Visit T1 or prior).  Frequency counts of new or worsening 
abnormalities will also be provided. 
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 value (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 40-50 sites in the United States and Canada.  
SPONSOR: 
Gemphire Therapeutics Inc.  
17199 N. Laurel Park Drive, Suite 401 
Livonia, MI 48152 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
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Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
11 
TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
SYNOPSIS ...................................................................................................................................... 4 
TABLE OF CONTENTS .............................................................................................................. 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 16 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 18 
1.1 
Background ................................................................................................................. 18 
1.2 
Dose Selection ............................................................................................................ 18 
1.3 
Population Overview and Rationale ........................................................................... 21 
1.4 
Risk/Benefit ................................................................................................................ 22 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 24 
2.1 
Objectives ................................................................................................................... 24 
2.1.1 Primary Objective ................................................................................................. 24 
2.1.2 Secondary Objectives............................................................................................ 24 
2.1.3 Exploratory Objectives ......................................................................................... 24 
2.2 
Endpoints .................................................................................................................... 24 
2.2.1 Primary Endpoint .................................................................................................. 24 
2.2.2 Secondary Efficacy Endpoints .............................................................................. 24 
2.2.3 Exploratory Endpoints .......................................................................................... 25 
2.2.4 Secondary Safety Endpoints ................................................................................. 25 
3 
STUDY DESCRIPTION .................................................................................................. 26 
3.1 
Summary of Study Design .......................................................................................... 26 
3.2 
Study Indication(s) ...................................................................................................... 27 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................... 28 
4.1 
Inclusion Criteria ........................................................................................................ 28 
4.2 
Exclusion Criteria ....................................................................................................... 28 
4.3 
Withdrawal Criteria .................................................................................................... 30 
5 
STUDY TREATMENTS .................................................................................................. 32 
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5.1 
Treatment Groups ....................................................................................................... 32 
5.2 
Dose Rationale ............................................................................................................ 32 
5.3 
Randomization and Blinding ...................................................................................... 32 
5.4 
Breaking the Blind ...................................................................................................... 32 
5.5 
Drug Supplies.............................................................................................................. 33 
5.5.1 Study Drug Identification ..................................................................................... 33 
5.5.2 Formulation and Packaging .................................................................................. 33 
5.5.3 Study Drug Preparation and Dispensing ............................................................... 34 
5.5.4 Study Drug Administration ................................................................................... 34 
5.5.5 Treatment Compliance .......................................................................................... 34 
5.5.6 Storage and Accountability ................................................................................... 34 
5.6 
Prior and Concomitant Medications and/or Procedures ............................................. 35 
5.6.1 Permitted Medications and/or Procedures ............................................................ 35 
5.6.2 Excluded Medications and/or Procedures ............................................................. 35 
5.6.3 Restrictions and Dietary Guidelines ..................................................................... 35 
5.6.4 Documentation of Prior and Concomitant Medication Use .................................. 36 
6 
STUDY PROCEDURES .................................................................................................. 37 
6.1 
Informed Consent........................................................................................................ 37 
6.2 
Pre-Screening Visit ..................................................................................................... 37 
6.3 
Screening Visits .......................................................................................................... 38 
6.3.1 Screening Visit 1 (up to Day -28/Week -4) .......................................................... 38 
6.3.2 Screening Visit 2 (up to Day -14/Week -2) .......................................................... 39 
6.3.3 Optional Screening Visit 3 (up to Day -7/Week -1) ............................................. 40 
6.4 
Treatment Period (Visit T1 through Visit T5) ............................................................ 40 
6.4.1 Visit T1 (Study Day 1) .......................................................................................... 40 
6.4.2 Visit T2 (Week 2) ................................................................................................. 41 
6.4.3 Visit T3 (Week 6) ................................................................................................. 42 
6.4.4 Visit T4 (Week 10) ............................................................................................... 42 
6.4.5 Visit T5 (Week 12) ............................................................................................... 43 
6.5 
Follow-up Visit (Week 16) ......................................................................................... 44 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................. 44 
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7 
EFFICACY ASSESSMENTS .......................................................................................... 46 
8 
SAFETY ASSESSMENTS ............................................................................................... 47 
8.1 
Adverse Events ........................................................................................................... 47 
8.1.1 Adverse (Drug) Reaction ...................................................................................... 48 
8.1.2 Unexpected Adverse Drug Reaction ..................................................................... 48 
8.1.3 Assessment of Adverse Events by the Investigator .............................................. 48 
8.1.4 Specific Safety Measures ...................................................................................... 50 
8.1.4.1 
Hemoglobin decrease ...................................................................................... 50 
8.1.4.2 
Creatinine increase .......................................................................................... 50 
8.1.4.3 
Possible muscle and liver injury ...................................................................... 50 
8.1.4.4 
Increased risk for pancreatitis (TG ≥ 2000 mg/dL) ......................................... 50 
8.2 
Serious Adverse Events .............................................................................................. 50 
8.3 
Serious Adverse Event Reporting ............................................................................... 51 
8.4 
Pregnancy Reporting ................................................................................................... 52 
8.5 
Expedited Reporting ................................................................................................... 52 
8.6 
Clinical Laboratory Evaluations ................................................................................. 53 
8.7 
Vital Signs ................................................................................................................... 54 
8.8 
Electrocardiograms ..................................................................................................... 54 
8.9 
Physical Examinations ................................................................................................ 54 
8.10 
Medical/Surgical History and Demographics ............................................................. 55 
8.11 
Reserve Samples and Pharmacokinetics (PK) ............................................................ 55 
8.12 
Diary ........................................................................................................................... 55 
9 
STATISTICS .................................................................................................................... 57 
9.1 
Sample Size ................................................................................................................. 57 
9.2 
Analysis Populations ................................................................................................... 57 
9.2.1 Full Analysis Set ................................................................................................... 57 
9.2.2 Per Protocol Set..................................................................................................... 57 
9.2.3 Safety Analysis Set ............................................................................................... 57 
9.3 
Statistical Methods ...................................................................................................... 57 
9.3.1 Analysis of Efficacy .............................................................................................. 57 
9.3.1.1 
Primary efficacy analyses ................................................................................ 57 
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9.3.2 Analysis of Safety ................................................................................................. 60 
10 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 61 
10.1 
Data Management ....................................................................................................... 61 
10.1.1 Data Handling ....................................................................................................... 61 
10.1.2 Computer Systems ................................................................................................ 61 
10.1.3 Data Entry ............................................................................................................. 61 
10.1.4 Medical Information Coding................................................................................. 61 
10.1.5 Data Validation ..................................................................................................... 61 
10.2 
Record Keeping .......................................................................................................... 62 
11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 63 
11.1 
Ethical Conduct of the Study ...................................................................................... 63 
11.2 
Institutional Review Board/Ethics Committee ........................................................... 63 
11.3 
Informed Consent........................................................................................................ 63 
11.4 
Study Monitoring Requirements ................................................................................. 64 
11.5 
Disclosure of Data....................................................................................................... 64 
11.6 
Retention of Records................................................................................................... 64 
11.7 
Publication Policy ....................................................................................................... 65 
11.8 
Financial Disclosure.................................................................................................... 65 
11.9 
Insurance and Indemnity ............................................................................................. 65 
11.10 Legal Aspects .............................................................................................................. 65 
11.11 Definition of End of Study .......................................................................................... 65 
11.12 Sponsor Discontinuation Criteria ................................................................................ 65 
12 
STUDY ADMINISTRATIVE INFORMATION ............................................................. 67 
12.1 
Protocol Amendments ................................................................................................. 67 
12.2 
Address List ................................................................................................................ 67 
12.2.1 Sponsor ................................................................................................................. 67 
12.2.2 Contract Research Organization ........................................................................... 67 
12.2.3 Biological Specimens............................................................................................ 67 
13 
REFERENCES ................................................................................................................. 68 
APPENDIX A: SCHEDULE OF PROCEDURES ....................................................................... 69 
APPENDIX B: CLINICAL LABORATORY ANALYTES ........................................................ 73 
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APPENDIX C: NEW YORK HEART ASSOCIATION CONGESTIVE HEART FAILURE 
CLASSIFICATION .......................................................................................................... 75 
APPENDIX D: REFERENCE LIST OF CYTOCHROME P450 3A4 INHIBITOR 
EXCLUSIONARY MEDICATIONS ............................................................................... 76 
APPENDIX E: MUSCLE INJURY AND HEPATIC MONITORING ....................................... 77 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance model 
ANGPTL4 
Angiopoietin like 4 
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 
EOS 
End of study 
ET 
Early Termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
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 
hsCRP 
High-sensitivity C-reactive protein 
IL-6 
Interleukin 6 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
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Abbreviation 
Definition 
IWRS/IVRS 
Interactive web/voice response system 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein(a) 
LPL 
LSM 
MedDRA 
Lipoprotein lipase 
Least squares mean 
Medical Dictionary for Regulatory Affairs 
Lp-PLA2 
Lipoprotein-associated phospholipase A2 
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 
OMG-3 
Omega-3 fatty acids 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetics 
PPS 
Per protocol set 
QD 
Once daily 
RLP-C 
Remnant lipoprotein cholesterol 
RLP-TG 
Remnant lipoprotein triglycerides 
RLP-ApoB 
Remnant lipoprotein apolipoprotein B 
SAA 
Serum amyloid A 
SAE 
SE 
Serious adverse event 
Standard error 
SHTG 
SOP 
Severe hypertriglyceridemia  
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 has a dual mechanism of action that 
involves: (1) enhancing the clearance of very-low density lipoprotein (VLDL); and (2) blocking 
the overall production of hepatic triglyceride (TG) and cholesterol synthesis.  
Gemcabene enhances the clearance of VLDL by decreasing the production of messenger RNA 
(mRNA) of the APOC3gene, thereby decreasing the production of the apolipoprotein C-III 
(apoC-III) protein.1 This in turn unmasks ApoE which (1) enhances the clearance of the VLDL 
remnants via ApoE remnant receptors; (2) reduces the formation of low-density lipoprotein 
(LDL) particles; and (3) enhances lipoprotein lipase mediated TG lipolysis allowing increased 
delivery of fatty acids to muscle and adipose tissue.  
Gemcabene may also block the overall production of hepatic TG and cholesterol. Given its 
structural similarities to long-chain fatty acid, gemcabene may act as an inhibitor of acetyl CoA-
carboxylase (ACC), subsequently leading to a decrease in hepatic TG production.2 Gemcabene 
may also inhibit one or more enzymes in the cholesterol synthesis pathway leading to less 
cholesterol in the cell, thereby upregulating LDL receptors in the liver. 
In inflammatory states, cytokines, such as interleukin-6 (IL-6) and interleukin 1-beta (IL1-b), 
activate nuclear hormone receptors (NHRs), such as C/EPB-b, C/EPB-d and nuclear factor kappa 
B (NF-kB), and lead them to bind to the C-reactive protein (CRP) promoter and increase CRP 
mRNA production. Based on preclinical studies, gemcabene may inhibit the interaction of these 
NHRs on the CRP promoter and therefore reduce CRP mRNA production.3  
Taken together, gemcabene’s mechanism of action should lower the full range of atherogenic 
particles (VLDL, IDL, and LDL) resulting in decreases in atherogenic particle number (apoB), 
particle cholesterol (non-HDL-C) and TG (when elevated); with concomitant lowering of 
hsCRP.  
Gemcabene calcium rapidly converts to gemcabene free acid when in contact with the gastric 
fluid.  Gemcabene is rapidly absorbed following oral administration. It distributes to the liver 
where it has its effect as the active molecule, with exposure increasing approximately linearly 
with dose. Steady state concentrations are achieved within six days of repeated dose 
administration, with an average half-life from 32 to 41 hours. Gemcabene's primary route of 
metabolism and elimination is renal, predominantly as a gemcabene glucuronide formed in the 
kidney. 
1.2 
Dose Selection  
We conducted (1) a prospective analysis in a gemcabene monotherapy study (1027-04) in 
subjects with mild-moderate hypertriglyceridemia (baseline TG ≥ 200 mg/dL); (2) a 
retrospective integrated analysis  of Phase 2 dyslipidemic studies that included subjects with 
baseline TG ≥ 200 mg/dL administered gemcabene monotherapy (1027-04, 1027-14 [healthy, 
obese subjects], and 4141001 [monotherapy arm of a study in hyperlipidemia subjects +/- 
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atorvastatin]); and (3) a retrospective integrated analysis of Phase 2 dyslipidemic studies that 
included subjects with baseline TGs ≥ 200 mg/dL administered gemcabene in combination with 
statin therapy (1027-18 and 4141001 [atorvastatin combination arms]) to determine the doses of 
gemcabene with the greatest TG lowering and the most favorable effects on LDL-C to test 
further in Phase 2 to support Phase 3.  Gemcabene 300 mg and the 600 mg were selected for 
following reasons: 
• The 300 mg once daily (QD) dose is optimal based on the highest level of TG reduction in 
the gemcabene monotherapy analyses and dose response curve data from studies that assess 
gemcabene over across the full dose range;   
• Gemcabene has a U-shaped TG dose response curve in hypertriglyceridemia subjects and 
including 600 mg along with 300 mg may further elucidate the mechanism; 
• Gemcabene 600 mg is the proposed dose for the treatment of hypercholesterolemia and as 
such its effects in severe hypertriglyceridemia are being evaluated; 
• Although TG lowering is mitigated at gemcabene 600 mg in hypertriglyceridemia subjects, 
LDL-C is significantly lowered at the 600 mg dose by a median % change of 17% (p = 
0.026), unlike an increase of 8% (p = 0.076) at the 300 mg dose;   
• Decreases in ApoB were observed across all doses.  
Study 1027-04 
In a pre-specified analysis in subjects with baseline TG ≥ 200 mg/dL (Study 1027-04) 
gemcabene lowered TG by a median % change at 12 weeks of 27% (p value for treatment 
difference < 0.05), 39% (p value for treatment difference < 0.01), 13% (p value for treatment 
difference = 0.623), and 9% (p value for treatment difference = 0.952) at the 150 mg, 300 mg, 
600 mg, and 900 mg doses, respectively, compared to a 5% lowering for placebo. The dose 
response curve was U-shaped with the maximum effect at 300 mg. There was a correlative 
decrease in ApoC-III of 24% (p < 0.05) and 31% (p < 0.01) at the 150 mg and 300 mg doses, 
respectively.  There was also a statistically significant lowering of ApoE by 37% (p < 0.01) at 
300 mg.   
Similar to OMG-3 compounds and fibrates, gemcabene increases LDL-C in subjects with 
isolated hypertriglyceridemia when TG levels are lowered. LDL-C elevation may be observed 
when triglyceride-rich VLDL lipolysis is facilitated as LDL are the metabolic product of VLDL 
catabolism.4 In study 1027-04, non-significant increases in LDL-C of 16% and 8% at 150 mg 
and 300 mg and significant lowering in LDL-C of 17% (p value for treatment difference = 0.026) 
and 23% (p value for treatment difference < 0.001) at gemcabene 600 mg and 900 mg, 
respectively; compared to an increase of 0.4% on placebo were observed.  It is hypothesized that 
in this population gemcabene is facilitating the formation of larger less atherogenic LDL 
particles, supported by a lowering of ApoB across all doses. 
Retrospective Integrated Analysis of Gemcabene Monotherapy 
A retrospective integrated analysis of  the effect of gemcabene monotherapy on TG in subjects 
with baseline TG ≥  200 mg/dL included studies 1027-04 (low HDL), 1027-14 (healthy obese) 
and 4141001 (hypercholesterolemic). 
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Gemcabene monotherapy subjects with baseline TG ≥ 200 mg/dL had a difference median % 
lowering in TG of 25% (p value for treatment difference = 0.0192) and 32% (p value for 
treatment difference = 0.0051) for gemcabene 150 mg (n = 22) and 300 mg (n = 27), 
respectively, compared to a lowering of 3% for placebo (n = 31).   No significant differences 
were observed in TG levels at the 600 mg or 900 mg doses versus placebo.   
A further sub-cut of subjects with baseline TG ≥ 400 mg/dL yielded enough subjects to perform 
an analysis in subjects similar to those at risk for pancreatitis and representative of subjects to be 
enrolled in GEM-401. In this integrated analysis, subjects with TG ≥ 400 mg/dL on gemcabene 
300 mg (n = 8) lowered TG by in median % change of 55% (p value for treatment difference = 
0.0228), compared to a lowering of 20% for placebo (n = 6).  Clinically significant, statistically 
non-significant TG lowering was observed for the gemacbene 150 mg and 600 mg.  Clinically 
non-significant, statistically non-significant TG lowering was observed for gemcabene 900 mg.  
Retrospective Integrated Analysis of Gemcabene Combined with Statin Therapy 
The effect of gemcabene as add-on or combination to statin therapy was also analyzed (1027-18; 
4141001 [atorvastain combination arms]) in subjects with baseline TG ≥ 200 mg/dL. Gemcabene 
had a median % lowering in TG similar to monotherapy: 38% (p value for treatment difference = 
0.0067) for gemcabene 300 mg + statin (n = 23), compared to a lowering of 19% with statin 
alone (n = 26).  There were no subjects in the dataset with baseline TG ≥ 400 mg/dL.  
Dose Response Curve over Full Dose Range 
In ONLY those studies that assessed gemcabene over its full dose range (1027-04 and 
A4141001), consistent TG dose effects were observed across all sub-cuts of baseline TG, with 
peak lowering at the gemcabene 300 mg dose.   
 
In hypertrigyceridemic subjects, monotherapy gemcabene produces a U-shaped TG-lowering 
curve over its dose range.  In subjects with baseline TGs ≥ 500 mg/dL gemcabene 300 mg lowers 
TG 50-60%.  The effect on TG is less at doses lower and higher than 300 mg, approximately 
30% with gemcabene 600 mg and 5% with gemcabene 900 mg.  Importantly, beneficial effect on 
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TG are still observed at the 600 mg dose in all hypertriglyceridemic populations. This waning in 
TG effect at the higher doses may be explained by the shift in the balance between the ApoE and 
ApoC proteins.  TG–rich particles are cleared through remnant receptors which is mediated by a 
balance between the levels of ApoE and the ApoC proteins on the particle.  ApoE facilitates 
clearance, while the apo C’s inhibit clearance.  High level of ApoC-I, Apo C-II or ApoC-III 
appear to mask apo E, preventing it from recognizing /interacting with the remnant receptor, 
while allowing the particle to undergo lipolysis in the circulation. However, too much ApoC-III 
prevents intravascular lipolysis by inhibiting lipoprotein lipase (LPL) and too little ApoC-II 
prevents adequate activation of LPL.  Therefore, an optimal balance of ApoC-II to ApoC-III, and 
between ApoE and the ApoC proteins are needed to be achieve optimal lipolysis of the TG-rich 
particle and clearance of its remnant.5-8   Preclinical data shows gemcabene lowers both ApoC-II 
and apo C-III, supporting enhanced ApoC-II reduction in humans at the higher gemcabene dose 
(600 and 900 mg), which results in a reduction of optimal TG clearance via inhibition of LPL 
activation.1   The gemcabene 600 mg dose in the current study will enhance the understanding of 
the effects of gemcabene on ApoC-II and ApoC-III and ultimately TGs.  
1.3 
Population Overview and Rationale  
Hypertriglyceridemia is a common condition present in about a third of the population. It is well 
established that severe HTG, defined as TG levels ≥ 500 mg/dL (≥ 5.65 mmol/L) can 
significantly increases the risk of acute pancreatitis, and controlling TG levels to well below 500 
mg/dL can effectively prevent the risk of its recurrence. 9, 10, 11   
In subjects with severe or very severe hypertriglyceridemia, fibrates, omega-3 fatty acids (OMG-
3) and occasionally niacin are first-line therapy.  
Niacin lowers TG and increases HDL-C levels in subjects with TG > 500 mg/dL.  At doses of 
500 to 2000 mg/day, niacin lowers TG by 10–30%, increases HDL-C by 10–40%, and lowers 
LDL-C by 5–20%.12,13 Increased risk of flushing, diarrhea, nausea, vomiting, cough, and pruritus 
with niacin has tended to limit its use in general practice. Moreover, when co-administered with 
lovastatin or simvastatin, the risk of rhabdomyolysis and abnormal liver function is increased, 
particularly in the elderly and in subjects with diabetes, chronic kidney disease, or uncontrolled 
hypothyroidism.14  
Fibrates decrease TG levels by 30–50% and sometimes increase HDL-C levels in subjects with 
TG > 500 mg/dL.15 In subjects with high TG levels, LDL-C levels may increase during therapy, 
likely due to an increased conversion of VLDL to LDL. Side effects associated with fibrates may 
include elevated liver enzymes, increased creatinine kinase (CK). Fibrates are contraindicated in 
subjects with liver and gall bladder disease and should be used with caution in renal 
insufficiency. Gemfibrozil (unlike fenofibrate) inhibits multiple glucuronosyltransferases, which 
can lead to reduced statin excretion and increased risk for myopathy and rhabdomyolysis.15  
Omega-3 compounds are used in the treatment of subjects with TG > 500 mg/dL.  To achieve a 
TG reduction of 20–50%, administration of 3–4 g/d of EPA plus DHA given in multiple capsules 
is required.12 As with fibrates, with the reductions of TG levels there can be increased levels of 
LDL-C. Most common side effects include fishy taste and burping with no increased in adverse 
effects reported for statin and OMG-3 co-administration.16 
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Background statin therapy is increasingly common in subjects with moderate to severe 
hypertriglyceridemia due to increased cardiovascular risk in subjects with moderate 
hypertriglyceridemia and has become standard of care in diabetic subjects across all severities of 
hypertriglyceridemia.  Therefore, a robust safety profile for TG-lowering compounds in 
combination with statins for these subjects is a necessity.12   However, current lipid lowering 
agents are not ideal due to their limited TG-lowering effects and the potential for safety and 
tolerance issues, specifically in combination with statins. 
Gemcabene has shown TG lowering from 20 to > 50% based on dose and severity of 
hypertriglyceridemia. To date, gemcabene has been shown to be generally well tolerated in 
combination with statins, with no drug interaction identified with either high-intensity 
simvastatin or atorvastatin.  The current study assesses the efficacy and safety of gemcabene 300 
mg and 600 mg in subjects with moderate to severe hypertriglyceridemia (TG ≥ 500 mg/dL to < 
1500 mg/dL) who may or may not be receiving background statin therapy (± ezetimibe 10 mg) 
and who may or may not have Type 2 diabetes, a population representative of those 
hypertriglyceridemic subjects at risk for pancreatitis.    
1.4 
Risk/Benefit 
The clinical program conducted to date has demonstrated that gemcabene is generally 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 QD. This includes 
837 subjects who received multiple doses of up to 900 mg for up to 12 weeks.  This also includes 
292 subjects (150 subjects on high-intensity) on gemcabene in combination with a statin.   Safety 
of these subjects was evaluated by adverse event monitoring, clinical laboratory assessments, 
electrocardiograms (ECGs), physical examinations, and vital sign assessments. 
No significant 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 subjects (1%) 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) 
slightly decreased 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 
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to baseline within approximately 2 weeks of cessation of gemcabene, suggesting a vascular 
effect and not renal injury.  
Based on data in 94 hypertriglyceridemic subjects (TG ≥ 200 mg/dL) in the 1027-04 protocol, 
the 300 mg dose of gemcabene showed the greatest TG effect (median percent change of -38.9% 
[p<0.001]). The current study (GEM-401) will assess the efficacy, safety and tolerability of 
gemcabene 300 mg and 600 mg in subjects with SHTG (TG ≥ 500 to < 1500 mg/dL) either on 
background statin therapy or statin naive with or without ezetimibe.   
 
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Version 4.0, 17 March 2017 
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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 2, randomized, double-blind, parallel-group, multi-center study. Subjects may 
enter the study with or without stable statin therapy, with or without ezetimibe (10 mg QD), and 
with or without diabetes, for at least 4 weeks prior to the Screening Visit.  Approximately 90 
subjects with severe hypertriglyceridemia (TG ≥ 500 mg/dL to < 1500 mg/dL) will be enrolled 
into the study. 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), up to 3 Screening Visits (to stabilize diet and lifestyle and determine TG levels), a 
12-week Treatment Period (with 5 Visits), and a Follow-up Visit (4 weeks after the last dose).  
Pre-Screening (Wash-Out Period): A Wash-Out Period will be required for potential subjects 
taking any lipid-regulating therapies or supplements, with the exception of statins or ezetimibe 
10 mg QD. Subjects may initiate the Wash-Out Period, if meeting all other criteria and have a 
qualifying fasting TG value of ≥ 350 mg/dL. For subjects requiring a Wash-Out Period, the Pre-
Screening Visit will be their first study visit and will occur anywhere from 4 to 8 weeks prior to 
the Screening Visit (S1, Week -4to -2) based on the type of lipid-regulating therapy and its 
associated duration of wash-out required.  
Subjects currently taking lipid-altering medications such as: niacin > 200 mg/day, fibrates, 
prescription or over-the-counter fish oil or other products containing omega-3 fatty acids (OMG-
3), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants, or 
other herbal products or dietary supplements with potential lipid-altering effects, must be able to 
safely discontinue therapy at the Pre-Screening Visit. 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, OMG-3 compounds, bile acid sequestrants or other lipid-regulating 
therapies will require a 4-week Wash-Out Period prior to the Screening Visit.  If the subject 
needs to be washed off more than one lipid-altering medication; the medication that requires the 
longest Wash-Out Period will be the default.  For example, if a subject is taking OMG-3 and 
fibrates, then the subject would undergo a six-week Wash-Out Period. Exception: if a potential 
subject is statin-naïve, or dosing only on a statin or ezetimibe (for at least 12 weeks) and not 
currently dosing on other lipid-altering medications, there is no requirement for a Pre-Screening 
Visit. 
During this Wash-Out Period, potential subjects will be counseled on the importance of 
maintaining a heart-healthy diet and limiting alcohol intake.  
Screening Period: This is the TG qualifying period. All potential subjects will participate in the 
Screening Period, including Screening Visit 1 (S1), Screening Visit 2 (S2) and, if necessary as 
outlined below, optional Screening Visit 3 (S3) up to 28 days prior to Study Day 1 (Visit T1). 
For potential subjects on stable statin therapy and/or ezetimibe for ≥12 weeks and who do not 
require a Wash-Out Period, S1 will be their first study visit.  For other subjects who have been 
washing out their other lipid medications, S1 occurs after the full required washout has been 
completed. 
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During this Screening Period, potential subjects must meet the TG qualifying values in order to 
be eligible for randomization on Day 1 (Visit T1). 
The screening visits can be completed up to 28 days but not less than 14 days prior to T1 (Day 
1).  The visits are provided with recommended timepoints; however, the minimum time between 
visits can be as short as 1 week with the Screening Period as short as 14 days for qualification 
with S1 and S2 visits or 21 days for qualification with S2 and S3. At the end of this 2-4-week 
diet and lifestyle stabilization and TG qualifying period, eligible subjects must have an average 
fasting TG level ≥ 500 mg/dL to < 1500 mg/dL in order to qualify for the 12-week double-blind 
treatment period. The TG level for qualification will be based on the average (arithmetic mean) 
of the Visit S1 and Visit S2 values. If a subject's average TG level from Visit S1 and Visit S2 
falls outside the required range for entry into the study, one additional sample for fasting TG 
value can be collected 1 week later (at the Optional Visit S3), and the arithmetic mean from 
Visits S2 and S3 will then be used to determine eligibility.   
Double-Blind Treatment Period: After confirmation of qualifying fasting TG values and all 
other inclusion and exclusion criteria, eligible subjects will be randomized and enter a 12-week, 
double-blind treatment period. At Visit T1, 90 eligible subjects will be randomized via an 
interactive web/voice response system (IWRS/IVRS) on Study Day 1 in a 1:1:1 ratio (30 subjects 
per group) to one of the following treatment groups:  
• Gemcabene 300 mg QD, or  
• Gemcabene 600 mg QD, or 
• Placebo 
Subjects will be stratified by statin therapy (yes or no) and qualifying TG value (< 880 mg/dL or 
≥ 880 mg/dL) to ensure background therapies and baseline TG values are balanced across all 
treatment groups.   
The primary evaluation of efficacy will be at EOS (using the average of Week 10 [T4] and Week 
12 [T5]).  The Follow-up Visit (telephone call) will occur 4 weeks (± 3 days) after the last dose 
of study drug. 
3.2 
Study Indication(s) 
Treatment with gemcabene is indicated as an adjunct to diet to reduce serum triglyceride (TG) 
levels in adult patients with severe hypertriglyceridemia (≥ 500 mg/dL); where lowering TG 
levels below 500 mg/dL may decrease a patient’s risk for developing pancreatitis. 
 
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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 ≥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 and may not 
donate sperm throughout the duration of the study and for 8 days after the last dose of 
study drug. 
3. Currently on a self-reported, stable, low-fat, low-cholesterol diet and if on a stable dose of 
statins and/or ezetimibe (10 mg), statins and ezetimibe must be started at least 12 weeks prior 
to the Screening Visit;  
4. Mean fasting TG value ≥ 500 mg/dL to < 1500 mg/dL (with the higher value no more than 
50% greater than the lower value) from the S1 and S2 Visits (or alternatively S2 and S3); 
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; and 
7. Subjects with Type 2 diabetes who take anti-diabetes pharmacologic therapy 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. 
Subjects may re-screen once if they were previously excluded from the study based on criteria 
that has now been altered by Amendment #3.   
1. Known and previously documented homozygous genetic deficiencies (LPL, ApoC-II, ApoC-
III, ApoA-V, GPIHBP1, or LMF1);  
2. History of pancreatitis within the last 6 months prior to screening (Visit S1);  
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3. History of bariatric surgery; symptomatic gallstone disease, unless treated with 
cholecystectomy; 
4. Abnormal liver function test at the Pre-Screening Visit or any of the Screening Visits 
(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; 
5. Creatine kinase (CK) at the Pre-Screening Visit or any of the Screening Visits > 3 × ULN 
and/or unexplained muscle pain, tenderness or weakness; 
6. 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;  
7. Moderate to severe renal insufficiency defined as an estimated GFR < 60 mL/min/1.73 m2 
(calculated using The Chronic Kidney Disease Epidemiology Collaboration equation) at the 
Pre-Screening Visit or at any of the Screening Visits;  
8. Abnormal urinalysis (defined as proteinuria ≥ 1+ or any male or non-menstruating female 
with ≥ 1+ hematuria), with a confirmatory abnormal urine protein:creatinine ratio  (e.g., ≥ 1+ 
proteinurea or hematuria without confirmation by abnormal protein:creatinine ratio will not 
be an exclusion);  
9. 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; 
10. Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus HbA1c value > 9.5% based 
on results from the Pre-Screening Visit or the Screening Visit), or any diabetic subject taking 
a thiazolidinedione (e.g., pioglitazone, rosiglitazone);   
11. New York Heart Association Class III or IV heart failure (see Appendix C);  
12. 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 (S1). Subjects with adequately treated stable angina, per 
Investigator assessment, may be included; 
13. Uncontrolled cardiac arrhythmia or prolonged QT on the Screening Visit or Study 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; 
14. Uncontrolled hypertension, defined as sitting systolic blood pressure > 180 mmHg or 
diastolic blood pressure > 110 mmHg, and confirmed by repeat measurement; 
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15. Currently receiving cancer treatment(s) or, in the Investigator’s opinion, at risk of relapse for 
recent cancer; 
16. Inadequate washout of a PCSK9 inhibitor (8 weeks prior to the Screening Visit S1), a fibrate 
lipid lowering agent (6 weeks prior to the Screening Visit S1), niacin > 200 mg/day, OMG-3, 
bile acid sequestrants or other lipid lowering therapies (4 weeks prior to the Screening Visit 
S1); 
17. Use of any excluded medications or supplements within 3 months prior to S1 (e.g., follow 
label restrictions for any concomitant medications including statins, see Appendix D for a 
reference list of cytochrome P450 [CYP] 3A4 inhibitors);  
18. Hypersensitivity to or a history of significant adverse reactions to any fibrate lipid regulating 
agent; 
19. History of drug or alcohol abuse within the past year or inability to comply with protocol 
requirements, including subject alcohol restrictions (see Section 5.6.3); 
20. Previously treated with gemcabene (i.e., 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 
21. 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 (ie, alert TG value ≥ 2000 mg/dL; 
8.1.4.4) 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 a 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 any regulatory authority(ies). 
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). When a subject withdraws due to a SAE, the SAE must be 
reported in accordance with the reporting requirements as defined. 
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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 15% 
dropout rate in the study.  
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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Ninety subjects will be randomized on Study Day 1 in a 1:1:1 ratio to the following treatment 
groups: placebo or gemcabene 300 mg or gemcabene 600 mg. Subjects may be on a stable statin 
regimen as appropriate, with or without ezetimibe 10 mg QD for at least 12 weeks prior to the 
Screening Visit. Subjects will be stratified by baseline statin therapy (yes or no) and qualifying 
TG value (< 880 mg/dL or ≥ 880 mg/dL).  
5.2 
Dose Rationale 
Based on a prospective analysis in a gemcabene monotherapy study (1027-04) in subjects with 
mild-moderate hypertriglyceridemia (TG ≥ 200 mg/dL) and a retrospective integrated analysis of 
all studies (1027-04, 1027-14 [healthy, obese subjects], and 4141001 [hyperlipidemia subjects 
+/- atorvastatin]) that tested gemcabene monotherapy in subjects with mild to severe 
hypertriglyceridemia, we conclude that the 300 mg QD dose is optimal based on monotherapy 
data.  The 600 mg dose will also be included in the GEM-401 protocol for the following reasons: 
gemcabene 600 mg is the proposed dose for the treatment of hypercholesterolemia and as such 
its effects in severe hypertriglyceridemia need to be understood; gemcabene has a U-shaped TG 
dose response curve in Type IV subjects and further study with gemcabene 600 mg may further 
elucidate the mechanism; although TG lowering is mitigated at gemcabene 600 mg in 
hypertriglyceridemia subjects, LDL-C is significantly lowered at the 600 mg dose by a median % 
change of 17% (p = 0.026), unlike an increase of 8% (p = 0.076) at the 300 mg dose.  Non-
significant decreases in ApoB were observed at all doses. Therefore, we propose including the 
300 mg and 600 mg dose in our Phase 2 study to assess efficacy, safety and tolerability in severe 
hypertriglyceridemia (TG ≥ 500 mg/dL to < 1500 mg/dL) prior to Phase 3.  
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 Study 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.  
5.4 
Breaking the Blind 
Blinding is not to be broken during the study unless considered necessary by the Investigator for 
emergency situations for reasons of subject safety. The Investigator should contact the Medical 
Monitor who will break the blind in a qualifying event. When the blind is broken, the reason 
must be fully documented.  
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Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
34 
5.5.3 
Study Drug Preparation and Dispensing 
Study drug will be administered at the site on clinic visit days. Subjects will receive a study drug 
kit comprised of two bottles, labeled Bottle A and Bottle B. Subjects must take one tablet from 
each bottle every day. In no case should the subject take two tablets from the same bottle on a 
given day.  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 prior to 6:00 PM, 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. 
5.5.6 
Storage and Accountability 
The study drug will be stored at controlled room temperature (15 to 30°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. 
The drug accountability logs will be signed by the individual who dispenses the study drug and 
copies will be provided to the Sponsor.  
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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, heart-healthy diet.  Randomized subjects should remain 
on previously prescribed background stable statins or ezetimibe 10 mg QD for the duration of the 
study, if started at least 12 weeks prior to the Screening visit. Subjects with Type 2 diabetes who 
receive pharmacologic treatment must be on a stable regimen for 3 months prior to signing 
informed consent at the Screening Visit (S2).  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 and OMG-3 compounds (4 weeks prior to the Screening Visit).  If subjects have a 
confirmed TG alert value of > 2000 mg/dL they should follow the steps in Section 8.1.4.4 which 
may require the subject to stop study treatment and begin TG-lowering rescue medication 
including OMG-3 compounds and/or fibrates. Subjects are not permitted the use of tamoxifen, 
estrogens or progestins that have not been stable for > 4 weeks prior to the Screening Visit (S1), 
nor the use of oral or injected corticosteroids or anabolic steroids. 
Subjects are instructed to follow the package label for all concomitant medications, including 
statins. See Appendix D for a reference 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 blood testing.  
Subjects are restricted from using alcohol within 48 hours prior to study visits. Subjects must not 
drink more than 2 units of alcohol per day.  A unit of alcohol is defined as a 12 ounces (350 ml) 
of beer, 5 ounces (150 ml) of wine, or 1.5 ounces (45) ml of 80-proof alcohol for mixed drinks; 
All clinic visit assessments require subjects to fast.  This is defined as no food or caloric 
beverages for at least 10 hours prior to sample collection. Subjects will be permitted to have 
water, black tea or black coffee.   
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.  
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Subjects will maintain a stable, heart-healthy diet (counselled per NCEP ATP-III guidelines or 
equivalent) throughout the study. 
5.6.4 
Documentation of Prior/Concomitant Medication Use and Procedures 
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. 
Concomitant Procedures are procedures (i.e. tooth extraction, CT scan), and NOT the clinically 
relevant diagnosis that precipitated the procedure. 
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. Concomitant procedures will be documented on 
the Concomitant Medication CRF and the reason for the procedure (i.e. diagnosis) will be 
documented on the Medical History or Adverse Event CRF, whichever is appropriate. 
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6 
STUDY PROCEDURES 
A tabular listing of the Schedule of Procedures can be found in Appendix A. ALL CLINIC 
VISITS REQUIRE THAT THE SUBJECT IS IN A FASTED STATE. This is defined as no food 
or caloric beverage for at least 10 hours prior to sample collection. Subjects will be permitted to 
have water, black tea or black coffee.  
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.  
Subjects must have a Pre-Screening TG value ≥ 350 mg/dL and < 1800 mg/dL before 
washing out of current TG-lowering therapies and proceeding to S1.   
A Wash-Out Period will be required for eligible subjects taking any lipid-regulating therapies or 
supplements, with the exception of statins or ezetimibe. 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. Specifically, PCSK9 inhibitors will 
require an 8-week Wash-Out Period, fibrates will require a 6-week Wash-Out Period, and niacin, 
OMG-3, bile acid sequestrants or other lipid-regulating therapies will require a 4-week Wash-
Out Period prior to the Screening Visit. If the subject needs to be washed off more than one 
lipid-altering medication; the medication that requires the longest Wash-Out Period will be the 
default.  For example, if a subject is taking OMG-3 and fibrates, then the subject would undergo 
a six-week Wash-Out Period. 
The Wash-Out Period will only be initiated after inclusionary lab values are received and 
reviewed.   
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 anti-diabetes pharmacologic therapy for 
subjects with Type 2 diabetes 
• Perform full physical examination; 
• Record vital signs, height, weight and calculate BMI; 
• Collect urine sample; 
• Perform urine pregnancy test (for women of child-bearing potential only); 
• Obtain blood sample for the following: 
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o Safety chemistry panel, coagulation, and hematology;  
o TSH, HbA1c, and serology (HBV, HCV, and HIV); and 
o Fasting serum TG only; 
• Explain importance of continued adherence to a stable, heart-healthy diet and limited alcohol 
intake; 
• Initiate wash-out; and 
• Assess adverse events (AEs that occur prior to the first dose of study drug [Study 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 Visits 
The screening visits can be completed up to 28 days but not less than 14 days prior to T1 
(Day 1).  The visits are provided with recommended timepoints; however the minimum 
time between visits can be as short as 1 week with the screening period as short as 14 days 
for qualification with S1 and S2 visits or 21 days for qualification with S2 and S3.  
To qualify for randomization into the treatment period, the mean of TG value at Visits S1 
and S2 must be ≥ 500 mg/dL (5.65 mmol/L) to < 1500 mg/dL (16.95 mmol/L) with the 
greater value not more than 50% of the lower value. If the mean of TG values at Visits S1 
and S2 is < 500 mg/dL or ≥ 1500 mg/dL or outside the 50% range in variability, the subject 
can be brought in for an additional TG value (lipid profile) one week later at Week -1 
(Screening Visit S3).  If the mean of TG values at Visits S2 and S3 is < 500 mg/dL or ≥ 1500 
mg/dL or outside the 50% range in variability, then the subject will be a screen failure.  
Subjects who are a screen failure may not re-screen at any time. 
If all of the inclusion criteria (Section 4.1) are met and the subject has none of the exclusion 
criteria (Section 4.2) the subject may be randomized into the 12-week treatment period. 
6.3.1 
Screening Visit 1 (up to Day -28 to -14/Week -4 or -2 ) 
Only those subjects NOT requiring wash-out from PCSK9 inhibitors, fibrates, niacin, 
OMG-3 or bile-acid sequestrants may participate in Screening Visit 1.  Subjects may be 
receiving statins (± ezetimibe 10 mg) only if therapy is stable for ≥ 12 weeks prior to 
Screening Visit 1.  
Subjects must have S1 TG value ≥ 425 mg/dL and < 1800 mg/dL before proceeding to S2.   
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). 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 -28): 
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• Obtain informed consent; 
• Confirm eligibility based on inclusion/exclusion criteria;  
• Obtain medical/surgical history and demographics;  
• Obtain concomitant medications; including all anti-diabetes pharmacologic therapy 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; 
• 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 
o Fasting lipid panel; 
• Perform 12-lead ECG;  
• Explain importance of continued adherence to a stable, heart-healthy diet and limited alcohol 
intake; and  
• Assess adverse events (AEs that occur prior to the first dose of study drug [Study 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. 
6.3.2 
Screening Visit 2 (up to Day -14 or -7/Week -2 or -1) 
All subjects determined as eligible as per the assessments at Screening Visit 1 and with a 
TG value ≥ 425 mg/dL and < 1800 mg/dL will participate in the Screening Visit 2. 
The following procedures will be performed at the Screening Visit 2 (up to Day -14): 
• Confirm eligibility based on inclusion/exclusion criteria;  
• Update medical/surgical history and demographics;  
• Update concomitant medications;  
• Record vital signs and weight; 
• Obtain blood sample for the following:  
o Fasting lipid panel; 
o Safety chemistry panel, coagulation, and hematology;  
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• Explain importance of continued adherence to a stable, heart-healthy diet and limited alcohol 
intake; and 
• Assess adverse events (SAEs that occur prior to the first dose of study drug [Study 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. 
6.3.3 
Optional Screening Visit 3 (up to Day -7/Week -1) 
All subjects determined as eligible as per the assessments at Screening Visit 2 (with the 
exception of TG) may participate in the Screening Visit 3. 
The following procedures will be performed at the Screening Visit 3 (up to Day -7): 
• Confirm eligibility based on inclusion/exclusion criteria;  
• Update medical/surgical history and demographics;  
• Update concomitant medications;  
• Record vital signs and weight; 
• Obtain blood sample for the following:  
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel; 
• Explain importance of continued adherence to a stable, heart-healthy diet and limited alcohol 
intake; and 
• Assess adverse events (SAEs that occur prior to the first dose of study drug [Study 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) 
6.4.1 
Visit T1 (Study Day 1)  
The following procedures will be performed pre-dose at Visit T1 (Study Day 1): 
• Perform symptom-directed physical examination; 
• Determine if there have been any changes in the subject’s health affecting eligibility; 
• Record vital signs, weight and waist circumference; 
• Collect urine sample; 
• 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 ultracentrifugation, and apolipoproteins; 
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o Fasting lipoprotein size and number (NMR); 
o Fasting insulin and FPG; 
o HbA1c; 
o hsCRP, IL-6, SAA, ANGPTL4, adiponectin, and fibrinogen 
o Cystatin-C;  
o Genotype reserve sample; and  
o Serum and plasma reserve samples. 
• Perform 12-lead ECG; 
• Randomize subjects via IVRS/IWRS; 
• Dispense study drug and instructions; 
• Explain importance of continued adherence to a stable, heart-healthy diet and limited alcohol 
intake;  
• Distribute subject dose diary; 
• Assess adverse events and update concomitant medications; and 
• Administer study drug (study drug will be administered at the site on Study Day 1).  
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 Serum and plasma pharmacokinetic (PK) reserve samples. 
• Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Dispense study drug and instructions; 
• Collect subject dose diary; 
• Distribute subject dose diary; 
• Assess adverse events and update concomitant medications; and 
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• Administer study drug (subjects will self-dose). 
6.4.3 
Visit T3 (Week 6) 
The following procedures will be performed at Visit T3 (Week 6/Day 43 ±3 days): 
• Perform symptom-directed physical examination; 
• Record vital signs and weight; 
• Collect urine sample; 
• 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 Serum and plasma PK reserve samples; 
•  Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Dispense study drug and instructions; 
• Explain importance of continued adherence to a stable, heart-healthy diet and limited alcohol 
intake;  
• Collect subject dose diary; 
• Distribute subject dose diary; 
• Assess adverse events and update concomitant medications; and 
• Administer study drug (subjects will self-dose). 
6.4.4 
Visit T4 (Week 10)  
The following procedures will be performed at Visit T4 (Week 10/Day 71 ±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, LDL-C ultracentrifugaton, apolipoproteins;  
o hsCRP, IL-6, SAA, and fibrinogen;  
o Reserve serum and PK plasma samples; 
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• Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Explain importance of continued adherence to a stable, heart-healthy diet and limited alcohol 
intake;  
• Collect subject dose diary; 
• Distribute subject dose diary; 
• 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/Study Day 85 [can be 
performed up to 3 days prior to Study Day 85, but not after Study Day 85]): 
• Perform full physical examination; 
• Record vital signs and weight; 
• Collect urine sample; 
• 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 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), coagulation, and hematology;  
o Fasting lipid panel, LDL-C ultracentrifugation, and apolipoproteins;  
o Fasting lipoprotein size and number (NMR); 
o Fasting insulin and FPG; 
o HbA1c; 
o hsCRP, IL-6, SAA, ANGPTL4, adiponectin, fibrinogen; 
o Cystatin-C;  
o Reserve serum and PK plasma samples; 
• Perform 12-lead ECG; 
• Assess and document study drug compliance; 
• Collect subject dose diary; 
• Assess adverse events and update concomitant medications.  
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6.5 
Follow-up Visit (Week 16) 
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 (Week 16 ±3 days): 
• Perform symptom-directed physical examination (only for subjects who had an abnormal 
result at Week 12 [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 
16 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event);  
• Obtain blood sample for safety chemistry panel, cystatin-C, coagulation, and hematology 
(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 
• Assess adverse events and update concomitant medications. 
6.6 
Early Termination Visit and Withdrawal Procedures 
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 and waist circumference; 
• Collect urine sample; 
• 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 Fasting lipid panel and apolipoproteins;  
o Fasting lipoprotein size and number (NMR); 
o Fasting insulin, and FPG; 
o HbA1c; 
o hsCRP, IL-6, SAA, ANGPTL4, adiponectin, and fibrinogen; 
o Cystatin-C;  
o Reserve serum and PK plasma samples; 
• Perform 12-lead ECG; 
• Assess and document study drug compliance;  
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• Collect subject dose diary; 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 (Study 
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 (Study 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 (Study 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 (Study 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 
(Study Day 1) should be reported in the medical history. Any SAEs occurring prior to the first 
dose of study drug (Study 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 (Study 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 (Study 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, 
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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. 
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 [specify eg, CRF] 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. 
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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. 
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. 
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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. 
8.1.4.2 
Creatinine increase 
If, at any visit, a creatinine increase of > 0.3 mg/dL (27 µmol/L) from baseline, a GFR decrease 
of >15 mL/min from baseline, or a > 30 urinary albumin:creatine ratio mg/g is observed, a repeat 
chemistry/urinalysis 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 studies at the time of assessment 
but may require additional or closer/follow-up monitoring of renal parameters.  Cystatin-C will 
be measured at baseline and Week 12.  
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. 
8.1.4.4 
Increased risk for pancreatitis (TG ≥ 2000 mg/dL) 
To prevent the risk for pancreatitis, lab alerts will be given for TG values ≥ 2000 mg/dL. A 
subject with a TG ≥ 2000 mg/dL should have a confirmatory TG value obtained within 1 week.  
As a first step, the subject should be immediately counseled and managed on their adherence to a 
heart-healthy diet, restricted alcohol intake and diabetic control. A follow-on TG value should be 
obtained 2 weeks later.  If the TG remains ≥ 2000 mg/dL then the study medication should be 
stopped, and the subject should complete the ET visit and be instructed to begin TG-lowering 
rescue medication (fibrates and/or OMG-3 compounds). 
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; 
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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 the 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, black tea or black coffee.  
Central laboratory results will be provided to the sites, with the exception of the post-
randomization lipid values. TG alert values with a risk mitigation plan is in place with the 
Central Laboratory (Section 8.1.4.4 Increased risk for pancreatitis [TG ≥ 2000 mg/dL]).  
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 
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. 
A full fasting lipid panel will be assessed at the Pre-Screening Visit, if applicable, and at all other 
study 
visits, 
including 
the 
Follow-up 
Visit. 
Fasting 
apolipoproteins 
and 
LDL-C 
(ultracentrifugation) will be assessed at Study Day 1, Week 10, Week 12, the Follow-Up Visit, 
and the ET Visit, if applicable. In addition to these lipid parameters, hsCRP, IL-6, SAA, and 
fibrinogen will also be measured at Study Day 1, Week 10, Week 12, and the ET Visit, if 
applicable.  Finally, ANGPLT4, adiponectin and cystatin-C will be measured at Study Day 1 and 
Week 12 (or the ET Visit, if applicable).  
A urine sample for urinalysis will be collected at the Pre-Screening Visit, if applicable, the 
Screening Visit, Study Day 1, Week 6, 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. Urine protein:creatinine ratio and 
albumin:creatinine ratio will be performed at the Screening Visit, Study Day 1, Week 6, Week 
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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 Study Day 1, Week 6, 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).  
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, Study Day 1, Week 2, Week 6, and Week 10.  
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. 
Fasting insulin levels and FPG will be measured at Study Day 1 and Week 12.  
HbA1c will be measured at the subject’s first study visit, either at the Pre-Screening Visit, if 
applicable, or the Screening Visit, Study Day 1 and Week 12.  
The estimated blood volume for the full study is 625 mL. 
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 diastolic 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.   
8.8 
Electrocardiograms 
Electrocardiograms (ECGs) 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, Study Day 1, Week 2, 
Week 6, Week 10, 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 
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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), Study Day 1, Week 2, Week 6, Week 10 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 Pre-Screening Visit or Screening Visit, Day 1, 
Week 10, and Week 12. Waist circumference will be measured at Day 1 and Week 12 [or the ET 
Visit, if applicable].    
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 Study 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 and Pharmacokinetics (PK) 
Additional 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 (which may include but will not limited to RLP-C, RLP-TG and RLP-apoB, 
Lp(a), ox-LDL, and Lp-PLA2), repeat lipid testing, blood drug levels including use in 
confirming subject compliance (PK analysis), and/or repeat or additional clinical laboratory 
testing in the event of a safety issue.  
Reserve samples will be stored for a minimum of 1 year following study completion and may be 
stored until the IND is withdrawn or the NDA is approved.  If requested, results of tests 
performed on study samples will be made available to subjects or investigators. Subjects may not 
withdraw their samples. 
The plasma reserve samples collected at Week 2, Week 6, Week 10 and Week 12 [or the ET 
Visit, if applicable] will be used for the analysis of PK. To facilitate the analysis of PK samples, 
the time and date of the last dose of study medication and statin if applicable (generic name and 
strength) prior to the clinic visit will be collected by the subject via a diary.  In addition, the time 
and date of the PK blood sample at the clinic visit will be collected.  
 
8.12 
Diary 
All subjects will complete a Sponsor-provided paper diary prior to all study visits that require PK 
samples. The subject will document the exact date and time of their last dose of study drug and, 
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if applicable, the last date and time of statin dosing. All diaries should be confirmed to be 
complete by the Principal Investigator or designee and maintained in the subject’s records. 
 
 
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9 
STATISTICS 
9.1 
Sample Size  
Approximately 90 subjects (30 subjects per treatment group) will be randomized into 1 of 3 
treatment groups: gemcabene 300 mg, gemcabene 600 mg or placebo. 
A sample size of 30 randomized subjects in the gemcabene 300 mg group, 30 randomized 
subjects in the 600 mg group and 30 randomized subjects in the placebo group is expected to 
provide 80% power to detect a difference of 35% in the percent change in TG from baseline to 
end of study (EOS) between either of the gemcabene treatment groups and the placebo group.  
This calculation is based on a 2-sided t-test at the 5% level of significance (α = 0.05), a common 
standard deviation of 43, and a drop-out rate of 15%.   
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. The FAS population will be 
the primary analysis population. 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 
database lock.  
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 SAS.  
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 serum TG from baseline to EOS.  
Baseline will be defined as the average of the (Screening Visits [S1 and S2] or [S2 and S3] 
occurring up to 28 days prior to Study Day 1) and Study Day 1 [pre-dose]) values.  EOS will be 
defined as the average of Week 10 and Week 12.  If either the Week 10 or Week 12 value is 
missing, then the single value (Week 10 or Week 12) will be used.  Completely missing values 
(both Week 10 and Week 12) will be imputed using last observation carried forward (LOCF), 
with the last on-treatment value carried forward as the EOS value.    
 
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The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA) with 
percent change from baseline to EOS in TG as the dependent variable; treatment and baseline 
statin (yes or no) as factors; and baseline fasting serum TG as a covariate. The ANCOVA will be 
performed using the FAS, with subjects included in their randomized treatment group regardless 
of the treatment they actually received.  The least-squares mean (LSM) and standard error (SE) 
will be provided for each treatment group, along with the placebo-corrected LSM, its 95% 
confidence interval (CI), and associated p value for both gemcabene groups.  A 2-sided test with 
a significance level of 0.05 will be used for the comparison of the gemcabene 300 mg and 600 
mg groups separately 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 efficacy analyses 
Secondary efficacy endpoints include: 
• Change and percent change from baseline to Weeks 2, 6, 10 and 12 in fasting serum TG, and 
change from baseline to EOS in fasting serum TG;  
• Change and percent change from baseline to Weeks 2, 6, 10, 12 and EOS in total cholesterol 
(TC), non-HDL-C, HDL-C, and VLDL-C;  
• Change and percent change from baseline to Weeks 10, 12 and EOS in Apo B, ApoA-I, 
ApoA-II, ApoA-V, ApoC-II, ApoC-III, and ApoE;  
• Change and percent change from baseline to Weeks 10, 12 and EOS in LDL-C 
(ultracentrifugation), LDL-TG, VLDL-TG, HDL-TG;  
• Change and percent change from baseline to Week 12 in lipoprotein size and particle number 
(NMR);  
• Change and percent change from baseline to Week 12 in hsCRP, IL-6, SAA, ANGPTL4, 
adiponectin and fibrinogen; and  
• Percent of subjects achieving a TG value <500 mg/dL (5.65 mmol/L) at EOS.   
For continuous secondary efficacy endpoints, the same ANCOVA model outlined above for the 
primary efficacy endpoint will be used, with the respective baseline included as the covariate.  
Baseline for TC, non-HDL-C, HDL-C, and VLDL-C will be defined as the average of the last 
two pre-dose values (generally will be the average of Visit S2 and pre-dose Study Day 1/Visit 
T1).  Baseline for fasting apolipoproteins, LDL-C (ultracentrifugation), LDL-TG, VLDL-TG, 
HDL-TG, hsCRP, IL-6, SAA, adiponectin, fibrinogen, and ANGPTL4 is defined as the value 
from pre-dose Study Day 1/Visit T1.  For the EOS time point, EOS will be defined as the 
average of Week 10 and Week 12.  If either the Week 10 or Week 12 value is missing, then the 
single value (Week 10 or Week 12) will be used.  Completely missing values (both Week 10 and 
Week 12) will be imputed using LOCF, with the last on-treatment value carried forward as the 
EOS value.  For all other time points, missing values will be imputed using LOCF, with the last 
on-treatment value carried forward to that time point. 
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confidence intervals and p-values will be presented to compare gemcabene 300 mg and 600 mg 
separately with the placebo group.    
The exploratory efficacy analyses will be repeated using the PPS. 
9.3.2 
Analysis of Safety 
Safety will be assessed using the SAS. The assessment of safety will include adverse events, 
clinical laboratory assessments, ECGs, physical examinations, and vital signs. In addition, the 
safety assessment will be based primarily on the frequency of new or worsening adverse events, 
laboratory abnormalities, and serious adverse events (SAEs). Other safety data will be 
summarized as appropriate.  
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 will be summarized by treatment group at baseline, and at each post-
baseline time point, if applicable, and change from baseline to End of Treatment (Week 12) or 
the ET Visit, if applicable. Baseline for safety laboratory data will be defined as the last pre-dose 
value (pre-dose Study Day 1/Visit T1 or prior).  Frequency counts of new or worsening 
abnormalities will also be provided. 
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 value (pre-dose Study Day 1/Visit T1 or prior). Abnormalities 
in ECGs and in PEs will be summarized. 
All safety data will be listed. 
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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 the Medical Dictionary for Regulatory Activities (MedDRA) for medical 
history and adverse events, and 
• World Health Organization Drug (WHO 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. 
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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. 
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11.4 
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. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB/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. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating 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 
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regulations, or as specified in the Clinical Study Agreement, whichever is longer. The 
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.  
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication 
rights until mutual agreement on the content, format, interpretation of data in the manuscript, and 
journal selected for publication are achieved. 
11.8 
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. 
11.9 
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. 
11.10 
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.  
11.11 
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. 
11.12 
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.  
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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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13 
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risk reduction to pancreatitis. Best Practice & Research Clinical Endocrinology & Metabolism 
2014; 28:423–437 
13. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the 
combination for the prevention of coronary disease. The New England Journal of Medicine 2001; 
345:1583–92. 
14. Bhardwaj SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clinics 
in Liver Disease 2007;11: 597–613 vii. 
15. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary 
heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs 
high-density lipoprotein cholesterol intervention trial study group. The New England Journal of 
Medicine 1999; 341:410–8.  
16. Musa-Veloso K, Binns MA, Kocenas AC, et al. Long-chain omega-3 fatty acids eicosapentaenoic 
acid and docosahexaenoic acid dose-dependently reduce fasting serum triglycerides. Nutrition 
Reviews 2010; 68:155–67.  
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Page 298 of 307
CI

Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
70 
Footnotes appear on the following page
hsCRP, SAA, IL-6, and fibrinogen 
 
 
 
 
X 
 
 
X 
X 
 
X 
Lipoprotein size and particle number  
 
 
 
 
X 
 
 
 
X 
 
X 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
Study drug administrations 
 
 
 
 
X 
X 
X 
X 
 
 
 
Dispense study drug and instructions 
 
 
 
 
X 
X 
X 
X 
 
 
 
Compliance check 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Distribute drug diary 
 
 
 
 
X 
X 
X 
X 
 
 
 
Dietary assessment (self-reported)t 
X 
X 
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 
X 
X 
Concomitant medications 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reserve serum samplesw 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Reserve plasma PK samplesx  
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Collect drug diary 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Reserve genotyping sample 
 
 
 
 
X 
 
 
 
 
 
 
Page 299 of 307

Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
71 
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, OMG-3, bile acid sequestrants or other lipid-regulating therapies 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 28 days prior to Study Day 1. 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.  
c. 
Study assessments will be completed ±3 days of given time point for all study visits from Study Day 1 through Week 10. Week 12 assessments can be performed up to 3 
days prior to Study Day 85, but not after Study Day 85. 
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 Study 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. 
Urine will be collected for a full urinalysis at the lab including protein:creatinine ratio and albumin:creatinine ratio at the Prescreening/screening Visit, Study Day 1, 
Week 6, 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 Study Day 1, Week 6, Week12, 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, Study Day 1, Week 2,  Week 6, and Week 10.  
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 4 week (±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.  
p. 
Includes non-HDL-C, TC, TG, HDL-C, and VLDL-C and HDL-TG. 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, black tea or black coffee.  
q. 
Includes 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, black 
tea or black coffee. 
r. 
Includes ApoB, ApoA-I, ApoA-II, ApoA-V, ApoC-II, ApoC-III, and ApoE. 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 Study Day 1. Subjects will self-dose at all other times during the Treatment Period.  
t. 
Subjects will self-report compliance to a stable, heart-healthy diet. 
u. 
Subjects should be lying quietly in a fully supine position for at least 10 minutes prior to each 12-lead ECG. 
Page 300 of 307

Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
72 
v. 
Serious adverse events that occur prior to the first dose of study drug (Study Day 1) should be reported as an update to medical history as well as be reported on the 
appropriate adverse event eCRF. 
w. The following may be analyzed: RLP-C, RLP-TG and RLP-apoB, Lp(a), ox-LDL, and Lp-PLA2. 
x. 
Plasma samples collected at Week 2, Week 6, Week 10, Week 12 and ET will be used for the analysis of gemcabene PK. The plasma sample collected at Day 1 will be 
reserve.   
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.
Page 301 of 307

Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
73 
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 Parameters  
Cystatin-C  
Fasting plasma glucose 
HbA1c 
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-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
74 
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 will be performed at the Screening Visit, Study Day 1, Study Day 28, Study Day 85, the 
Follow-up Visit (only for subjects who had an abnormal result at Study Day 85 [or the ET Visit, if applicable] or an 
ongoing treatment-related adverse event), and the ET Visit, if applicable.  
3. 
Urine protein:creatinine ratio will be performed at the Screening Visit, Study Day 1, Study Day 28, Study Day 85, the 
Follow-up Visit (only for subjects who had an abnormal result at Study Day 85 [or the ET Visit, if applicable] or an 
ongoing treatment-related adverse event), and the ET Visit, if applicable.  
4. 
Urinary NGAL will be measured at Study Day 1, Study Day 28, Study Day 85, the Follow-up Visit (only for subjects 
who had an abnormal result at Study Day 85 [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: 
Apo A-I 
ApoA-II 
ApoB 
ApoA-V 
ApoC-II  
ApoC-III 
Triglycerides 
ApoE 
High-density lipoprotein cholesterol  
Low-density lipoprotein cholesterol  
Non-high-density lipoprotein cholesterol 
Very low-density lipoprotein cholesterol 
SAA 
Total cholesterol 
High-sensitivity C-reactive protein 
IL-6 
ANGPTL4 
Fibrinogen 
 
 
 
Page 303 of 307

Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
75 
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.  
Page 304 of 307

Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
76 
APPENDIX D: REFERENCE LIST OF CYTOCHROME P450 3A4 
INHIBITOR 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 
 
 
 
 
 
Page 305 of 307

Gemphire Therapeutics Inc. 
Clinical Study Protocol GEM-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
77 
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-401 
Confidential & Proprietary 
 
Version 4.0, 17 March 2017 
78 
• 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. 
 
 
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