Clinical trial NCT02722408
Conditions: Hypercholesteremia
Keywords: LDL-C Lipid Regulator
Sponsor: NeuroBo Pharmaceuticals Inc.
Start date: 2016-06-01; Completion date: 2017-07-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the efficacy, safety, and tolerability of multiple doses of Gemcabene in patients with HoFH on stable, lipid-lowering therapy.

Detailed description:

Arms: arm 1: Participants with homozygous familial hypercholesterolemia (HoFH) on stable lipid lowering therapy received 300 milligram (mg) of Gemcabene, orally once daily from day 1 to 28 followed by 600 mg of Gemcabene, orally once daily from day 29 to 56 followed by 900 mg of Gemcabene, orally once daily from day 57 to 84. Participants were followed until Day 112.
Interventions: intervention 1: Gemcabene
Intervention descriptions: intervention 1: 300 mg tablet orally once daily for four weeks followed by 600 mg tablet orally once daily for four weeks followed by 900 mg tablet orally once daily for four weeks.

Protocol documents:
Prot_001.pdf: 
Title: A Phase 2 Open-Label, Dose-Finding Study to Assess the Efficacy, Safety, and Tolerability of 
Gemcabene in Patients with Homozygous Familial Hypercholesterolemia on Stable, Lipid-Lowering 
Therapy (COBALT-1) 
 
 
NCT ID: NCT02722408 
 
 
Approval Date: 19-Feb-2016 


 
16. 
APPENDICES 
APPENDIX 16.1: 
STUDY INFORMATION 
APPENDIX 16.1.1: PROTOCOL AND PROTOCOL AMENDMENTS 
Original Protocol (Version 1.0), 19 February 2016 .........................................................................2 


 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2 Open-Label, Dose-Finding Study to Assess the Efficacy, 
Safety, and Tolerability of Gemcabene in Patients with Homozygous 
Familial Hypercholesterolemia on Stable, Lipid-Lowering Therapy 
(COBALT-1) 
 
Investigational Product: Gemcabene calcium tablets (gemcabene) 
Protocol Number: GEM-201 
 
 
Sponsor: 
Gemphire Therapeutics Inc.  
43334 Seven Mile Road, Suite 1000 
Northville, Michigan 48167 
United States 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
 
 
Version Number: 1.0 
Date: 19 February 2016 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Gemphire Therapeutics Inc. except to the extent that disclosure would be required by 
law and for the purpose of evaluating and/or conducting a clinical study for Gemphire Therapeutics 
Inc. You are allowed to disclose the contents of this document only to your Institutional Review 
Board (IRB) and study personnel directly involved with conducting this protocol. Persons to whom 
the information is disclosed must be informed that the information is confidential and proprietary 
to Gemphire Therapeutics Inc. and that it may not be further disclosed to third parties. 




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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 patients. 
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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regulatory-approved, not excluded lipid-lowering therapy (i.e., statins, monoclonal antibodies to 
PCSK9, cholesterol-absorption inhibitors, bile acid sequestrants, or nicotinic acid, or any 
combination thereof). 
STUDY DESIGN AND DURATION: 
This is a Phase 2, open-label, dose-finding, 3-period, 3-treatment study using successively 
escalating doses of 300 mg, 600 mg, and 900 mg gemcabene in patients with HoFH. All patients 
will be on each of the successive doses for 4 weeks at a time. Patients will remain on their current 
stable, lipid-lowering therapy throughout the study. Patients will not be allowed in the study if 
they are undergoing apheresis or taking mipomersen or lomitapide.  
Efficacy, PK, and safety data from this study will be used along with previously completed studies 
and a planned randomized, placebo-controlled study in patients with hypercholesterolemia 
(GEM-301) to confirm the appropriate dose of gemcabene for use in Phase 3 studies. An effective 
dose is defined as a dose that achieves 15% mean reduction in LDL-C after 4 weeks of treatment 
with the study totaling 12 weeks of treatment.  
Approximately 8 patients will be enrolled into the study. Total study duration will be up to 
18 weeks and will consist of a Screening Visit, a Treatment Period, and a Follow-up Visit.  
The Screening Visit will occur up to 14 days prior to Day 1. Patients will sign the informed consent 
form prior to any study procedures being performed. Patients must meet all of the inclusion and 
none of the exclusion criteria to be eligible for study participation.  
The Treatment Period is a sequential design whereby each patient will receive gemcabene 300 mg 
QD for 4 weeks. The same patients will then receive a 600 mg dose QD for 4 weeks and finally 
900 mg dose QD for 4 weeks. There will be no interruptions in gemcabene dosing when changing 
from the 300 mg to the 600 mg dose or when changing from the 600 mg to the 900 mg dose unless 
there are clinically significant safety issues resulting in the temporary or permanent 
discontinuation of study drug. The first 300 mg dose of study drug will be administered at the site 
on Day 1. For days when patients will self-dose, they will be instructed to take study drug at the 
same time each morning on an empty stomach 30 to 60 minutes prior to breakfast. For patients 
also taking bile acid sequestrants, study drug should be taken at least 2 hours before administration 
of bile acid sequestrants. Assessments will be performed after the patient has been on the study 
drug for 2 weeks for each dosing level and on the last day of each dose. 
For each escalated dose, percent change from baseline in LDL-C will be calculated using the 
baseline LDL-C value and the final LDL-C value measured for each dose. Baseline will be defined 
as the average of the Screening Visit occurring up to 14 days prior to Day 1 and Day 1 (pre-dose) 
measurements. 
Pharmacokinetic samples will be collected pre-dose (must be 24 ±2 hours from the previous day’s 
dose) and 0.5, 1, 2, 3, 5, and 12 hours post-dose on Day 28, Day 56, and Day 84 in collection tubes 
containing dipotassium ethylenediaminetetraacetic acid as the anticoagulant; for determination of 
gemcabene repeat-dose PK parameters, steady state is assumed following QD administration for 
28 days and therefore, plasma gemcabene concentrations at 24 hours post-dose are considered to 
be equal to pre-dose concentrations. For all other study visits where routine plasma drug 
monitoring will be performed (Day 1, Day 14, Day 42, Day 70, and the Early Termination Visit, 




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PHARMACOKINETIC VARIABLES: 
The following PK parameters will be calculated, as appropriate, from the individual plasma 
concentrations of gemcabene on Day 28, Day 56, and Day 84: 
 Cmax: maximum plasma concentration, 
 tmax (h): time to maximum plasma concentration, 
 AUC0-t (ng·h/mL): area under the concentration-time curve to the last quantifiable time, and 
 AUC0-24 (ng·h/mL): area under the concentration-time curve to the 24-hour time point. 
SAFETY VARIABLES: 
The safety variables include adverse events; safety laboratory parameters (chemistry, hematology, 
coagulation, 
and 
urinalysis) 
with 
particular 
attention 
to 
hepatic 
(e.g., 
alanine 
aminotransferase/aspartate aminotransferase, bilirubin, alkaline phosphatase), renal (e.g., blood 
urea nitrogen, serum creatinine, protein:creatinine ratio, urinalysis sediments, pH, electrolytes), 
and skeletal muscle (i.e., creatine kinase) toxicities; 12-lead electrocardiograms (ECGs); physical 
examinations; and vital signs. 
STATISTICAL ANALYSES: 
Given the proposed crossover design of this study, a within-patient analysis can be performed for 
the comparison of dose groups. For continuous variables, the dose groups will be compared on 
their change and percent reduction from baseline (using their pre-treatment baseline value). A 
longitudinal analysis will be performed with a mixed-effects model repeated measures analysis 
including percent change in LDL-C as the dependent variable, visit as a fixed effect and patient 
as a random effect.  The additional drug benefit with increasing dose will be estimated from the 
mixed-effects model. Least-squares mean differences and corresponding 95% confidence 
intervals, separately for each of the 3 paired comparisons (300 versus 600 mg, 300 versus 900 mg, 
and 600 versus 900 mg) will be provided. In addition, a scatterplot with regression curve fit of the 
percent reduction from baseline versus dose will be performed. For binary variables such as the 
percentage of patients, descriptive statistics will be calculated for each dose group.  
The PK parameters will be calculated, as appropriate, from the individual plasma concentrations 
of gemcabene using a non-compartmental approach. Pharmacokinetic variables will be computed 
using WinNonlin Professional® or other appropriate software. 
Safety will be assessed using the population of all patients who receive any amount of study drug. 
The assessment of safety will include adverse events, clinical laboratory assessments, ECGs, 
physical examinations, and vital signs. The safety analysis will be based primarily on the 
frequency of new or worsening adverse events, laboratory abnormalities, and serious adverse 
events. Other safety data will be summarized as appropriate.  
Safety laboratory data will be summarized at baseline, Day 28, Day 56, and Day 84, and change 
from baseline to Day 28, Day 56, and Day 84. Frequency counts of new or worsening 
abnormalities will also be provided. 


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SAMPLE SIZE DETERMINATION: 
The primary goal of the study is to assess the mean percent change in LDL-C from baseline over 
12 weeks of treatment from the 3 dose levels. Dosing 8 patients per group will yield reasonable 
precision in estimation in mean change from baseline in LDL-C. 
SITES: Approximately 9 sites worldwide, including the United States, Canada, and Israel. 
SPONSOR: 
Gemphire Therapeutics Inc.  
43334 Seven Mile Road, Suite 1000 
Northville, Michigan 48167 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 


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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
SYNOPSIS ...................................................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................ 9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 13 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 15 
1.1 
Background ................................................................................................................. 15 
1.2 
Rationale ..................................................................................................................... 15 
1.3 
Risk/Benefit ................................................................................................................ 15 
2 
STUDY OBJECTIVES ..................................................................................................... 17 
2.1 
Primary Objective ....................................................................................................... 17 
2.2 
Secondary Objectives.................................................................................................. 17 
2.3 
Exploratory Objective ................................................................................................. 17 
3 
STUDY DESCRIPTION .................................................................................................. 18 
3.1 
Summary of Study Design .......................................................................................... 18 
3.2 
Study Indication(s) ...................................................................................................... 19 
4 
SELECTION AND WITHDRAWAL OF PATIENTS .................................................... 20 
4.1 
Inclusion Criteria ........................................................................................................ 20 
4.2 
Exclusion Criteria ....................................................................................................... 20 
4.3 
Withdrawal Criteria .................................................................................................... 22 
5 
STUDY TREATMENTS .................................................................................................. 23 
5.1 
Treatment Groups ....................................................................................................... 23 
5.2 
Rationale for Dosing ................................................................................................... 23 
5.3 
Randomization and Blinding ...................................................................................... 23 
5.4 
Breaking the Blind ...................................................................................................... 23 
5.5 
Drug Supplies.............................................................................................................. 23 
5.5.1 Study Drug Identification ..................................................................................... 23 
5.5.2 Formulation and Packaging .................................................................................. 24 
5.5.3 Study Drug Preparation and Dispensing ............................................................... 24 
5.5.4 Study Drug Administration ................................................................................... 24 


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5.5.5 Treatment Compliance .......................................................................................... 24 
5.5.6 Storage and Accountability ................................................................................... 24 
5.6 
Prior and Concomitant Medications and/or Procedures ............................................. 25 
5.6.1 Permitted Medications and/or Procedures ............................................................ 25 
5.6.2 Excluded Medications and/or Procedures ............................................................. 25 
5.6.3 Restrictions and Dietary Guidelines ..................................................................... 25 
5.6.4 Documentation of Prior and Concomitant Medication Use .................................. 26 
6 
STUDY PROCEDURES .................................................................................................. 27 
6.1 
Informed Consent........................................................................................................ 27 
6.2 
Screening Visit (up to Day -14) .................................................................................. 27 
6.3 
Treatment Period (Visit T1 through Visit T7) ............................................................ 27 
6.3.1 Visit T1 (Day 1) .................................................................................................... 27 
6.3.2 Visit T2 (Day 14) .................................................................................................. 28 
6.3.3 Visit T3 (Day 28) .................................................................................................. 29 
6.3.4 Visit T4 (Day 42) .................................................................................................. 29 
6.3.5 Visit T5 (Day 56) .................................................................................................. 30 
6.3.6 Visit T6 (Day 70) .................................................................................................. 30 
6.3.7 Visit T7 (Day 84) .................................................................................................. 31 
6.4 
Follow-up Visit (Day 112) .......................................................................................... 32 
6.5 
Early Termination Visit and Withdrawal Procedures ................................................. 32 
7 
EFFICACY ANALYSES ................................................................................................. 33 
8 
PHARMACOKINETIC ASSESSMENTS ....................................................................... 34 
9 
SAFETY ASSESSMENTS ............................................................................................... 35 
9.1 
Adverse Events ........................................................................................................... 35 
9.1.1 Adverse (Drug) Reaction ...................................................................................... 36 
9.1.2 Unexpected Adverse Drug Reaction ..................................................................... 36 
9.1.3 Assessment of Adverse Events by the Investigator .............................................. 36 
9.1.4 Specific Safety Measures ...................................................................................... 37 
9.1.4.1 
Hemoglobin decrease ...................................................................................... 37 
9.1.4.2 
Creatinine increase .......................................................................................... 37 
9.1.4.3 
Possible muscle and liver injury ...................................................................... 37 
9.2 
Serious Adverse Events .............................................................................................. 38 


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9.3 
Serious Adverse Event Reporting − Procedures for Investigators.............................. 38 
9.4 
Pregnancy Reporting ................................................................................................... 39 
9.5 
Expedited Reporting ................................................................................................... 39 
9.6 
Clinical Laboratory Evaluations ................................................................................. 40 
9.7 
Vital Signs ................................................................................................................... 41 
9.8 
Electrocardiograms ..................................................................................................... 41 
9.9 
Physical Examinations ................................................................................................ 41 
9.10 
Medical/Surgical History and Demographics ............................................................. 41 
9.11 
Genetic Testing ........................................................................................................... 42 
9.12 
Additional Samples ..................................................................................................... 42 
10 
STATISTICS .................................................................................................................... 43 
10.1 
Analysis Populations ................................................................................................... 43 
10.2 
Statistical Methods ...................................................................................................... 43 
10.2.1 Analysis of Efficacy .............................................................................................. 43 
10.2.1.1 
Primary efficacy analysis ................................................................................. 43 
10.2.1.2 
Secondary efficacy analyses ............................................................................ 43 
10.2.1.3 
Exploratory analysis ........................................................................................ 44 
10.2.1.4 
Pharmacokinetic analysis ................................................................................ 44 
10.2.2 Missing Data ......................................................................................................... 44 
10.2.3 Analysis of Safety ................................................................................................. 45 
10.2.4 Sample Size Determination................................................................................... 45 
11 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 46 
11.1 
Data Management ....................................................................................................... 46 
11.1.1 Data Handling ....................................................................................................... 46 
11.1.2 Computer Systems ................................................................................................ 46 
11.1.3 Data Entry ............................................................................................................. 46 
11.1.4 Medical Information Coding................................................................................. 46 
11.1.5 Data Validation ..................................................................................................... 46 
11.2 
Record Keeping .......................................................................................................... 46 
12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 47 
12.1 
Ethical Conduct of the Study ...................................................................................... 47 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 47 


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12.3 
Informed Consent........................................................................................................ 47 
12.4 
Patient Card ................................................................................................................. 47 
12.5 
Study Monitoring Requirements ................................................................................. 48 
12.6 
Disclosure of Data....................................................................................................... 48 
12.7 
Retention of Records................................................................................................... 48 
12.8 
Publication Policy ....................................................................................................... 49 
12.9 
Financial Disclosure.................................................................................................... 49 
12.10 Insurance and Indemnity ............................................................................................. 49 
12.11 Legal Aspects .............................................................................................................. 49 
12.12 Definition of End of Study .......................................................................................... 49 
12.13 Sponsor Discontinuation Criteria ................................................................................ 49 
13 
STUDY ADMINISTRATIVE INFORMATION ............................................................. 50 
13.1 
Protocol Amendments ................................................................................................. 50 
13.2 
Address List ................................................................................................................ 50 
13.2.1 Sponsor ................................................................................................................. 50 
13.2.2 Contract Research Organization ........................................................................... 50 
13.2.3 Biological Specimens............................................................................................ 50 
14 
REFERENCES ................................................................................................................. 51 
APPENDIX A: SCHEDULE OF PROCEDURES ....................................................................... 52 
APPENDIX B: CLINICAL LABORATORY ANALYTES ........................................................ 55 
APPENDIX C: NEW YORK HEART ASSOCIATION CONGESTIVE HEART FAILURE 
CLASSIFICATION .......................................................................................................... 57 
APPENDIX D: CYTOCHROME P450 3A4 INHIBITORS: EXCLUSIONARY 
MEDICATIONS ............................................................................................................... 58 
APPENDIX E: MUSCLE INJURY AND HEPATIC MONITORING ....................................... 59 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ALT 
Alanine aminotransferase 
Apo 
Apolipoprotein 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the concentration-time curve to the 24-hour time point 
AUC0-t 
Area under the concentration-time curve to the last quantifiable time
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
Cmax 
Maximum plasma concentration 
CRA 
Clinical research associate 
CRP 
C-reactive protein 
CTA 
Clinical trial authorisation 
CYP 
Cytochrome P450 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HbA1c 
Hemoglobin A1c 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HoFH 
Homozygous familial hypercholesterolemia 
hsCRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical Dictionary for Regulatory Affairs 


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Abbreviation 
Definition 
NCEP ATP-III 
National Cholesterol Education Program Adult Treatment Panel III 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NIMP 
Non-investigational medical product 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetic 
QD 
Once daily 
SAE 
Serious adverse event 
SOP 
Standard Operating Procedure 
TC 
Total cholesterol 
TG 
Triglyceride 
tmax 
Time to maximum plasma concentration 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL 
Very low-density lipoprotein 
VLDL-C 
Very low-density lipoprotein cholesterol 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Gemcabene calcium is the monocalcium salt of a dialkyl ether dicarboxylic acid having 2 terminal 
gem dimethyl carboxylate moieties. Gemcabene is a novel lipid-regulating compound with a dual 
mechanism of action that involves: (1) blocking the hepatic production of triglyceride (TG) and 
cholesterol synthesis; and (2) enhancing the clearance of very low-density lipoprotein (VLDL). 
Based on prior clinical studies, the combined effects for these mechanisms has been observed to 
result in a reduction of plasma VLDL cholesterol (VLDL-C), low-density lipoprotein cholesterol 
(LDL-C), TGs, as well as an elevation in high-density lipoprotein cholesterol (HDL-C). 
Gemcabene has also been shown to markedly lower C-reactive protein (CRP). 
Gemphire Therapeutics Inc. (Gemphire) is developing gemcabene as an adjunct to diet and statin 
therapy for the treatment of patients with dyslipidemia, including patients with Homozygous 
Familial Hypercholesterolemia (HoFH). 
1.2 
Rationale 
Homozygous familial hypercholesterolemia is a rare, genetic disease that typically results when 
an individual inherits a substantial defect in clearance of low-density lipoprotein (LDL) particles, 
resulting in high and dangerous levels of LDL-C from birth. In patients with HoFH, LDL-C usually 
exceeds 500 mg/dL (12.92 mmol/L) prior to treatment, and the clinical outlook for untreated HoFH 
patients is bleak, with a life expectancy of not much more than 30 years.1 Current treatment 
generally includes a combination of dietary intervention, lipid-regulating medications, and 
plasmapheresis or LDL-apheresis. However, even when combinations of therapies are utilized, the 
vast majority of patients still do not reach LDL-C levels considered optimal or consistent with 
halting the progression of coronary heart disease. 
When administered in LDL receptor-deficient mice, a model of HoFH, gemcabene significantly 
reduced LDL-C both alone and in combination with atorvastatin.2 Study results further suggest 
that the mechanism(s) for modulating plasma cholesterol by gemcabene may be independent of 
hepatic LDL receptors. 
Three Phase 2 clinical studies in over 500 patients have been conducted with gemcabene to 
evaluate changes in lipid parameters in patients with hypercholesterolemia or dyslipidemia. 
Overall, these studies demonstrated that gemcabene doses of 300 mg to 900 mg significantly 
lowered LDL-C by approximately 20% to 30% when administered as monotherapy and when used 
as an adjunctive treatment in patients with uncontrolled hypercholesterolemia despite stable statin 
therapy. Across several studies, reduction in LDL-C has been accompanied by a reduction in 
apolipoprotein (Apo) B and CRP/high-sensitivity CRP (hsCRP), which are known to contribute to 
cardiovascular disease. These studies also demonstrated that gemcabene doses of 150 mg were 
less effective at lowering LDL-C. The current study seeks to demonstrate the effects of treatment 
with gemcabene on LDL-C and other lipid parameters in patients with HoFH. 
1.3 
Risk/Benefit 
Depending on residual LDL receptor activity, patients often demonstrate a significantly limited 
response to otherwise highly efficacious statin therapy. Medications that have been approved 
specifically for the treatment of HoFH include lomitapide and mipomersen. Unfortunately, clinical 


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application of these therapies is limited, as both treatments carry a product label BOX WARNING 
for hepatotoxicity. In addition, patients are often unable to tolerate other side effects of these 
medications, including injection site reactions and flu-like symptoms associated with mipomersen 
and gastrointestinal discomfort associated with lomitapide.  
Whereas compounds such as mipomersen and lomitapide act late in the process of 
VLDL assembly, gemcabene reduces the synthesis of lipids required for lipoprotein assembly 
earlier in the process.3 This allows the precursors of cholesterol and fatty acid synthesis to be 
utilized in other metabolic processes without causing subsequent accumulation of intracellular TGs 
or hepatic fat leading to hepatic steatosis. 
The recently Food and Drug Administration (FDA)-approved proprotein convertase 
subtilisin/kexin type 9 (PCSK9) inhibitor, Repatha™, has demonstrated substantial 
LDL-C-lowering ability, but because the mechanism of action is dependent upon the presence of 
LDL-C receptors with some residual function, the LDL-C-lowering effect is typically reduced in 
patients with HoFH compared to that seen in other populations.4,5  
The safety and efficacy profile of gemcabene has been demonstrated through 18 Phase 1 and 
Phase 2 clinical studies (17 completed and 1 Phase 1 study stopped due to a business decision), 
involving 1272 healthy adult subjects and patients. 
The clinical program conducted to date has demonstrated that gemcabene is well tolerated. A total 
of 895 healthy adult subjects and patients 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 once daily (QD). This includes 
837 subjects who received multiple doses of up to 900 mg daily for up to 12 weeks. Safety of these 
subjects was evaluated by regular adverse event monitoring, clinical laboratory assessments, 
electrocardiograms (ECGs), physical examinations, and vital sign assessments. 
Phase 1 pharmacokinetic (PK) studies have demonstrated that gemcabene is rapidly absorbed 
following oral administration, with exposure increasing approximately linearly with dose. No 
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 interval or blood pressure has 
been observed.  
Across all clinical studies, the majority of treatment-emergent adverse events were mild to 
moderate in intensity. The most common adverse events reported included headache, asthenia 
(feeling of weakness), nausea, dizziness, dyspepsia (upset stomach), infection, abnormal bowel 
movements, myalgia, and abnormal kidney function tests. Ten healthy adult patients 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, suggesting that gemcabene does not cause tubular or glomerular injury. And, the 
increase was reversible with all creatinine values returning to baseline within approximately 
2 weeks of cessation of gemcabene, suggesting a vascular effect and not renal injury. 




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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 2, open-label, dose-finding, 3-period, 3-treatment study using successively 
escalating doses of 300 mg, 600 mg, and 900 mg gemcabene in patients with HoFH. All patients 
will be on each of the successive doses for 4 weeks at a time. Patients will remain on their current 
stable, lipid-lowering therapy throughout the study. Patients will not be allowed in the study if they 
are undergoing apheresis or taking mipomersen or lomitapide.  
Efficacy, PK, and safety data from this study will be used along with previously completed studies 
and a planned randomized, placebo-controlled study in patients with hypercholesterolemia 
(GEM-301) to confirm the appropriate dose of gemcabene for use in Phase 3 studies. An effective 
dose is defined as a dose that achieves 15% mean reduction in LDL-C after 4 weeks of treatment 
with the study totaling 12 weeks of treatment.  
Approximately 8 patients will be enrolled into the study. Total study duration will be up to 
18 weeks and will consist of a Screening Visit, a Treatment Period, and a Follow-up Visit.  
The Screening Visit will occur up to 14 days prior to Day 1. Patients will sign the informed consent 
form (ICF) prior to any study procedures being performed. Patients must meet all of the inclusion 
and none of the exclusion criteria to be eligible for study participation.  
The Treatment Period is a sequential design whereby each patient will receive gemcabene 300 mg 
QD for 4 weeks. The same patients will then receive a 600 mg dose QD for 4 weeks and finally 
900 mg dose QD for 4 weeks. There will be no interruptions in gemcabene dosing when changing 
from the 300 mg to the 600 mg dose or when changing from the 600 mg to the 900 mg dose unless 
there are clinically significant safety issues resulting in the temporary or permanent 
discontinuation of study drug. The first 300 mg dose of study drug will be administered at the site 
on Day 1. For days when patients will self-dose, they will be instructed to take study drug at the 
same time each morning on an empty stomach 30 to 60 minutes prior to breakfast. For patients 
also taking bile acid sequestrants, study drug should be taken at least 2 hours before administration 
of bile acid sequestrants. Assessments will be performed after the patient has been on the study 
drug for 2 weeks for each dosing level and on the last day of each dose. 
For each escalated dose, percent change from baseline in LDL-C will be calculated using the 
baseline LDL-C value and the final LDL-C value measured for each dose. Baseline will be defined 
as the average of the Screening Visit occurring up to 14 days prior to Day 1 and Day 1 (pre-dose) 
measurements. 
Pharmacokinetic samples will be collected pre-dose (must be 24 ±2 hours from the previous day’s 
dose) and 0.5, 1, 2, 3, 5, and 12 hours post-dose on Day 28, Day 56, and Day 84 in collection tubes 
containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) as the anticoagulant; for 
determination of gemcabene repeat-dose PK parameters, steady state is assumed following QD 
administration for 28 days and therefore, plasma gemcabene concentrations at 24 hours post-dose 
are considered to be equal to pre-dose concentrations. For all other study visits where routine 
plasma drug monitoring will be performed (Day 1, Day 14, Day 42, Day 70, and the Early 
Termination [ET] Visit, if applicable), samples will be collected pre-dose (must be 24 ±2 hours 
from the previous day’s dose if a previous day’s dose occurred). 
The Follow-up Visit will occur 4 weeks (±3 days) after the last dose of study drug. 


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3.2 
Study Indication(s) 
The indication for this study is for the treatment of hypercholesterolemia, specifically patients with 
HoFH. 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Provision of written and signed informed consent (by patient or legal guardian) prior to any 
study-specific procedure; 
2. Male or female 17 years of age at time of consent; 
3. Diagnosis of HoFH by genetic confirmation (including compound heterozygosity) or a clinical 
diagnosis based on either (1) a history of an untreated LDL-C concentration >500 mg/dL 
(12.92 mmol/L) together with either appearance of xanthoma before 10 years of age, or 
evidence of heterozygous familial hypercholesterolemia in both parents or, if history is 
unavailable, (2) LDL-C >300 mg/dL (7.76 mmol/L) on maximally tolerated lipid-lowering 
drug therapy; 
4. Currently on a stable, low-fat, low-cholesterol diet in combination with a pre-existing, 
regulatory-approved, not excluded lipid-lowering therapy (i.e., statins, monoclonal antibodies 
to PCSK9, cholesterol-absorption inhibitors, bile acid sequestrants, or nicotinic acid, or any 
combination thereof) at a stable dose for at least 4 weeks prior to the Screening Visit;  
5. Fasting LDL-C value 130 mg/dL (3.36 mmol/L) at the Screening Visit; 
6. Physical examination, including vital signs, that is within normal limits or clinically acceptable 
to the Investigator; 
7. Weight 50 kg; 
8. Female patients 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; and 
9. 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. For this 
study, double-barrier contraception is required. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Other forms of primary hyperlipoproteinemia and secondary causes of hypercholesterolemia 
(e.g., nephrotic syndrome or hypothyroidism); 
2. Abnormal liver function test at the Screening Visit (aspartate aminotransferase or alanine 
aminotransferase 2 × the upper limit of normal [ULN]; total bilirubin 1.5 × ULN; or alkaline 
phosphatase 2 × ULN based on appropriate age and gender normal values). Patients with 
bilirubin 1.5 × ULN and history of Gilbert’s syndrome may be included; reflexive direct 
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3. Moderate (Grade B) or severe (Grade C) chronic hepatic impairment according to the 
Child-Pugh classification; 
4. Active liver disease (e.g., cirrhosis, alcoholic liver disease, hepatitis B virus [HBV], hepatitis C 
virus [HCV], autoimmune hepatitis, liver failure, liver cancer), history of liver transplant, or 
known diagnosis of human immunodeficiency virus (HIV);  
5. Triglycerides value 400 mg/dL (4.52 mmol/L) at the Screening Visit; 
6. Moderate to severe renal insufficiency defined as an estimated GFR 30 mL/min/1.73 m2 
(calculated using The Chronic Kidney Disease Epidemiology Collaboration equation) at the 
Screening Visit;  
7. Abnormal urinalysis (proteinuria greater than trace or any male or non-menstruating female 
with greater than trace hematuria), confirmed by reflexive urine protein:creatinine ratio testing;  
8. Uncontrolled thyroid disease: hyperthyroidism or hypothyroidism as defined by 
thyroid-stimulating hormone (TSH) below the lower limit of normal or >1.5 × ULN, 
respectively, at the Screening Visit. If controlled, treatment should be stable for at least 
3 months prior to the Screening Visit; 
9. Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] 
value 8%), or any diabetic patient taking insulin and/or thiazolidinediones; 
10. New York Heart Association Class III or IV heart failure (see Appendix C);  
11. 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. Patients with adequately treated stable angina, per Investigator 
assessment, may be included; 
12. Uncontrolled cardiac arrhythmia or prolonged QT on the Screening Visit or Day 1 prior to 
dosing ECG (QTcF >450 msec for men and >470 msec for women) or known family history 
of prolonged QT or unexplained sudden cardiac death; 
13. Uncontrolled hypertension, defined as sitting systolic blood pressure 180 mmHg or diastolic 
blood pressure 110 mmHg, and confirmed by repeat measurement; 
14. Currently receiving cancer treatments or, in the Investigator’s opinion, at risk of relapse for 
recent cancer; 
15. Use of fibrate lipid-lowering agent 6 weeks prior to the Screening Visit;  
16. Hypersensitivity to or a history of significant adverse reactions to any fibrate lipid-lowering 
agent; 
17. Use of apheresis (LDL or plasma) 8 weeks prior to the Screening Visit;  
18. Use of lomitapide 2 months prior to the Screening Visit; 
19. Use of mipomersen 5 months prior to the Screening Visit; 
20. Use of any excluded medications or supplements (e.g., potent cytochrome P450 [CYP] 3A4 
inhibitors, see Appendix D); 


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21. History of drug or alcohol abuse within the past year or inability to comply with protocol 
requirements, including subject restrictions (see Section 5.6.3); 
22. Previously treated with gemcabene; 
23. 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 
24. Any other finding which, in the opinion of the Investigator, would compromise the patient’s 
safety or participation in the study. 
4.3 
Withdrawal Criteria 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
 The patient withdraws consent or requests discontinuation from the study for any reason; 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient 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 patient; 
 Pregnancy; 
 Requirement of prohibited concomitant medication; 
 Patient failure to comply with protocol requirements or study-related procedures; or  
 Termination of the study by the Sponsor or the regulatory authority. 
If a patient 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 
ET Visit. The reason for patient withdrawal must be documented in the electronic Case Report 
Form (eCRF). 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. 
Withdrawn patients will not be replaced unless the number of withdrawn patients study-wide is 
2. If 2 patients are withdrawn from the study, then replacement patients will be enrolled to 
ensure 6 patients complete the entire study (the entire Treatment Period).  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
During the 12-week Treatment Period, all patients will receive gemcabene 300 mg QD for 4 weeks, 
followed by 600 mg QD for 4 weeks, followed by 900 mg QD for 4 weeks. 
5.2 
Rationale for Dosing 
Based on the results from a completed clinical study (Study 1027-018), oral gemcabene 
significantly lowered LDL-C with mean percent changes of -24% and -28% at 300 mg and 900 mg, 
respectively, compared to -6% in the placebo group in hypercholesterolemic patients on stable 
statin therapy.  
Gemcabene was observed to be well tolerated at single doses up to 1500 mg and multiple doses 
up to 900 mg. This included 837 subjects and patients with varying underlying conditions who 
received multiple doses of up to 900 mg for up to 12 weeks. Adverse events were generally mild 
to moderate in intensity with no treatment-related SAEs reported.  
5.3 
Randomization and Blinding 
This is an open-label study, therefore, no randomization or blinding is necessary.  
5.4 
Breaking the Blind 
This is an open-label study, therefore, no blinding is necessary.  
5.5 
Drug Supplies 
5.5.1 
Study Drug Identification 
Established names 
Gemcabene calcium – parent gemcabene 
CAS registry number 
209789-08-2 – parent 183293-82-5 
Chemical class 
Anti-hypercholesterolemic 
Chemical name 
6,6’-oxybis (2,2-dimethylhexanoic acid) 
monocalcium salt - parent 6,6'-oxybis(2,2-
dimethylhexanoicacid) 
Molecular formula 
C16H28O5∙Ca – parent C16H30O5 
Molecular weight 
340.48 – parent 302.408 
Drug name/formulation/concentration 
Gemcabene (parent)/tablets/300 mg 
Manufacturer (drug substance) 
  
Manufacturer (drug product) 
 
Storage requirements 
Room temperature (20 ±5C) in a secured location 
(locked) with no access for unauthorized 
personnel.  
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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 patient-by-patient 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.  
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 
Patients are required to be on a stable, low-fat, low-cholesterol diet in combination with a 
pre-existing, regulatory-approved, not excluded lipid-lowering therapy (i.e., statins, monoclonal 
antibodies to PCSK9, cholesterol-absorption inhibitors, bile acid sequestrants, or nicotinic acid, or 
any combination thereof) during the study.  
5.6.2 
Excluded Medications and/or Procedures 
Patients are not permitted to receive treatment with lomitapide 2 months prior to the Screening 
Visit, mipomersen 5 months prior to the Screening Visit, or a fibrate lipid-lowering agent 6 weeks 
prior to the Screening Visit. Patients are not permitted to use strong CYP3A4 inhibitors while on 
the study drug. See Appendix D for a specific list of CYP3A4 inhibitors.  
Additionally, plasmapheresis or LDL-apheresis is not permitted 8 weeks prior to the Screening 
Visit or during the study. Excluded procedures are specified in the exclusion criteria (Section 4.2).  
5.6.3 
Restrictions and Dietary Guidelines 
It is important that patients are instructed to not undertake any form of strenuous physical activity 
for at least 24 hours prior to repeat blood testing.  
Patients are restricted from using alcohol within 48 hours prior to study visits.  
Assessments that require a patient to fast will be defined as no food or caloric beverage for at least 
10 hours prior to sample collection. Patients will be permitted to have water. Study drug should be 
taken at the same time in the morning on an empty stomach 30 to 60 minutes prior to breakfast. 
For patients also taking bile acid sequestrants, study drug should be taken at least 2 hours before 
administration of bile acid sequestrants. 
Patients will be counseled on maintaining a low-fat, low-cholesterol diet (National Cholesterol 
Education Program Adult Treatment Panel III [NCEP ATP-III] or equivalent) throughout the 
study. 


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5.6.4 
Documentation of Prior and Concomitant Medication Use 
A concomitant medication is any treatment including nutritional supplements, vitamins, or 
over-the-counter medications received by or prescribed to the patient concomitantly to the study, 
from the time of informed consent to the Follow-up Visit or the ET Visit, if applicable. 
The Investigator should record the use of all concomitant medications taken during the study, both 
prescribed and over the counter, in the eCRF and the source document. This includes drugs used 
on a chronic and as needed basis. Patients should be discouraged from starting any new medication, 
both prescribed and over the counter, without consulting the Investigator, unless the new 
medication is required for an emergency. 


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6 
STUDY PROCEDURES 
A tabular listing of the Schedule of Procedures can be found in Appendix A. Assessments that 
require a patient to fast will be defined as no food or caloric beverage for at least 10 hours prior to 
sample collection. Patients will be permitted to have water. 
6.1 
Informed Consent 
Written informed consent for the study will be obtained from all patients before any 
protocol-specific procedures are performed. See Section 12.3 for details on informed consent.  
6.2 
Screening Visit (up to Day -14)  
The following procedures will be performed at the Screening Visit (up to Day -14): 
 Obtain informed consent; 
 Conduct eligibility assessment based on inclusion/exclusion criteria; 
 Obtain medical/surgical history and demographics; 
 Perform full physical examination; 
 Record vital signs, height, and weight; 
 Collect urine sample for urinalysis including urine protein:creatinine ratio; 
 Perform serum pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o TSH, HbA1c, and serology (HBV, HCV, and HIV); and 
o Fasting lipid panel; 
 Perform 12-lead ECG; 
 Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
 Assess adverse events (SAEs that occur prior to the first dose of study drug [Day 1] should be 
reported as an update to medical history as well as be reported on the appropriate adverse event 
eCRF) and concomitant medications. 
6.3 
Treatment Period (Visit T1 through Visit T7) 
6.3.1 
Visit T1 (Day 1)  
The following procedures will be performed pre-dose at Visit T1 (Day 1): 
 Perform symptom-directed physical examination; 
 Determine if there have been any changes in the patient’s health affecting eligibility; 
 Record vital signs and weight; 


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 Collect urine sample for urinalysis including urine protein:creatinine ratio and neutrophil 
gelatinase-associated lipocalin (NGAL); 
 Perform urine pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel and apolipoproteins;  
o hsCRP and fibrinogen; 
o 
 
o Genetic testing for HoFH genotype; and 
o Additional samples; 
 Perform 12-lead ECG pre-dose; 
 Obtain PK sample pre-dose; 
 Dispense study drug and instructions; 
 Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); 
 Assess adverse events and update concomitant medications; and 
 Administer study drug. 
6.3.2 
Visit T2 (Day 14) 
The following procedures will be performed at Visit T2 (Day 14 ±3 days): 
 Perform symptom-directed physical examination; 
 Record vital signs and weight; 
 Collect urine sample for urinalysis; 
 Perform urine pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel; and 
o Additional samples; 
 Perform 12-lead ECG pre-dose; 
 Obtain PK sample pre-dose (must be 24 ±2  hours after previous day’s dose); 
 Administer study drug; 
 Assess and document study drug compliance; 
 Dispense study drug and instructions; 
 Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
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 Assess adverse events and update concomitant medications. 
6.3.3 
Visit T3 (Day 28) 
The following procedures will be performed at Visit T3 (Day 28 ±3 days): 
 Perform symptom-directed physical examination; 
 Record vital signs and weight; 
 Collect urine sample for urinalysis including urine protein:creatinine ratio and NGAL; 
 Perform urine pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel and apolipoproteins;  
o hsCRP and fibrinogen; and  
o Additional samples; 
 Perform 12-lead ECG pre-dose and 2 hours post-dose; 
 Obtain PK sample pre-dose (must be 24 ±2 hours after previous day’s dose) and 0.5, 1, 2, 3, 5, 
and 12 hours post-dose. The window for PK samples obtained at time intervals <24 hours will 
be ±10 minutes; 
 Administer study drug; 
 Assess and document study drug compliance; 
 Dispense study drug and instructions; 
 Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
 Assess adverse events and update concomitant medications. 
6.3.4 
Visit T4 (Day 42) 
The following procedures will be performed at Visit T4 (Day 42 ±3 days): 
 Perform symptom-directed physical examination; 
 Record vital signs and weight; 
 Collect urine sample for urinalysis; 
 Perform urine pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel; and 
o Additional samples; 
 Perform 12-lead ECG pre-dose; 


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 Obtain PK sample pre-dose (must be 24 ±2  hours after previous day’s dose); 
 Administer study drug; 
 Assess and document study drug compliance; 
 Dispense study drug and instructions; 
 Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
 Assess adverse events and update concomitant medications. 
6.3.5 
Visit T5 (Day 56) 
The following procedures will be performed at Visit T5 (Day 56 ±3 days): 
 Perform symptom-directed physical examination; 
 Record vital signs and weight; 
 Collect urine sample for urinalysis including urine protein:creatinine ratio and NGAL; 
 Perform urine pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel and apolipoproteins;  
o hsCRP and fibrinogen; and 
o Additional samples; 
 Perform 12-lead ECG pre-dose and 2 hours post-dose; 
 Obtain PK sample pre-dose (must be 24 ±2 hours after previous day’s dose) and 0.5, 1, 2, 3, 5, 
and 12 hours post-dose. The window for PK samples obtained at time intervals <24 hours will 
be ±10 minutes; 
 Administer study drug; 
 Assess and document study drug compliance; 
 Dispense study drug and instructions; 
 Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
 Assess adverse events and update concomitant medications. 
6.3.6 
Visit T6 (Day 70) 
The following procedures will be performed at Visit T6 (Day 70 ±3 days): 
 Perform symptom-directed physical examination; 
 Record vital signs and weight; 
 Collect urine sample for urinalysis; 
 Perform urine pregnancy test (for women of child-bearing potential only); 


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 Obtain blood sample for the following:  
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel; and 
o Additional samples; 
 Perform 12-lead ECG pre-dose; 
 Obtain PK sample pre-dose (must be 24 ±2  hours after previous day’s dose); 
 Administer study drug; 
 Assess and document study drug compliance; 
 Dispense study drug and instructions; 
 Explain dietary instructions (counsel per NCEP ATP-III guidelines or equivalent); and 
 Assess adverse events and update concomitant medications. 
6.3.7 
Visit T7 (Day 84) 
The following procedures will be performed at Visit T7 (Day 84 [can be performed up to 3 days 
prior to Day 84, but not after Day 84]): 
 Perform full physical examination; 
 Record vital signs and weight; 
 Collect urine sample for urinalysis including urine protein:creatinine ratio and NGAL; 
 Perform serum pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel (clinically significant abnormal creatinine results at Day 84 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 and apolipoproteins; 
o hsCRP and fibrinogen; 
o 
 and 
o Additional samples; 
 Perform 12-lead ECG pre-dose and 2 hours post-dose; 
 Obtain PK sample pre-dose (must be 24 ±2 hours after previous day’s dose) and 0.5, 1, 2, 3, 5, 
and 12 hours post-dose. The window for PK samples obtained at time intervals <24 hours will 
be ±10 minutes; 
 Administer study drug; 
 Assess and document study drug compliance; and 
 Assess adverse events and update concomitant medications. 
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6.4 
Follow-up Visit (Day 112) 
The Follow-up Visit will be conducted as a telephone call 4 weeks (±3 days) after the last dose of 
study drug, unless the patient requires a site visit due to an abnormal result at Day 84 (or the ET 
Visit, if applicable) or an ongoing treatment-related adverse event.  
The following procedures will be performed at the Follow-up Visit (Day 112 ±3 days): 
 Perform symptom-directed physical examination (only for patients who had an abnormal result 
at Day 84 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event); 
 Collect urine sample for urinalysis including urine protein:creatinine ratio and NGAL (only 
for patients who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing 
treatment-related adverse event); 
 Obtain blood sample for safety chemistry panel, coagulation, and hematology (only for patients 
who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing 
treatment-related adverse event); and 
 Assess adverse events and update concomitant medications. 
6.5 
Early Termination Visit and Withdrawal Procedures 
For patients who are withdrawn from the study prior to completion, the following procedures will 
be performed at the ET Visit:  
 Perform full physical examination; 
 Record vital signs and weight; 
 Collect urine sample for urinalysis including urine protein:creatinine ratio and NGAL; 
 Perform serum pregnancy test (for women of child-bearing potential only); 
 Obtain blood sample for the following: 
o Safety chemistry panel, coagulation, and hematology;  
o Fasting lipid panel and apolipoproteins; 
o hsCRP and fibrinogen; 
o 
and 
o Additional samples; 
 Perform 12-lead ECG; 
 Obtain PK sample (must be 24 ±2 hours after previous day’s dose); 
 Assess and document study drug compliance; and 
 Assess adverse events and update concomitant medications. 
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7 
EFFICACY ANALYSES 
The following efficacy assessments will be measured in order to obtain the primary, secondary, 
and exploratory endpoints: 
 Fasting LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), 
TG, HDL-C, and VLDL-C at baseline, Day 14, Day 28, Day 42, Day 56, Day 70, and Day 84 
(or the ET Visit, if applicable); 
 Fasting ApoB, ApoA-I, ApoA-II, ApoC-II, ApoC-III, ApoE, and lipoprotein(a) (Lp[a]) at 
baseline, Day 28, Day 56, and Day 84 (or the ET Visit, if applicable); 
 hsCRP at baseline, Day 28, Day 56, and Day 84 (or the ET Visit, if applicable); 
 Fibrinogen at baseline, Day 28, Day 56, and Day 84 (or the ET Visit, if applicable); and 
 
 
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8 
PHARMACOKINETIC ASSESSMENTS 
The PK assessments of this study are to evaluate the gemcabene systemic exposure on Day 28, 
Day 56, and Day 84 and perform routine plasma drug monitoring on Day 1, Day 14, Day 42, and 
Day 70. 
The actual PK blood sampling times will be captured on the eCRF. The actual dosing time on PK 
sampling days and days preceding sampling will also be captured on the eCRF. 
Pharmacokinetic samples will be collected pre-dose (must be 24 ±2 hours from the previous day’s 
dose) and 0.5, 1, 2, 3, 5, and 12 hours post-dose on Day 28, Day 56, and Day 84 in collection tubes 
containing K2EDTA as the anticoagulant; for determination of gemcabene repeat-dose PK 
parameters, steady state is assumed following QD administration for 28 days and therefore, plasma 
gemcabene concentrations at 24 hours post-dose are considered to be equal to pre-dose 
concentrations. For all other study visits where routine plasma drug monitoring will be performed 
(Day 1, Day 14, Day 42, Day 70, and the ET Visit, if applicable), samples will be collected 
pre-dose (must be 24 ±2 hours from the previous day’s dose if a previous day’s dose occurred). 
The window for PK samples obtained at time intervals <24 hours will be ±10 minutes and the 
window for samples obtained at 24 hours will be ±2 hours.  


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9 
SAFETY ASSESSMENTS 
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include abnormal and clinically significant clinical laboratory test 
variables, will be monitored and documented from the time of first dose of study drug (Day 1) 
until study participation is complete (the Follow-up Visit). Patients should be instructed to report 
any adverse event that they experience to the Investigator. Beginning with the signing of the 
informed consent until the time of the first dose of study drug (Day 1), investigators should make 
updates to medical history and record any pre-existing medical condition or signs or symptoms 
that changes in severity, frequency, or seriousness in the medical history. Serious adverse events 
that occur prior to the first dose of study drug (Day 1) should be reported as an update to medical 
history as well as be reported on the appropriate adverse event eCRF. Beginning with the first dose 
of study drug (Day 1), investigators should make an assessment for adverse events at each visit 
and record all adverse events, non-serious and serious, on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure. 
Concomitant procedures should be recorded as such on the appropriate eCRF.  
Any medical condition already present prior to the patient taking the first dose of study drug 
(Day 1) should be reported in the medical history. Any SAEs occurring prior to the first dose of 
study drug (Day 1) should be reported as an update to medical history as well as an adverse event. 
Any pre-existing medical condition or signs or symptoms that changes in severity, frequency, or 
seriousness after the patient takes the first dose of study drug (Day 1) and through the Follow-up 
Visit should be reported as an adverse event. 
Clinically significant abnormal laboratory values or other examinations (e.g., ECG) that are 
detected at the time of the first dose of study drug (Day 1) and worsen during the study should be 
reported as adverse events. An abnormal laboratory result that is not verified by repeat testing does 
not necessitate reporting as an adverse event. The Investigator will exercise his or her medical, 
scientific, and clinical judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Any abnormal test that is determined to be an error does not 
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9.1.1 
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. 
9.1.2 
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. 
9.1.3 
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 relationship of an adverse event to the administration of the study drug is to 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 patient may have. 


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 Concomitant drug - 
o The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
 Known response pattern for this class of study drug - 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
 Exposure to physical and/or mental stresses - 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 
 The pharmacology and PK of the study drug - 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
9.1.4 
Specific Safety Measures 
9.1.4.1 
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 patient’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. 
9.1.4.2 
Creatinine increase 
If, at any visit, a creatinine increase of >0.3 mg/dL (27 µmol/L) from baseline or a GFR decrease 
of >15 mL/min from baseline is observed, repeat chemistry will be performed. The patient’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 patients who have unremarkable creatinine/BUN studies at the time of assessment but 
may require additional or closer/follow-up monitoring of renal studies.  
9.1.4.3 
Possible muscle and liver injury 
For muscle injury, creatine kinase (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. 


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9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
 Death; 
 A life-threatening adverse event; 
o NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
 Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 
situational reasons (i.e., no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 A congenital anomaly/birth defect; or 
 An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or 
the development of drug dependency or drug abuse. 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to 
Clinical Safety within 24 hours of the 
knowledge of the occurrence (this refers to any adverse event that meets any of the aforementioned 
serious criteria). All SAEs that the Investigator considers related to study drug occurring after the 
30-day follow-up period must be reported to the Sponsor. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, 
 Safety personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not possible to 
access 
the 
EDC 
system, 
send 
an 
email 
to 
 
Safety 
at 
PI
PI
PI




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case no later than 7 days after knowledge by the Sponsor of such a case, and that relevant follow-up 
information will subsequently be communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA, applicable 
competent authorities concerned, and to the Central Ethics Committee concerned as soon as 
possible, but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all investigators as required.  
Expedited reporting of suspected unexpected serious adverse reactions related to 
non-investigational medical products (NIMPs) used in this study will not be necessary. Listings of 
cases related to these NIMPs will be included in the Development Safety Update Report. 
9.6 
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 patient to fast will be defined as no food or caloric beverage for at least 
10 hours prior to sample collection. Patients will be permitted to have water.  
Central laboratory results will be provided to the sites. Laboratory results that appear potentially 
spurious based on the Investigator’s clinical assessment and review of the patient’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 patients who had an abnormal result 
at Day 84 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event). Clinically 
significant abnormal creatinine results at Day 84 (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 and description of when 
repeat or reflexive testing will be required. 
A fasting lipid panel will be assessed at all study visits, excluding the Follow-up Visit. Fasting 
apolipoproteins, hsCRP, and fibrinogen will be assessed at Day 1, Day 28, Day 56, Day 84, and 
the ET Visit, if applicable. In addition to these lipid parameters, 
will also be measured at 
Day 1, Day 84, and the ET Visit, if applicable.  
A urine sample for urinalysis will be collected at all study visits and the Follow-up Visit (only for 
patients who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing 
treatment-related adverse event). A urine microscopic examination will be performed when the 
dipstick result is abnormal (positive for blood, leukocyte esterase, or nitrites). Urine 
protein:creatinine ratio will be performed at the Screening Visit, Day 1, Day 28, Day 56, Day 84, 
the Follow-up Visit (only for patients who had an abnormal result at Day 84 [or the ET Visit, if 
applicable] or an ongoing treatment-related adverse event), and the ET Visit, if applicable. Urinary 
NGAL will be measured at Day 1, Day 28, Day 56, Day 84, the Follow-up Visit (only for patients 
who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing 
treatment-related adverse event), and the ET Visit, if applicable. 
Serology tests for HBV, HCV, and HIV will be conducted at the Screening Visit. 
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For women of child-bearing potential only, a serum pregnancy test will be conducted at the 
Screening Visit, Day 84, and the ET Visit, if applicable. A urine pregnancy test will be conducted 
at all other study visits, excluding the Follow-up Visit.  
Thyroid-stimulating hormone and HbA1c will be measured at the Screening Visit. 
9.7 
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 patient 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 patient throughout the study when possible. Care should be taken to ensure an appropriate 
cuff size is utilized.   
9.8 
Electrocardiograms 
Electrocardiograms will be performed in triplicate and sent to a central reviewer. Patients 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 and pre-dose on Day 1, Day 14, Day 42, 
Day 70, and the ET Visit, if applicable. Electrocardiograms will be performed pre-dose and 2 hours 
post-dose on Day 28, Day 56, and Day 84.  
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 tracings will be kept as source data. 
9.9 
Physical Examinations 
A full physical examination will be performed at the Screening Visit, Day 84, and the ET Visit, if 
applicable, and includes genitourinary examination per the Investigator’s discretion and does not 
include a rectal examination. Assessment for xanthoma or arcus should also be part of the full 
physical examination. Any changes or improvements in xanthoma or arcus will be captured on the 
appropriate eCRF.  
A symptom-directed physical examination will be conducted at all other study visits and the 
Follow-up Visit (only for patients who had an abnormal result at Day 84 [or the ET Visit, if 
applicable] or an ongoing treatment-related adverse event). 
Height will be measured at the Screening Visit and weight will be measured at all study visits, 
excluding the Follow-up Visit.  
9.10 
Medical/Surgical History and Demographics 
Medical and surgical history and demographics will be recorded at the Screening Visit. Patient 
eligibility will be evaluated to determine all inclusion and none of the exclusion criteria are met. 
The Investigator will inquire with the patient at Day 1 to determine if there have been any changes 
in the patient’s health affecting eligibility or requiring an update to their medical and surgical 
history. 


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9.11 
Genetic Testing 
Peripheral blood cell DNA for determination of genetic testing for the HoFH genotype mutational 
status will be collected at Day 1 for all patients.  
This data will be used to confirm diagnosis, categorize receptor function according to published 
data, and possibly show responses for receptor negative patients (if enrolled) separately from those 
with at least one defective receptor. 
9.12 
Additional Samples 
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, repeat lipid testing, blood drug levels, and/or repeat or additional clinical laboratory 
and urine testing in the event of a safety issue.  


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10 
STATISTICS 
10.1 
Analysis Populations 
Two analysis populations are designed for the study: the Intent-to-Treat (ITT) Population and the 
Safety Population. The Safety Population will include all patients who are enrolled into the study 
and have at least 1 dose of study drug, while the ITT Population will include patients from the 
Safety Population who also have a post-baseline efficacy assessment. 
10.2 
Statistical Methods 
10.2.1 
Analysis of Efficacy 
Given the proposed crossover design of this study, a within-patient analysis can be performed for 
the comparison of dose groups. For continuous variables, the dose groups will be compared on 
their change and percent reduction from baseline (using their pre-treatment baseline value). A 
longitudinal analysis will be performed with a mixed-effects model repeated measures analysis 
including percent change in LDL-C as the dependent variable, visit as a fixed effect and patient as 
a random effect.  The additional drug benefit with increasing dose will be estimated from the 
mixed-effects model. Least-squares mean differences and corresponding 95% confidence 
intervals, separately for each of the 3 paired comparisons (300 versus 600 mg, 300 versus 900 mg, 
and 600 versus 900 mg) will be provided. In addition, a scatterplot with regression curve fit of the 
percent reduction from baseline versus dose will be performed. For binary variables such as the 
percentage of patients, descriptive statistics will be calculated for each dose group.  
Baseline will be defined as the average of the Screening Visit occurring up to 14 days prior to 
Day 1 and Day 1 (pre-dose) measurements. 
10.2.1.1 
Primary efficacy analysis 
The primary efficacy analysis is the percent change in LDL-C from baseline to Day 28, Day 56, 
and Day 84.  
10.2.1.2 
Secondary efficacy analyses 
The secondary efficacy analyses are the following: 
 The change in LDL-C from baseline to Day 28, Day 56, and Day 84; 
 The change and percent change in lipid parameters (non-HDL-C, TC, TG, HDL-C, and 
VLDL-C) from baseline to Day 28, Day 56, and Day 84; 
 The change and percent change in lipid parameters (non-HDL-C, TC, TG, HDL-C, and 
VLDL-C) from baseline to Day 28, Day 56, and Day 84 according to the receptor mutation 
status; 
 The number (%) of patients achieving LDL-C reduction of 15%, 20%, 25%, and 30% at 
Day 28, Day 56, and Day 84; 
 The number (%) of patients achieving an LDL-C value 100 mg/dL (2.59 mmol/L) at Day 28, 
Day 56, Day 84, and at any time during the study; 
 The change and percent change in ApoB, ApoA-I, ApoA-II, ApoC-II, ApoC-III, ApoE, and 
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repeat measurements will be recorded in the clinical database. In listings and narratives, all 
laboratory values including unscheduled and repeat values will be included. 
10.2.3 
Analysis of Safety 
Safety will be assessed using the population of all patients who receive any amount of study drug. 
The assessment of safety will include adverse events, clinical laboratory assessments, ECGs, 
physical examinations, and vital signs. The safety analysis will be based primarily on the frequency 
of new or worsening adverse events, laboratory abnormalities, and SAEs. Other safety data will 
be summarized as appropriate.  
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by treatment group, system organ class, and 
preferred term. 
Safety laboratory data will be summarized at baseline, Day 28, Day 56, and Day 84, and change 
from baseline to Day 28, Day 56, and Day 84. Frequency counts of new or worsening abnormalities 
will also be provided. 
10.2.4 
Sample Size Determination 
The primary goal of the study is to assess the mean percent change in LDL-C from baseline over 
12 weeks of treatment from the 3 dose levels. Dosing 8 patients per group will yield reasonable 
precision in estimation in mean change from baseline in LDL-C.  


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
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. 
11.1.2 
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). 
11.1.3 
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. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Latest version of MedDRA for medical history and adverse events, and 
 World Health Organization Drug Dictionary for prior and concomitant medications. 
11.1.5 
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. 
11.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data 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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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
12.1 
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 patients. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study patients 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
12.2 
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 patients in research studies. The IRB/EC will review all appropriate study 
documentation in order to safeguard the rights, safety, and well-being of patients. The study will 
only be conducted at sites where IRB/EC approval has been obtained. The protocol, Investigator’s 
Brochure, ICF, advertisements (if applicable), written information given to the patients, safety 
updates, annual progress reports, and any revisions to these documents will be provided to the 
IRB/EC by the Investigator. 
Prior to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for 
patient recruitment, and any other written information regarding this study being provided to a 
patient or patient’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. 
12.3 
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 patient (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 
patient has been informed of his/her rights to privacy. The Investigator or delegate will allow the 
patient adequate opportunity to read the written informed consent and ask any questions. The 
Investigator will obtain written informed consent from each patient 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 
patient. 
12.4 
Patient Card 
On enrollment in the study, the patient will receive a patient card to be carried at all times. The 
patient card will state that the patient is participating in a clinical research study, type of treatment, 
number of treatment packs received, and contact details in case of an SAE. 


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12.5 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, Directive 2001/20/EC, and applicable regulatory 
requirements (e.g., 21 CFR 312 Part D), 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 patients 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 patient 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. 
12.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB/EC as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal physician or 
other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
12.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 


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49 
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.  
12.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
12.9 
Financial Disclosure 
Clinical Investigators are required to provide financial disclosure information to the Sponsor to 
permit the Sponsor to fulfill its obligations under 21 CFR §54. In addition, investigators must 
commit to promptly updating this information if any relevant changes occur during the study and 
for a period of 1 year after the completion of the study. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out clinical trial 
insurance. This insurance provides coverage to the Sponsor in the event of physical injury or death 
related to the study drug or any procedure related to the protocol. 
12.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorisation (CTA). 
The study will commence (i.e., initiation of study centres) when the CTA and favourable Ethics 
opinion have been received. 
12.12 
Definition of End of Study 
The End of Study is defined as the completion of the Follow-up Visit or the ET Visit, if applicable. 
12.13 
Sponsor Discontinuation Criteria 
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the IRB/EC, drug safety problems, or at the discretion of Gemphire. In addition, 
Gemphire retains the right to discontinue development of gemcabene at any time.  
If a study is prematurely terminated or discontinued, Gemphire will promptly notify the 
Investigator. After notification, the Investigator must contact all participating patients 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 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the investigators by 
 or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented only after it has been approved by 
the IRB, unless immediate implementation of the change is necessary for patient safety. In this 
case, the situation must be documented and reported to the IRB within 5 working days. 
13.2 
Address List 
13.2.1 
Sponsor 
Gemphire Therapeutics Inc.  
43334 Seven Mile Road, Suite 1000 
Northville, Michigan 48167 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
13.2.2 
Contract Research Organization 
PI
PI


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51 
14 
REFERENCES 
1. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new 
insights and guidance for clinicians to improve detection and clinical management. A position 
paper from the Consensus Panel on Familial Hypercholesterolaemia of the European 
Atherosclerosis Society. Eur Heart J. 2014;35(32):2146-2157. 
2. Bisgaier and Auerbach, 2015. Gemcabene and atorvastatin alone and combined markedly 
reduce LDL-C in LDL receptor-deficient mice, a model of Homozygous Familial 
Hypercholesterolemia. Circulation. 2015; 132: A17824. 
3. Sexton KE, Lee HT, Massa M, et al. Inhibitors of lipoprotein(a) assembly. Bioorg Med Chem. 
2003;11(22):4827-45. 
4. Stein EA. Low-density lipoprotein cholesterol reduction by inhibition of PCSK9. Curr Opin 
Lipidol. 2013;24(6):510-7. 
5. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and 
adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 
2015;36(36):2425-37. 


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52 
APPENDIX A: SCHEDULE OF PROCEDURES 
Footnotes appear on the following page
 
Screening 
Treatment Perioda 
Follow-upb 
ET 
300 mg Gemcabene 
600 mg Gemcabene 
900 mg Gemcabene 
up to Day -14 
Day 1c 
Day 14 
Day 28 
Day 42 
Day 56 
Day 70 
Day 84 
Day 112 
 
Visit S1 
Visit T1 
Visit T2 
Visit T3 
Visit T4 
Visit T5 
Visit T6 
Visit T7 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Full physical examinationd 
X 
 
 
 
 
 
 
X 
 
X 
Symptom-directed physical examination 
 
X 
X 
X 
X 
X 
X 
 
Xe 
 
Vital signsf, heightg, and weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysish 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
X  
Serum/urine pregnancy testi 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety chemistry panel, coagulation, and 
hematologyj 
X 
X 
X  
X 
X 
X 
X 
X 
Xe 
X 
TSH, HbA1c, and serologyk 
X 
 
 
 
 
 
 
 
 
 
Fasting lipid panell 
X 
X 
X  
X 
X 
X 
X 
X 
 
X 
Fasting apolipoproteinsm 
 
X 
 
X 
 
X 
 
X 
 
X 
hsCRP and fibrinogen 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense study drug and instructions 
 
X 
X 
X 
X 
X 
X 
 
 
 
Compliance check 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Dietary instructionsn 
X 
X 
X 
X 
X 
X 
X 
 
 
 
PK samplingo 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECGp 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse events 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic testing 
 
X 
 
 
 
 
 
 
 
 
Additional samples 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
CI


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a. 
Study assessments will be completed ±3 days of given time point for all study visits from Day 1 through Day 70. Day 84 assessments can be performed up to 3 days prior 
to Day 84, but not after Day 84.  
b. 
The Follow-up Visit will be conducted as a telephone call 4 weeks (±3 days) after the last dose of study drug, unless the patient requires a site visit due to an abnormal 
result at Day 84 (or the ET Visit, if applicable) or an ongoing treatment-related adverse event.  
c. 
Procedures will be performed pre-dose. The Investigator will inquire with the patient at Day 1 to determine if there have been any changes in the patient’s health 
affecting eligibility or requiring an update to their medical and surgical history. 
d. 
A full physical examination includes genitourinary examination per the Investigator’s discretion and does not include a rectal examination. Assessment for xanthoma or 
arcus should also be part of the full physical examination. Any changes or improvements in xanthoma or arcus will be captured on the appropriate eCRF. 
e. 
Only for patients who had an abnormal result at Day 84 (or the ET Visit, if applicable) or an ongoing treatment-related adverse event.  
f. 
Vital signs include pulse rate, blood pressure, respiration rate, and temperature. Blood pressure should be obtained in the seated position, after the patient 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 patient throughout the study when 
possible. Care should be taken to ensure an appropriate cuff size is utilized. 
g. 
Height will be measured only at the Screening Visit. 
h. 
A urine microscopic examination will be performed when the dipstick result is abnormal (positive for blood, leukocyte esterase, or nitrites). Urine protein:creatinine ratio 
will be performed at the Screening Visit, Day 1, Day 28, Day 56, Day 84, the Follow-up Visit (only for patients who had an abnormal result at Day 84 [or the ET Visit, if 
applicable) or an ongoing treatment-related adverse event]), and the ET Visit, if applicable. Urinary NGAL will be measured at Day 1, Day 28, Day 84, the Follow-up 
Visit (only for patients who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event), and the ET Visit, if 
applicable. 
i. 
For women of child-bearing potential only, a serum pregnancy test will be conducted at the Screening Visit, Day 84, and the ET Visit, if applicable. A urine pregnancy 
test will be conducted at all other study visits, excluding the Follow-up Visit.  
j. 
Clinically significant abnormal creatinine results at Day 84 (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. 
k. 
Serology includes HBV, HCV, and HIV.  
l. 
Includes LDL-C, non-HDL-C, TC, TG, HDL-C, and VLDL-C. Fasting will be defined as no food or caloric beverage for at least 10 hours prior to sample collection. 
Patients will be permitted to have water.  
m. Includes ApoB, ApoA-I, ApoA-II, ApoC-II, ApoC-III, ApoE, and Lp(a). Fasting will be defined as no food or caloric beverage for at least 10 hours prior to sample 
collection. Patients will be permitted to have water.  
n. 
Patients will be counseled on a low-fat, low-cholesterol diet (NCEP ATP-III guidelines or equivalent). 
o. 
Pharmacokinetic samples will be collected pre-dose (must be 24 ±2 hours from the previous day’s dose) and 0.5, 1, 2, 3, 5, and 12 hours post-dose on Day 28, Day 56, and 
Day 84 in collection tubes containing K2EDTA as the anticoagulant. For all other study visits where routine plasma drug monitoring will be performed (Day 1, Day 14, 
Day 42, Day 70, and the ET Visit, if applicable), samples will be collected pre-dose (must be 24 ±2 hours from the previous day’s dose if a previous day’s dose occurred). 
The window for PK samples obtained at time intervals <24 hours will be ±10 minutes. 
p. 
Electrocardiograms will be performed in triplicate and sent to a central reviewer. A 12-lead ECG will be performed at the Screening Visit and pre-dose on Day 1, Day 14, 
Day 42, Day 70, and the ET Visit, if applicable. Electrocardiograms will be performed pre-dose and 2 hours post-dose on Day 28, Day 56, and Day 84. Patients should be 
lying quietly in a fully supine position for at least 10 minutes prior to each 12-lead ECG. 
q. 
Serious adverse events that occur prior to the first dose of study drug (Day 1) should be reported as an update to medical history as well as be reported on the appropriate 
adverse event eCRF. 
Apo = apolipoprotein; ECG = electrocardiogram; eCRF = electronic Case Report Form; ET = Early Termination; HbA1c = hemoglobin A1c; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; 
K2EDTA = dipotassium ethylenediaminetetraacetic acid; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); NCEP ATP-III = National Cholesterol Education 


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Program Adult Treatment Panel III; NGAL = neutrophil gelatinase-associated lipocalin; non-HDL-C = non-high-density lipoprotein;
 
 PK = pharmacokinetic; TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone; VLDL-C = very low-density lipoprotein cholesterol.
CI
CI


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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel  
Alanine aminotransferase  
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate  
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine [1] 
Gamma-glutamyl transferase 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Total bilirubin [2] 
Total protein 
Estimated glomerular filtration rate (GFR) [3] 
 
1. 
For a creatinine increase of >0.3 mg/dL (27 µmol/L) from baseline during the study, repeat chemistry will be performed.  
2. 
If total bilirubin is elevated, reflexive direct bilirubin testing will be performed. 
3. 
For an estimated GFR decrease of >15 mL/min from baseline during the study, repeat chemistry will be performed. 
Additional Chemistry Parameter 
Glycosylated hemoglobin 
 
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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Urinalysis [1] 
pH 
Proteinuria [2] 
Ketones 
Blood 
Leukocyte esterase 
Specific Gravity 
Glucose 
Bilirubin  
Nitrite 
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, Day 1, Day 28, Day 56, Day 84, the Follow-up Visit 
(only for patients who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing treatment-related 
adverse event), and the ET Visit, if applicable. 
3. 
Urinary NGAL will be measured at Day 1, Day 28, Day 56, Day 84, the Follow-up Visit (only for patients who had an 
abnormal result at Day 84 [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 patients of child-bearing 
potential. 
Serology 
Hepatitis B 
Hepatitis C  
Human Immunodeficiency Virus 
 
Coagulation  
Prothrombin time 
Activated partial thromboplastin time 
International normalized ratio 
 
 
Genetic Testing 
Homozygous familial hypercholesterolemia genotyping 
 
 
Efficacy Parameters  
The following efficacy parameters will be assessed in this study: 
Apolipoprotein (Apo) A-I 
ApoA-II 
ApoB 
ApoC-II 
ApoC-III 
ApoE 
High-density lipoprotein cholesterol  
Low-density lipoprotein cholesterol  
Non-high-density lipoprotein cholesterol 
Very low-density lipoprotein cholesterol 
Triglycerides 
Total cholesterol  
High-sensitivity C-reactive protein 
Lipoprotein(a) 
 
Fibrinogen 
CCI


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APPENDIX C: NEW YORK HEART ASSOCIATION CONGESTIVE 
HEART FAILURE CLASSIFICATION 
 Class I: patients 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: patients 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: patients 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: patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is increased. 
Source: The Criteria of the New York Heart Association. Nomenclature and Criteria for Diagnosis 
of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.  


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APPENDIX D: CYTOCHROME P450 3A4 INHIBITORS: 
EXCLUSIONARY MEDICATIONS  
Amiodarone 
Amprenavir 
Atazanavir 
Cimetidine 
Clarithromycin 
Conivaptan 
Darunavir 
Delavirdine 
Diltiazem 
Erythromycin 
Fluconazole 
Fluvoxamine 
Fosamprenavir 
Grapefruit juice 
Imatinib 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir 
Miconazole 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telithromycin 
Tipranavir 
Troleandomycin 
Verapamil 
Voriconazole 
 
 


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59 
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 patients with suspected or confirmed muscle injury should be managed according to the 
standard of care at the discretion of the Investigator. 
 Patients 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. 
 Patients 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 patients 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 patients are instructed to not undertake any form of strenuous physical activity 
for at least 24 hours prior to repeat blood testing. 
Hepatic Monitoring 
Patients with hepatic enzyme elevations should be managed according to the standard of care, at 
the discretion of the Investigator. For patients with signs or symptoms suggestive of hepatitis, an 
unscheduled visit and a chemistry panel should be performed. Patients with an alanine 
aminotransferase (ALT) >2 × ULN with symptoms suggestive of hepatitis should have an 
unscheduled visit. Patients 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 patient 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; 
 ALT or AST >3 × ULN and either total bilirubin >2 × ULN or international normalized 
ratio >1.5; and/or 


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 ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
If patients are receiving statins in addition to study treatment, 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. 

SAP_000.pdf: 
Title: A Phase 2 Open-Label, Dose-Finding Study to Assess the Efficacy, Safety, and Tolerability of 
Gemcabene in Patients with Homozygous Familial Hypercholesterolemia on Stable, Lipid-Lowering 
Therapy (COBALT-1) 
 
NCT ID: NCT02722408 
 
Approval Date: 07-Jun-2017 
 


APPENDIX 16.1.9: DOCUMENTATION OF STATISTICAL METHODS 
Statistical Analysis Plan Version 1.0, 07 June 2017 ........................................................................2 


M 
p 
CE 
THE ADVANTAGE OF FOCUS 
STATISTICAL ANALYSIS PLAN 
A Phase 2 Open-Label, Dose-Finding Study to Assess the Efficacy, 
Safety, and Tolerability of Gemcabene in Patients with Homozygous 
Familial Hypercholesterolemia on Stable, Lipid-Lowering Therapy 
(COBALT-1) 
Investigational Product: Gemcabene calcium tablets (gemcabene) 
Protocol Number: GEM-201 
Sponsor: 
Gemphire Therapeutics Inc. 
43334 Seven Mile Road, Suite 1000 
Northville, Michigan 48167 
United States 
Telephone: +1-248-681-9815 
Facsimile: + 1-734-864-5765 
Version Number: 1.0 
Date: 7 June 2017 
CONFIDENTIAL 
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. 


SIGNATURE PAGE 
Protocol Title: A Phase 2 Open-Label, Dose-Finding Study to Assess the Efficacy, Safety, and 
Tolerability of Gemcabene in Patients with Homozygous Familial Hypercholesterolemia on 
Stable, Lipid-Lowering Therapy (COBALT-I) 
Protocol Number: GEM-201 
We, the undersigned, have reviewed and approve this Statistical Analysis Plan. 
Signature 
Gemphire Therapeutics Inc. 
Statistical Analysis Plan 
Version Number: 1.0 
Page2 
Date 
Protocol Number: GEM-20 l 
Version Date: 7 June 2017 
PI
PI


Date 
07 June 2017 
Statistical Analysis Plan 
Version Number: 1.0 
VERSION HISTORY 
Description 
Original signed version 
Page3 
Protocol Number: GEM-201 
Version Date: 7 June 2017 


TABLE OF CONTENTS 
Introduction ............................................................................................................................. 8 
2 
Overview ................................................................................................................................. 8 
2.1 Objectives ......................................................................................................................... 8 
2.1.1 Primary Objective ................................................................................................... 8 
2.1.2 Secondary Objectives ............................................................................................. 8 
2.1.3 Exploratory Objective ............................................................................................ 8 
2.2 Trial Design ...................................................................................................................... 8 
3 
Analysis Variables ................................................................................................................. 13 
3.1 Efficacy Variables .......................................................................................................... 13 
3 .1.1 Primary efficacy variable ..................................................................................... 13 
3.1.2 Secondary efficacy variables ................................................................................ 13 
3.1.3 Exploratory efficacy variables .............................................................................. 13 
3.2 Safety Variables ............................................................................................................. 13 
3 .2.1 Adverse Events ..................................................................................................... 14 
3 .2.2 Safety Laboratory Evaluations ............................................................................. 14 
3.2.3 Vital Signs ............................................................................................................ 14 
3.2.4 Electrocardiograms ............................................................................................... 14 
3.2.5 Physical Examinations ......................................................................................... 14 
3.3 Pharmacokinetic Variables ............................................................................................. 15 
3.3 .1 Concentration Data ............................................................................................... 15 
3 .3 .2 Pharmacokinetic Parameters ................................................................................ 15 
4 
Analysis Populations ............................................................................................................. 15 
4.1.1 Safety Population ................................................................................................. 15 
4.1.2 Full Analysis Set Population ................................................................................ 15 
5 
General Considerations for Data Analysis ............................................................................ 15 
5.1 Evaluation of Center Effect ............................................................................................ 16 
5.2 Assessment Windows ..................................................................................................... 16 
5.3 Handling of Dropouts and Missing Data ........................................................................ 16 
5.4 Programming Specifications .......................................................................................... 16 
6 
Analysis of Disposition and Subject Characteristics ............................................................. 16 
6.1 Disposition and Analysis Populations ............................................................................ 16 
6.2 Demographics and Baseline Characteristics .................................................................. 17 
6.3 Concomitant Medications .............................................................................................. 17 
7 
Analysis ofEfficacy .............................................................................................................. 17 
7.1 Primary Efficacy Analysis ............................................................................................. 18 
7.2 Secondary Efficacy Analyses ......................................................................................... 18 
7.3 Exploratory Efficacy Analyses ....................................................................................... 19 
Statistical Analysis Plan 
Version Number: 1.0 
Page4 
Protocol Number: GEM-201 
Version Date: 7 June 2017 


8 
Analysis of Safety ........................................................................... : ...................................... 19 
8.1 Extent ofExposure ......................................................................................................... 19 
8.2 Adverse Events ............................................................................................................... 20 
8.3 Safety Laboratory Parameters ........................................................................................ 20 
8.4 Vital Signs ...................................................................................................................... 21 
8.5 ECG Parameters ............................................................................................................. 21 
8.6 Physical Examinations ................................................................................................... 21 
8.7 Pharmacokinetic Analysis .............................................................................................. 21 
9 
Data Safety Monitoring Board .............................................................................................. 21 
10 Interim Analysis .................................................................................................................... 21 
11 Sample Size and Power Considerations ................................................................................ 22 
12 Changes from Protocol-Specified Statistical Analyses ......................................................... 22 
13 References ............................................................................................................................. 22 
Statistical Analysis Plan 
Version Number: 1.0 
Page 5 
Protocol Number: GEM-20 1 
Version Date: 7 June 2017 


LIST OF ABBREVIATIONS 
Apo 
Apolipoprotein 
ATC 
Anatomical Therapeutic Chemical 
AUCo-24 
Area under the concentration-time curve to the 24-hour time point 
AU Co-t 
Area under the concentration-time curve to the last quantifiable time 
Cmax 
Maximum plasma concentration 
CSR 
Clinical Study Report 
cv 
Coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FAS 
Full Analysis Set 
HbAlc 
Hemoglobin Ale 
HDL-C 
High-density lipoprotein cholesterol 
HoFH 
Homozygous familial hypercholesterolemia 
hsCRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
KzEDTA 
Dipotassium ethylenediaminetetraacetic acid 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein( a) 
MedDRA 
Medical Dictionary for Regulatory Affairs 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetic 
QD 
Once daily 
RTF 
Rich Text Format 
SAE 
Serious adverse event 
Statistical Analysis Plan 
Version Number: 1.0 
Page 6 
Protocol Number: GEM-201 
Version Date: 7 June 2017 


SAP 
Statistical Analysis Plan 
SP 
Safety Population 
SOP 
Standard Operating Procedure 
TC 
Total cholesterol 
TG 
Triglyceride 
tmax 
Time to maximum plasma concentration 
TSH 
Thyroid -stimulating hormone 
VLDL-C 
Very low-density lipoprotein cholesterol 
WHO 
World Health Organization 
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1 
INTRODUCTION 
The purpose of this document is to provide a description of the statistical methods and procedures 
to be implemented for the analysis of data from Gemphire Therapeutics Inc. ("Gemphire"), 
Clinical Trial Protocol GEM-201. This document is based on protocol version 1.0 dated February 
19, 2016. If circumstances arise during the study such that more appropriate analytic procedures 
become available, the statistical analysis plan (SAP) may be revised. Any revisions to the SAP 
(both alternative and additional methods) will be made prior to database lock and reasons for such 
revisions will be described in the final Clinical Study Report (CSR). 
2 
OVERVIEW 
2.1 
Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to evaluate the efficacy, safety, and tolerability of multiple 
doses of gemcabene in patients with Homozygous Familial Hypercholesterolemia (HoFH) on 
stable, lipid-lowering therapy. 
2.1.2 Secondary Objectives 
The secondary objectives are the following: 
• 
To confirm the appropriate dose for use in Phase 3 registration studies as assessed by 
efficacy, pharmacokinetic (PK), and safety data (an effective dose is defined as a dose that 
achieves :2::15% mean reduction in low-density lipoprotein cholesterol [LDL-C] after 4 
weeks of treatment); 
• 
To further evaluate the efficacy of gemcabene in patients with HoFH following 4 weeks of 
dosing with gemcabene 300 mg once daily (QD), 4 weeks of dosing with gemcabene 600 
mg QD, and 4 weeks of dosing with gemcabene 900 mg QD, as assessed by measurements 
of lipid and apolipoprotein parameters, high-density C-reactive protein (hsCRP), and 
fibrinogen; and 
• 
To evaluate trough plasma concentrations of gemcabene at doses 300 mg, 600 mg, and 
900mg. 
2.1.3 Exploratory Objective 
 
 
2.2 
Trial Design 
This is a Phase 2, open-label, dose-finding, 3-period, 3-treatment study using successively 
escalating doses of 300 mg, 600 mg, and 900 mg gemcabene in patients with HoFH. All patients 
will be on each of the successive doses for 4 weeks at a time. Patients will remain on their current 
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stable, lipid-lowering therapy throughout the study. Patients will not be allowed in the study if they 
are undergoing apheresis or taking mipomersen or lomitapide. 
The population for this study is male and female patients, 
years of age, diagnosed with HoFH 
by genetic confirmation or a clinical diagnosis based on either (1) a history of an untreated LDL-C 
concentration >500 mg/dL (12.92 mmol/L) together with either appearance of xanthoma before 
10 years of age, or evidence of heterozygous familial hypercholesterolemia in both parents or, if 
history is unavailable, (2) LDL-C >300 mg/dL (7.76 mmol/L) on maximally tolerated 
lipid-lowering drug therapy. Approximately 8 patients will be enrolled into the study. Total study 
duration will be up to 18 weeks and will consist of a Screening Visit, a Treatment Period, and a 
Follow-up Visit. 
The Treatment Period is a sequential design whereby each patient will receive gemcabene 300 mg 
QD for 4 weeks. The same patients will then receive a 600 mg dose QD for 4 weeks and finally 
900 mg dose QD for 4 weeks. There will be no interruptions in gemcabene dosing when changing 
from the 300 mg to the 600 mg dose or when changing from the 600 mg to the 900 mg dose unless 
there are clinically significant safety issues resulting in the temporary or permanent 
discontinuation of study drug. The first 300 mg dose of study drug will be administered at the site 
on Day 1. Assessments will be performed after the patient has been on the study drug for 2 weeks 
for each dosing level and on the last day of each dose. 
The Follow-up Visit will occur 4 weeks (±3 days) after the last dose of study drug. 
The schedule of events for the trial is provided in Table 1. 
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Table 1. SCHEDULE OF PROCEDURES 
Informed consent 
Inclusion/exclusion criteria 
MedicaVsurgical history and demographics 
Full physical examinationd 
Symptom-directed physical examination 
Vital signsf, heights, and weight 
Urinalysish 
Serum/urine pregnancy testi 
Safety chemistry panel, coagulation, and 
hematologyi 
TSH, HbAlc, and serologyk 
Fasting lipid panel1 
Fasting apolipoproteinsm 
hsCRP and fibrinogen 
 
Study drug administration 
Dispense study drug and instructions 
Compliance check 
Dietary instructions" 
PK sampling0 
12-lead ECGP 
Adverse events 
Concomitant medications 
Genetic testing 
Additional samples 
Footnotes appear on the followmg page 
Statistical Analysis Plan 
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Screening 
up to Day -14 
Visit 81 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xq 
X 
Treatment Period• 
300 mg Gemcabene 
600 mg Gemcabene 
Day tt 
Day 14 
Day28 
Day42 
Day 56 
VisitT1 
VisitT2 
VisitT3 
Visit T4 
VisitTS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 10 
900 mg Gemcabene 
Follow-upb 
ET 
Day70 
VisitT6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day84 
Day 112 
VisitT7 
X 
X 
xe 
X 
X 
X 
xe 
X 
X 
X 
X 
xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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a. 
Study assessments will be completed ±3 days of given time point for all study visits from Day I through Day 70. Day 84 assessments can be performed up to 3 days prior 
to Day 84, but not after Day 84. 
b. 
The Follow-up Visit will be conducted as a telephone call4 weeks (±3 days) after the last dose of study drug, unless the patient requires a site visit due to an abnormal 
result at Day 84 (or the ET Visit, if applicable) or an ongoing treatment-related adverse event. 
c. 
Procedures will be performed pre-dose. The Investigator will inquire with the patient at Day I to determine ifthere have been any changes in the patient's health 
affecting eligibility or requiring an update to their medical and surgical history. 
d. 
A full physical examination includes genitourinary examination per the Investigator's discretion and does not include a rectal examination. Assessment for xanthoma or 
arcus should also be part of the full physical examination. Any changes or improvements in xanthoma or arcus will be captured on the appropriate eCRF. 
e. 
Only for patients who had an abnormal result at Day 84 (or the ET Visit, if applicable) or an ongoing treatment-related adverse event. 
f. 
Vital signs include pulse rate, blood pressure, respiration rate, and temperature. Blood pressure should be obtained in the seated position, after the patient 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 patient throughout the study when 
possible. Care should be taken to ensure an appropriate cuff size is utilized. 
g. 
Height will be measured only at the Screening Visit. 
h. 
A urine microscopic examination will be performed when the dipstick result is abnormal (positive for blood, leukocyte esterase, or nitrites). Urine protein:creatinine ratio 
will be performed at the Screening Visit, Day I, Day 28, Day 56, Day 84, the Follow-up Visit (only for patients who had an abnormal result at Day 84 [or the ET Visit, if 
applicable) or an ongoing treatment-related adverse event]), and the ET Visit, if applicable. Urinary NGAL will be measured at Day I, Day 28, Day 84, the Follow-up 
Visit (only for patients who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing treatment-related adverse event), and the ET Visit, if 
applicable. 
i. 
For women of child-bearing potential only, a serum pregnancy test will be conducted at the Screening Visit, Day 84, and the ET Visit, if applicable. A urine pregnancy 
test will be conducted at all other study visits, excluding the Follow-up Visit. 
j. 
Clinically significant abnormal creatinine results at Day 84 (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. 
k. 
Serology includes HBV, HCV, and HIV. 
I. 
Includes LDL-C, non-HDL-C, TC, TG, HDL-C, and VLDL-C. Fasting will be defined as no food or caloric beverage for at least I 0 hours prior to sample collection. 
Patients will be permitted to have water. 
m. 
Includes ApoB, ApoA-I, ApoA-II, ApoC-II, ApoC-III, ApoE, and Lp(a). Fasting will be defined as no food or caloric beverage for at least IO hours prior to sample 
collection. Patients will be permitted to have water. 
n. 
Patients will be counseled on a low-fat, low-cholesterol diet (NCEP ATP-III guidelines or equivalent). 
o. 
Pharmacokinetic samples will be collected pre-dose (must be 24 ±2 hours from the previous day's dose) and 0.5, I, 2, 3, 5, and I2 hours post-dose on Day 28, Day 56, and 
Day 84 in collection tubes containing K:£DTA as the anticoagulant. For all other study visits where routine plasma drug monitoring will be performed (Day I, Day I4, 
Day 42, Day 70, and the ET Visit, if applicable), samples will be collected pre-dose (must be 24 ±2 hours from the previous day's dose if a previous day's dose occurred). 
The window for PK samples obtained at time intervals <24 hours will be ±IO minutes. 
p. 
Electrocardiograms will be performed in triplicate and sent to a central reviewer. A I2-lead ECG will be performed at the Screening Visit and pre-dose on Day I, Day I4, 
Day 42, Day 70, and the ET Visit, if applicable. Electrocardiograms will be performed pre-dose and 2 hours post-dose on Day 28, Day 56, and Day 84. Patients should be 
lying quietly in a fully supine position for at least I 0 minutes prior to each I2-lead ECG. 
q. 
Serious adverse events that occur prior to the first dose of study drug (Day I) should be reported as an update to medical history as well as be reported on the appropriate 
adverse event eCRF. 
Apo = apolipoprotein; ECG =electrocardiogram; eCRF =electronic Case Report Form; ET =Early Termination; HbAlc =hemoglobin Ale; HBV =hepatitis B virus; 
HCV =hepatitis C virus; HDL-C =high-density lipoprotein cholesterol; HIV =human immunodeficiency virus; hsCRP =high-sensitivity C-reactive protein; 
KzEDTA =dipotassium ethylenediaminetetraacetic acid; LDL-C =low-density lipoprotein cholesterol; Lp(a) =lipoprotein( a); NCEP ATP-III =National Cholesterol Education 
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Program Adult Treatment Panel III; NGAL =neutrophil gelatinase-associated lipocalin; non-HDL-C =non-high-density lipoprotein; 
 
 PK = pharmacokinetic; TC =total cholesterol; TG =triglyceride; TSH =thyroid-stimulating hormone; VLDL-C =very low-density lipoprotein cholesterol. 
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3 
ANALYSIS VARIABLES 
3.1 
Efficacy Variables 
3.1.1 Primary efficacy variable 
The primary efficacy analysis is the percent change in LDL-C from baseline to Day 28, Day 56, 
and Day 84. 
3.1.2 Secondary efficacy variables 
The secondary efficacy analyses are the following: 
• 
The change in LDL-C from baseline to Day 28, Day 56, and Day 84; 
• 
The change and percent change in lipid parameters (non-high-density lipoprotein cholesterol 
[non-HDL-C], total cholesterol [TC], triglycerides [TG], high-density lipoprotein cholesterol 
[HDL-C], and very low-density lipoprotein cholesterol [VLDL-C]) from baseline to Day 28, 
Day 56, and Day 84; 
• 
The change and percent change in lipid parameters (LDL-C, non-HDL-C, TC, TG, HDL-C, 
and VLDL-C) from baseline to Day 28, Day 56, and Day 84 according to the receptor mutation 
status; 
• 
The number(%) of patients achieving LDL-C reduction of:2:15%, :2:20%,:2:25%, and :2:30% at 
Day 28, Day 56, and Day 84; 
• 
The number(%) of patients achieving an LDL-C value <100 mg/dL (2.59 mmol/L) at Day 28, 
Day 56, and Day 84, and at any time during the study; 
• 
The change and percent change in apolipoprotein (Apo) B, ApoA-I, ApoA-II, ApoC-II, 
ApoC-III, ApoE, and lipoprotein(a) [Lp(a)] from baseline to Day 28, Day 56, and Day 84; 
• 
The change and percent change in hsCRP from baseline to Day 28, Day 56, and Day 84; and 
• 
The change and percent change in fibrinogen from baseline to Day 28, Day 56, and Day 84. 
3.1.3 Exploratory efficacy variables 
 
3.2 
Safety Variables 
The safety variables include adverse events (AEs); safety laboratory parameters (chemistry, 
hematology, coagulation, and urinalysis) with particular attention to hepatic (e.g., alanine 
aminotransferase/aspartate aminotransferase, bilirubin, alkaline phosphatase), renal (e.g., blood 
urea nitrogen, serum creatinine, protein:creatinine ratio, urinalysis sediments, pH, electrolytes), 
and skeletal muscle (i.e., creatine kinase) toxicities; 12-lead electrocardiograms (ECGs); physical 
examinations (PEs); and vital signs. 
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3.2.1 Adverse Events 
AEs will be assessed at all study visits and the Follow-up Visit. Adverse events that occur on or 
after the first dose of study drug (Day 1) will be considered treatment-emergent adverse events 
(TEAEs ). Further details regarding AEs, such as the definition of an AE or serious adverse event 
(SAE), TEAEs, assessment of severity, assessment of causality, etc., are described in Section 9.1 
and 9.2 ofthe protocol. 
3.2.2 Safety Laboratory Evaluations 
Standard clinical laboratory evaluations for safety chemistry, coagulation, hematology, and 
urinalysis will be conducted at all study visits and the Follow-up Visit (only for patients who had 
an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing treatment-related 
adverse event). Clinically significant abnormal creatinine results at Day 84 (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. 
3.2.3 
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. 
Height will be measured at the Screening Visit and weight will be measured at all study visits, 
excluding the Follow-up Visit. 
3.2.4 Electrocardiograms 
ECGs will be performed in triplicate and sent to a central reviewer. A 12-lead ECG will be 
performed at the Screening Visit and pre-dose on Day 1, Day 14, Day 42, Day 70, and the ET 
Visit, if applicable. Electrocardiograms will be performed pre-dose and 2 hours post-dose on Day 
28, Day 56, and Day 84. 
3.2.5 Physical Examinations 
A full PE will be performed at the Screening Visit, Day 84, and the ET Visit, if applicable, and 
includes genitourinary examination per the Investigator's discretion and does not include a rectal 
examination. Assessment for xanthoma or arcus should also be part of the full PE. 
A symptom-directed PE will be conducted at all other study visits and the Follow-up Visit (only 
for patients who had an abnormal result at Day 84 [or the ET Visit, if applicable] or an ongoing 
treatment-related adverse event). 
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3.3 
Pharmacokinetic Variables 
3.3.1 
Concentration Data 
Pharmacokinetic samples will be collected pre-dose (must be 24 ±2 hours from the previous day's 
dose) and 0.5, 1, 2, 3, 5, and 12 hours post-dose on Day 28, Day 56, and Day 84 in collection tubes 
containing K2EDTA as the anticoagulant. For all other study visits where routine plasma drug 
monitoring will be performed (Day 1, Day 14, Day 42, Day 70, and the ET Visit, if applicable), 
samples will be collected pre-dose (must be 24 ±2 hours from the previous day's dose if a previous 
day's dose occurred). 
3.3.2 Pharmacokinetic Parameters 
The following PK parameters will be calculated, as appropriate, from the individual plasma 
concentrations of gemcabene on Day 28, Day 56, and Day 84: 
• 
Cmax: maximum plasma concentration, 
• 
tmax (h): time to maximum plasma concentration in hours, 
• 
AUCo-t (ng·h/mL): area under the concentration-time curve to the last quantifiable time, and 
• 
AUCo-24 (ng·h/mL): area under the concentration-time curve to the 24-hour time point. 
4 
ANALYSIS POPULATIONS 
Two analysis populations are designed for the study: the Full Analysis Set (F AS) Population and 
the Safety Population (SP). 
4.1.1 Safety Population 
The SP will include all patients who are enrolled into the study and have at least 1 dose of study 
drug. This population will be used to summarize all safety data. 
4.1.2 Full Analysis Set Population 
The F AS will include patients from the Safety Population who also have a valid post-baseline 
efficacy assessment, for a given dose level. 
5 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
is responsible for the statistical analyses for this trial. The statistical planning and 
conduct of analyses of the data from this trial will follow the principles defined in relevant 
Intemational Conference of Harmonisation (ICH)-E9 guidelines and 
 biostatistical 
standard operating procedures (SOPs). All tables, figures, and listings will be generated with 
SAS® (SAS Institute Inc., Cary, North Carolina, USA) Version 9.3 or higher and printed using a 
Rich Text Format (RTF) file format. 
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5.1 
Evaluation of Center Effect 
Due to the design, objectives, and sample size of the trial, center effects will not be evaluated. 
5.2 
Assessment Windows 
To summarize laboratory variables, consecutive time windows will be created around each planned 
visit. In the descriptive statistics oflaboratory variables, only measurements from scheduled visits 
will be used if values are available. If no values from a scheduled visit are available but values 
from unscheduled visits are available, the values from the last unscheduled visit from that window 
will be used for the summary statistics. The results of all laboratory values from unscheduled and 
repeat measurements will be recorded in the clinical database. In listings and narratives, all 
laboratory values including unscheduled and repeat values will be included. 
For analysis purposes, if the event date is on or after the first treatment date, the study day is 
defined as follows: 
Study Day = Event date -First treatment date + 1 
Therefore, the day of first treatment will be Day 1. If the event date is prior to the first treatment 
date, the addition of 1 will not be included in the calculation; thus, there will be no Day 0. 
5.3 
Handling of Dropouts and Missing Data 
The primary analyses of the primary and secondary outcome variables will use linear mixed effects 
models. This analysis method will allow for inclusion of patients with missing values thus using 
the maximum amount of data for the analysis and making fewer assumptions about the missing 
data compared to a more traditional per-protocol analysis. 
Adverse events with missing start dates will be considered as treatment-emergent unless the partial 
date excludes that possibility, e.g. the adverse event month is prior to the treatment infusion month. 
Otherwise, the first day of the month will be used to impute missing start days and January will be 
used to impute missing start months. 
5.4 
Programming Specifications 
The programming specifications, including the mock-up analysis tables, figures, and data listings, 
as well as the derived database specifications, will be prepared in stand-alone documents. The 
programming specification documents will be finalized prior to database lock. 
6 
ANALYSIS OF DISPOSITION AND SUBJECT CHARACTERISTICS 
6.1 
Disposition and Analysis Populations 
Subject disposition information will be summarized. Counts (number and percent) of subjects 
who are randomized, who are dosed with study medication, who complete the study, and who 
withdraw early from the study will be presented. The primary reasons for early withdrawals will 
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also be tabulated. The SP will be used as the denominator for the percentage calculation. Subject 
disposition, inclusion I exclusion criteria and comments will be listed. 
The number and percent of patients in each analysis population will also be tabulated. 
6.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively for the Safety 
population and for F AS population, if it differs from the SP. 
Demographic and baseline characteristics include, but are not limited to, age at informed consent, 
gender, race, ethnicity, height, baseline weight, and baseline body mass index. Continuous 
variables (e.g., age, weight, etc.) will be summarized by descriptive statistics. Categorical variables 
(e.g., gender, race, and ethnicity) will be summarized by the number and percentage of patients in 
corresponding categories. Demographic characteristics will also be listed. 
Medical/surgical history will be summarized for the number and percentage of patients for each 
system organ class and preferred term. Medical history will also be listed. 
Genetic testing results for the HoFH genotype mutational status will be listed by patient. 
6.3 
Concomitant Medications 
All medications administered during the study will be listed and coded using the most current 
version ofthe World Health Organization (WHO) Drug Reference List. A listing of all prior and 
concomitant medications including the reported term, preferred term, and Anatomical Therapeutic 
Chemical (ATC) class, start and stop dates, and other relevant data will be provided for the SP. 
Concomitant medications include all medications taken on or after the date of the first dose of 
study drug. Prior medications include all medications taken before the date of the first dose of 
study drug and discontinued before the first dose of study drug. 
7 
ANALYSIS OF EFFICACY 
The following efficacy assessments will be measured in order to obtain the primary, secondary, 
and exploratory endpoints: 
• 
Fasting LDL-C, non-HDL-C, TC, TG, HDL-C, and VLDL-C at baseline, Day 14, Day 28, Day 
42, Day 56, Day 70, and Day 84 (or the ET Visit, if applicable); 
• 
Fasting ApoB, ApoA-1, ApoA-11, ApoC-11, ApoC-111, ApoE, and Lp(a) at baseline, Day 28, 
Day 56, and Day 84 (or the ET Visit, if applicable); 
• 
hsCRP at baseline, Day 28, Day 56, and Day 84 (or the ET Visit, if applicable); 
• 
Fibrinogen at baseline, Day 28, Day 56, and Day 84 (or the ET Visit, if applicable); and 
• 
 
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Given the proposed crossover design of this study, a within-patient analysis can be performed for 
the comparison of dose groups. For continuous variables, the dose groups will be compared on 
their change and percent reduction from baseline (using their pre-treatment baseline value). For 
binary variables such as the percentage of patients, descriptive statistics will be calculated for each 
dose group. 
Baseline lipid measurements will be defined as the average of the last two fasting measurements 
prior to the first dose of study medication. If only one measurement is available then this 
measurement will be used as baseline. Baseline for all other efficacy variables will be the last 
measurement prior to the first dose of study medication. 
7.1 
Primary Efficacy Analysis 
Descriptive statistics of the percent change from baseline in LDL-C will be presented by treatment 
group at each visit, with the focus being on the percent change from baseline to Day 28, Day 56, 
and Day 84 in LDL-C, using the F AS. A longitudinal analysis will be performed with a mixed-
effects model repeated measures analysis including percent change in LDL-C as the dependent 
variable, visit as a fixed effect and patient as a random effect. The additional drug benefit with 
increasing dose will be estimated from the mixed-effects model. The F AS will be used for this 
analysis. Least-squares mean differences and corresponding 95% confidence intervals, separately 
for each of the 3 paired comparisons (300 versus 600 mg, 300 versus 900 mg, and 600 versus 900 
mg) will be provided. 
The mixed-effect model repeated measures analysis will use an unstructured covariance matrix for 
the within-subject correlation; if the model does not converge with this correlation structure, an 
auto-regressive correlation structure will be assumed. If the model still does not converge then 
other covariance structures will be explored. The final correlation structure will be determined by 
the information criteria of Akaike and Schwarz. The data from each scheduled visit will be 
included in the model. Example SAS® code for performing this analysis is as follows: 
PROC MIXED; 
CLASS SUBJID VISIT; 
MODEL PCHG = VISIT; 
REPEATED VISIT I type=UN subject=SUBJID; 
LSMEANS VISIT I cl pdiff; 
RUN; 
In addition, a scatterplot with a linear regression fit of the percent reduction from baseline versus 
dose will be performed. 
7.2 
Secondary Efficacy Analyses 
Similar summaries and analyses will be carried out for the continuous secondary efficacy 
variables, assessing change from baseline and percent change from baseline in LDL-C (change 
from basline only), non-HDL-C, TC, TG, HDL-C, VLDL-C, ApoB, ApoA-1, ApoA-11, ApoC-11, 
ApoC-111, ApoE, Lp(a), hsCRP, and fibrinogen at each scheduled time point. Sub-group analyses 
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will be performed for LDL-C, non-HDL-C, TC, TG, HDL-C, and VLDL-C, according to receptor 
mutation status. The F AS will also be used for the summary and analysis of the secondary efficacy 
endpoints. 
Descriptive statistics, including the count and percentage, will be obtained for patients achieving 
LDL-C reduction of2::15%, 2::20%,2::25%, and 2::30% at each visit, with the focus being on Day 28, 
Day 56, and Day 84 using the FAS. Similar analyses will be obtained for patients achieving an 
LDL-C value <100 mg/dL (2.59 mmol/L) at Day 28, Day 56, Day 84, and at any time during the 
study. 
7.3 
Exploratory Efficacy Analyses 
 
 
8 
ANALYSIS OF SAFETY 
Safety will be assessed using the SP. The assessment of safety will include adverse events, clinical 
laboratory assessments, ECGs, physical examinations, and vital signs. The safety analysis will be 
based primarily on the frequency of new or worsening adverse events, laboratory abnormalities, 
and SAEs. Other safety data will be summarized as appropriate. 
8.1 
Extent of Exposure 
Patients 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 by means of tablet counts based on 
the assessment of empty bottles returned to the site at each study visit after Day 1 during the 
Treatment Period and the ET Visit, if applicable. 
Days of exposure to study drug will be summarized with descriptive statistics by treatment group 
for the Safety population. 
Days of possible exposure, within a given dose level, is defined as the date of last dose of study 
drug minus the date of first dose of study drug plus 1. When the last known dose date is missing, 
the last known clinic visit date will be used. 
Percent compliance with the study drug will be summarized by treatment group for the SP using 
descriptive statistics. Within a given dose level, compliance will be calculated by the total number 
of tablets taken divided by the total number of tablets presumed taken during the treatment period 
times 100. The total number of tablets taken is calculated by the total number of tablets dispensed 
minus the total number of tablets returned. The total number of tablets presumed taken is calculated 
by the number of days during the treatment period times the number of tables scheduled to be 
taken daily for the treatment period (i.e. 1 tablet for 300 mg period, 2 tables for the 600 mg period, 
and 3 tables for the 900 mg period). 
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The analysis will include listings for drug exposure and compliance. 
8.2 
Adverse Events 
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by treatment group, system organ class, and preferred term. 
A summary overview of TEAEs will be provided which presents the number and percentage of 
patients in each treatment group satisfying each of the following categories: 
• 
All TEAEs, 
• 
Drug-related TEAEs, 
• 
Maximum severity of TEAEs, 
• 
Maximum severity of drug-related TEAEs, 
• 
All treatment-emergent SAEs, 
• 
Drug-related treatment-emergent SAEs, 
• 
Death due to TEAEs, 
• 
TEAEs leading to study drug discontinuation, and 
• 
Drug-related TEAEs leading to study drug discontinuation. 
The numbers and percentages of patients with TEAEs will be summarized by MedDRA preferred 
term within system organ class, by treatment group and overall. For the summaries by treatment 
group, multiple AEs with the same MedDRA preferred term within system organ class from the 
same patient within a given treatment will only be counted once. For overall summaries, multiple 
AEs with the same MedDRA preferred term within system organ class from the same patient will 
only be counted once. The AE onset date will determine the treatment group classification for the 
AE. 
All TEAEs related to study drug, SAEs, and AEs leading to study drug discontinuation will be 
summarized in the same manner. Summaries will also be provided for the numbers and percentages 
of patients by system organ class, preferred term, and maximum severity, for TEAEs and drug-
related TEAEs. 
All AEs will be included in by-patient listings containing additional information of interest such 
as onset and resolution times, maximum severity, causal relationship to study medication, and 
action taken. Specific by-patient listings of SAEs and TEAEs leading to study discontinuation 
will be provided. 
8.3 
Safety Laboratory Parameters 
Clinical chemistry, coagulation, hematology, and urinalysis results will be summarized with 
descriptive statistics at all visits with the focus on Day 28, Day 56, and Day 84. Change from 
baseline will also be summarized. Frequency counts of new or worsening abnormalities will also 
be provided. Laboratory values will also be listed by visit, within patient. 
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8.4 
Vital Signs 
Vital signs and the change from baseline will be summarized descriptively by visit. Vital sign 
data will also be listed by visit, within patient. 
8.5 
ECG Parameters 
Electrocardiogram results will be summarized with counts and percentages by visit and results will 
also be listed. 
8.6 
Physical Examinations 
Physical examinations at baseline and the change from baseline will be summarized by visit. 
Physical examination results will also be listed by visit, within patient. 
8. 7 
Pharmacokinetic Analysis 
A separate Pharmacokinetic Analysis Plan will be prepared by Gemphire describing the details 
regarding the PK analysis, including the data handling and methods for the analysis. Gemphire 
will perform the PK analysis and generate the corresponding PK Report which will be included 
as an appendix to the CSR. 
9 
DATA SAFETY MONITORING BOARD 
Not applicable. 
10 INTERIM ANALYSIS 
Interim analysis #1 occurred based on study data through a cut-off date of January 12, 2017. The 
purpose of this interim analysis was to provide preliminary efficacy and safety information to 
Gemphire and prospective partners. The timeframe includes data through Week 12 for subject 
, through Week 12 for subject 
 and through Week 8 for subject 
 based on 
source data that was monitored and checked for quality control. The interim analysis included the 
following information: 
• 
Patient demographics and exposure 
• 
Genetic analysis of HoFH status 
• 
Primary efficacy parameter of LDL-C 
• 
Adverse events 
Interim analysis #2 will occur based on study data through a cut-off date corresponding to the last 
subject's Week 12 visit. The purpose of this interim analysis is to provide preliminary efficacy 
and safety information to Gemphire and prospective partners. The timeframe includes data 
through Week xxx for subjects xxxx based on source data that is monitored and checked for quality 
control. The interim analysis includes the following information: 
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PI
PI
PI


• 
Patient demographics, exposure, and concomitant lipid medications 
• 
Genetic analysis of HoFH status 
• 
Primary efficacy parameter ofLDL-C 
• 
Summary ofLDL-C by receptor mutation status (HoFH status) 
• 
Adverse events 
11 SAMPLE SIZE AND POWER CONSIDERATIONS 
The primary goal of the study is to assess the mean percent change in LDL-C from baseline over 
12 weeks of treatment from the 3 dose levels. Dosing 8 patients per group will yield reasonable 
precision in estimation in mean change from baseline in LDL-C. 
12 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
It was decided that the Intent-to-Treat (ITT) population defined in the protocol will be renamed as 
the F AS for the analysis. No changes were made to the statistical methodology described in the 
protocol. 
13 REFERENCES 
None 
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