Clinical trial NCT03508687
Conditions: Familial Partial Lipodystrophy Hypertriglyceridemia Fatty Liver NASH - Nonalcoholic Steatohepatitis
Sponsor: Elif Oral
Start date: 2018-03-13; Completion date: 2019-07-31
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The overall objective of this study is to assess the efficacy and safety of two dosing regimens of gemcabene (300 mg once daily for 24 weeks or 300 mg daily for 12 weeks followed by 600 mg daily for 12 weeks) in up to eight patients with Familial Partial Lipodystrophy with high triglycerides and Non-Alcoholic Fatty Liver Disease. The study will consist of a six week Wash Out Period, up to a 28 day Screening Period, a 24 week Treatment Period, and a follow-on safety assessment four weeks post final dose. Study participation will last approximately 4 months and includes at least 9 study visits, and can be as many as 11 study visits.

Detailed description:
Patients with typical Familial Partial Lipodystrophy Disease (FPLD) have a marked loss of subcutaneous fat from the extremities and trunk accompanied by a variable amount of excess fat deposition in the nonlipodystrophic areas such as the face, chin, back, and intraabdominal regions. Dietary fat restriction and other lifestyle changes are first line therapy to avoid weight gain, critical for effective management of metabolic complications in patients with lipodystrophy. However, despite lifestyle changes and conventional hypoglycemic and hypolipidemic therapies, some FPLD patients continue to have extreme hypertriglyceridemia, hepatic steatosis, and poorly controlled diabetes.Hypertriglyceridemia is a common condition of FPLD and serum triglyceride levels of 250-1999 mg/dL, classified as moderate to severe hypertriglyceridemia, indicate risk for development of very severe hypertriglyceridemia, causative of pancreatitis and hepatic steatosis. In patients such as those with FPLD with severe or very severe hypertriglyceridemia, fibrates, omega-3 fatty acids (OMG-3) and occasionally niacin are first-line therapy. Non-alcoholic fatty liver disease (NAFLD) is often associated with FPLD. The spectrum of NAFLD associated with FPLD which appears to be more frequent than what is seen in common Type 2 diabetes and appears more severe than common forms of NAFLD and very often associated with NASH. The etiology for the latter is not clear, however, the fact that a mouse model of liver specific laminopathy develops NASH in a cell -autonomous manner suggests that the specific cellular defects seen in FPLD may play a role in the development of NAFLD/NASH. Triglyceride content in the liver is regulated by fatty acid uptake as well as fatty acid and VLDL production rates. Derangements in these processes, such as excessive production of fatty acids and triglycerides that can occur with excessive carbohydrate consumption contribute to NAFLD. Patients with NAFLD compared to controls, present with an atherogenic dyslipidemic profile, characterized by increased serum levels of triglycerides, ApoB, VLDL-C, and LDL-C with a proportionally greater content of small dense LDL-C (sdLDL-C) 18-20. NAFLD is also associated with aberrant nuclear receptor function and systemic inflammation. NAFLD can progress to NASH. NASH is marked by hepatocyte ballooning and liver inflammation, which may progress to scarring and irreversible damage. Macro and microscopically, NASH is characterized by lobular and/or portal inflammation, varying degrees of fibrosis, hepatocyte death and pathological angiogenesis. At its most severe, NASH can progress to cirrhosis, hepatocellular carcinoma (HCC) and liver failure. It is estimated that 20-33% NAFLD patients will progress to NASH, with about 5% ultimately progressing to cirrhosis. Cirrhosis has a reported 7- to 10-year mortality of 12-25%. As NAFLD and NASH continue to be a growing epidemic, gemcabene's clinical and preclinical data suggest that this novel agent may provide benefit to patients with the diagnosis of NAFLD and/or NASH. As such, further development of gemcabene may help meet an unmet medical need in these patient populations. In Phase 2 studies, gemcabene has shown triglyceride lowering from 20 to \> 50% based on dose and severity of hypertriglyceridemia and lowering in hsCRP of up to 50%. Additionally, in animal and cell based models, gemcabene studies have provided evidence demonstrating: reduction in de-novo lipogenesis, reduction in intrahepatic TG levels, modulation of inflammation and reduction of the NAFLD activity score, particularly related to hepatic ballooning, steatosis, fibrosis, and collagen accumulation. As such gemcabene may have utility in hypertriglyceridemia of FLP and ultimately in the prevention or treatment of NASH in these patients.

Arms: arm 1: Patients took Gemcabene 300mg daily for weeks 1-12. After 12 weeks, at visit T4, patients were randomized 1:1 according to pre-generated randomization code. This arm received 300mg Gemcabene daily for 12 weeks total, starting at week 12. arm 2: Patients took Gemcabene 300mg daily for weeks 1-12. After 12 weeks, at visit T4, patients were randomized 1:1 according to pre-generated randomization code. This arm received 600mg Gemcabene daily for 12 weeks total, starting at week 12.
Interventions: intervention 1: 300mg Gemcabene intervention 2: 600mg Gemcabene
Intervention descriptions: intervention 1: 300mg Gemcabene intervention 2: 600mg Gemcabene

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
COVER PAGE 
 
Type of Document: Study Protocol 
 
Official Title of the study: An Investigator-Initiated Open-Label, 
Randomized Study of Gemcabene in Adults with Familial Partial 
Lipodystrophy Disease (FPLD) 
 
NCT number: NCT03508687 
 
Date of document: 9-11-19 
 
 
 
 
 
 
 
 
 
 


The University of Michigan 
Clinical Study Protocol HUM00130803 / GEM-IIT-602 
 
Confidential & Proprietary 
 
Version 2.4, 9/11/2019 
2 
CLINICAL STUDY PROTOCOL 
 
An Investigator-Initiated Open-Label, Randomized Study of 
Gemcabene in Adults with Familial Partial Lipodystrophy Disease 
(FPLD) 
 
 
Investigational Product: Gemcabene calcium tablets (gemcabene) 
Protocol Number:  HUM00130803/GEM-IIT-602  
Principal Investigator: 
Dr. Elif A. Oral, MD 
The University of Michigan 
Ann Arbor, MI 48105 
Brehm Center for Diabetes 
Metabolism, Endocrinology, and Diabetes Division 
1000 Wall Street, Room 5313 
Ann Arbor, MI 48105 
 
 
 
 
Final Version Number: 2.4 
Version Date:  9/11/2019 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of the University of Michigan and 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 either party. The contents of this document are only made available to the 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 The University of Michigan and Gemphire Therapeutics Inc. and that it may not be 
further disclosed to third parties. 


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SIGNATURE PAGE 
STUDY TITLE: An Investigator-Initiated Open-Label, Randomized Study of Gemcabene 
in Adults with Familial Partial Lipodystrophy Disease (FPLD) 
We, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
 
Signature 
 
 
 
 
 
 
 
Date 
 
Elif A. Oral, MD 
The University of Michigan 
Brehm Center for Diabetes 
Metabolism, Endocrinology, and Diabetes Division 
1000 Wall Street, Room 5313 
Ann Arbor, MI 48105 
 


The University of Michigan 
Clinical Study Protocol HUM00130803 / GEM-IIT-602 
 
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SYNOPSIS 
TITLE: An Investigator-Initiated Open-Label, Randomized Study of Gemcabene in Adults with 
Familial Partial Lipodystrophy Disease (FPLD) 
PROTOCOL NUMBER: HUM00130803 / GEM-IIT-602 
INVESTIGATIONAL PRODUCT: Gemcabene calcium tablets (gemcabene) 
PHASE: Investigator Initiated IND Phase I/II 
INDICATION(S): Treatment with gemcabene is indicated as an adjunct standard of care to diet 
to reduce triglyceride (TG) levels and indicators of nonalcoholic fatty liver disease (NAFLD) in 
adult patients with Familial Partial Lipodystrophy Disease (FPLD) 
OBJECTIVE:  
The overall objective of this study is to assess the efficacy and safety of two dosing regimens of 
gemcabene (300 mg once daily (QD) for 24 weeks or 300 mg QD for 12 weeks followed by 600 
mg QD for 12 weeks) in up to eight patients with FPLD with elevated TGs and NAFLD.   
POPULATION: 
Up to eight male and female patients, ≥ 18 years of age with confirmed FPLD will be enrolled in 
the study. Patients must have a fasting TG value ≥ 250 mg/dL and quantifiable hepatic steatosis 
(as determined by magnetic resonance proton density fat fraction [MRI-PDFF] – Stage 2 or 3) 
while on a stable, low-fat, low-cholesterol diet (per self-report). 
STUDY DESIGN: 
Although this is a pilot INDstudy, measures must be put in place to stabilize TG measures at 
baseline and concomitant TG-lowering therapies to ensure the collection of meaningful data 
during study conduct. 
Pre-Screening Visit/Wash-Out Period: A Pre-Screening Visit followed by a Wash-Out Period 
will be required for eligible patients taking fibrates, niacin ≥250 mg/day or over-the-counter fish 
oil or other products containing omega-3 fatty acids (OMG-3), or thiazolidinediones (TZDs). For 
patients requiring a Wash-Out Period, the Pre-Screening Visit will be their first study visit and 
will occur prior to the Screening Visit based on the duration of the Wash-Out Period required.  
Patients currently taking fibrates, niacin ≥250 mg/day, prescription or over-the-counter fish oil or 
other products containing OMG-3, or TZDs must be able to safely discontinue therapy at 
screening. The Wash-Out Period will be six weeks. If patients are on metreleptin for 
investigational use, they should be washed out for four months and their leptin level must have 
returned to pre-metreleptin treatment state, which is indirect evidence that any binding antibodies 
may have decayed as well. 


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Screening Period: All eligible patients will participate in the Screening Visit up to 28 days prior 
to Day 1. For eligible patients taking stable, allowable, lipid-lowering therapy (statins, ezetimibe, 
proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, or other herbal products or 
dietary supplements with potential lipid-altering effects) for greater than six weeks and who do 
not require a Wash-Out Period, the Screening Visit will be their first study visit.  
At the end of the two-to four-week diet and lifestyle stabilization and TG qualifying period, 
eligible patients must have a fasting TG ≥ 250 mg/dL prior to their MRI-PDFF performed at Visit 
S2. The TG level for qualification will be based on Visit S1. If a patient's TG value from Visit S1 
falls outside the required range for entry into the study, one additional sample for fasting TG 
measurement can be collected between Visits S1 and S2.   
At Visit S2 potential patients must have hepatic steatosis ≥10% based on the core imaging lab 
assessment of liver fat content (MRI-PDFF) to be eligible for enrollment on Day 1 (Visit T1).   If 
the core imaging lab assessment of liver fat content is below the minimum range outlined in the 
protocol the patient will be ineligible and will not be eligible for re-screening.  A determination 
of hepatic fibrosis (MR elastography) will also be performed at this visit.    
Patients meeting screening criteria including TG and 10% liver fat will be offered an optional liver 
biopsy which will be performed for the assessment of a baseline NAFLD Activity Score (NAS). 
If patients opt-out of the liver biopsy, they can still move to the treatment phase.  
Open-label, Randomized Treatment Period: After confirmation of qualifying fasting TG values 
and MRI-PDFF confirmed hepatic steatosis ≥10%, eligible patients will have a fasting, optional 
liver biopsy performed, if they opt in, and enter the treatment phase to receive 300 mg gemcabene 
daily for 12 weeks starting on Day 1/Visit T1. Up to eight patients will be treated. After 12 weeks 
at visit T4, patients will be randomized 1:1 according to a pre-generated randomization code to 
the remaining 12 -week treatment period to one of the following groups:  
• Group 1: Gemcabene 300 mg QD for 12-24 weeks 
• Group 2: Gemcabene 600 mg QD for 12-24 weeks 
The primary evaluation of TG efficacy will be after 12 weeks of treatment.  The primary 
evaluation for the secondary parameters of liver fat (MRI-PDFF) and NAS (histology) will be at 
24 weeks.  The Follow-up Visit will occur four weeks (±3 days) after the last dose of study drug. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
The tablet drug product for oral administration is an immediate-release tablet containing 300 mg 
of the parent gemcabene in a formulation comprising the following inactive ingredients: lactose 
monohydrate, hydroxypropyl cellulose, croscarmellose sodium magnesium stearate, Opadry® 
White YS 1-7040, and Simethicone.  
Study drug will be packaged in high-density polyethylene bottles with child-resistant closures.  
• 300 mg: one 300 mg tablet orally QD, or 
• 600 mg; two 300 mg tablets orally QD.  


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Patients will be instructed to take study drug at the same time in the morning either with or without 
food.   
PRIMARY AND SECONDARY EFFICACY ENDPOINTS: 
Primary Efficacy Endpoint: 
The primary endpoint of this study is the percent change from baseline to Week 12 in fasting 
serum TG.   
Secondary Efficacy Endpoints: 
The secondary endpoints are as follows: 
• Change and percent change in fasting serum TG from baseline to average of Weeks 6 and 12, 
and Week 24 and change in fasting serum TG from baseline to Week 12;  
• Change and percent change in liver fat content as determined by MRI-PDFF from baseline to 
Week 12 and Week 24; 
• Change and percent change in hepatic fibrosis as determined by MR elastography from 
baseline to Week 12 and Week 24; 
• Change and percent change in total cholesterol (TC), low-density lipoprotein cholesterol 
(LDL-C) (ultracentrifugation), apolipoprotein B (apo B), ApoA-1, ApoA-II, ApoA-V from 
baseline to Weeks 12 and 24; 
• Change and percent change in high-sensitivity C-reactive protein (hsCRP), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) from baseline to Weeks 12 and 
24.  
Exploratory Endpoints: 
Exploratory endpoints will be analyzed from previously collected data or reserve samples if the 
above analyses show benefit: 
The exploratory efficacy endpoints are as follows:  
• Change and percent change in additional biomarkers of hepatic steatosis including AST/ALT 
ratio; γ-glutamyl transpeptidase, (GGT); alkaline phosphatase; international normalized ratio 
(INR), albumin, total bilirubin from baseline to Week 12 and Week 24;   
• Liver mRNA levels which may include denovo cholesterol synthesis and lipogenesis, 
inflammation, LDL receptor, β-oxidation, and sulfatase from baseline to Week 24; 
• Change and percent change in leptin, adiponectin and fasting insulin levels, fasting plasma 
glucose (FPG), and hemoglobin A1c (HbA1c), non-high-density lipoprotein cholesterol (non-
HDL C), very low density lipoprotein cholesterol (VLDL-C), ApoC-II, ApoC-III, ApoE, and 
Lp(a) from baseline to Week 12 and Week 24; 
• Change and percent change in interleukin-6 (IL-6), interleukin 1β (IL-1β), angiopoietin like 
4 transpeptidase (ANGPTL4), angiopoietin like 3 transpeptidase (ANGPTL3), fibrinogen, 
and serum amyloid A (SAA) from baseline to Weeks 12 and 24;  


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• Change and percent change in NAS (NAFLD activity score)23 including steatosis, lobular 
inflammation and hepatocyte ballooning from baseline to Week 24;   
• Change and percent change in quality of life (QOL) measures including visual analog scale 
(VAS) of pain and short form-36 (SF-36) from baseline to Weeks 12 and 24. 
SAFETY VARIABLES: 
The safety variables include adverse events, safety laboratory parameters (chemistry, hematology, 
coagulation, and urinalysis) with particular attention to hepatic (e.g., ALT/AST, bilirubin, alkaline 
phosphatase, GGT, renal (e.g., blood urea nitrogen [BUN], serum creatinine, protein:creatinine 
ratio, albumin/creatinine ratio, urinalysis sediments, pH, electrolytes), and skeletal muscle 
toxicities (i.e., creatine kinase), ketone bodies, 12-lead electrocardiograms (ECGs), physical 
examinations, and vital signs. 
STATISTICAL METHODS: 
Patient Populations: 
The Full Analysis Set (FAS) is defined as all randomized patients who received at least one dose 
of study drug, and have both a baseline and at least one post-baseline lipid value.  All efficacy 
summaries and analyses will be performed using the FAS. 
The Safety Analysis Set (SAS) is defined as all randomized patients who received at least one 
dose of study drug.  All safety summaries will be performed using the SAS. 
Primary efficacy analyses: 
The primary efficacy endpoint is the percent change from baseline to Week 12 in fasting serum 
TG. If the Week 12 TG value is missing, then the “Week 12” TG value will be imputed using 
last observation carried forward (LOCF).  
Baseline will be defined as the average of the pre-dose Day 1/Visit T1 value and the last 
qualifying screening visit.   
The primary efficacy endpoint will be summarized by treatment group and timepoint using the 
FAS. 
Secondary efficacy analyses: 
The secondary TG efficacy endpoints are the change from baseline to Week 12 and change and 
percent change from baseline to the average of Weeks 6 and 12, and Week 24 in fasting serum 
TG.  Baseline will be defined as outlined above for the primary variable.  For the “average of 
Weeks 6 and 12” TG efficacy assessment, if only the Week 6 or Week 12 TG value is available, 
then that single value will be used.  If both the Week 6 and Week 12 TG values are missing, then 
the average “Week 6 and Week 12” TG value will be imputed using LOCF. For the “Week 24” 
TG efficacy assessment, if Week 24 values are missing, then the value will be imputed using 
LOCF. 
The change and percent change in all other secondary efficacy biomarkers will be summarized for 
Week 12 and Week 24 as described above.   


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An additional secondary analysis is change and percent change from baseline to Week 12 and 
Week 24 in the percentage of liver fat content as measured by MRI-PDFF.  Baseline liver fat 
content is defined as the value from Screening.  Missing percentage liver fat content at Week 24 
will be imputed using LOCF.  It will be summarized by treatment group and timepoint using the 
FAS.  Hepatic fibrosis as measured by MR elastography will be summarized as outlined above 
for liver fat content via MRI-PDFF.  
An additional secondary analysis in change and percent change from baseline to Week 24 in NAS 
as determined by histology. It will be summarized by treatment group at Week 24 using the FAS. 
Exploratory efficacy analyses: 
The exploratory variables (if determined as necessary) will be summarized as described for the 
secondary endpoints above.  Missing values will be imputed using LOCF.  
Safety analyses: 
Safety will be assessed using the SAS.  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 by treatment group at baseline (pre-dose Day 1/Visit 1 
value), End of Treatment (Week 24), or the ET Visit, if applicable, and change from baseline to 
End of Treatment (Week 24) or the ET Visit, if applicable. Frequency counts of new or worsening 
abnormalities will also be provided. 
SITES: One site; University of Michigan, Ann Arbor, Michigan USA   
SPONSOR: 
Dr. Elif A. Oral, MD 
The University of Michigan 
Brehm Center for Diabetes 
Metabolism, Endocrinology, and Diabetes Division 
1000 Wall Street, Room 5313 
Ann Arbor, MI 48105 
DRUG SUPPLIED BY: 
Gemphire Therapeutics Inc.  
17199 N. Laurel Park Drive, Suite 401 
Livonia, MI 48152 
United States 
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 


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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 3 
SYNOPSIS ...................................................................................................................................... 4 
Secondary Efficacy Endpoints: ........................................................................................... 6 
Exploratory Endpoints: ....................................................................................................... 6 
TABLE OF CONTENTS ................................................................................................................ 9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 14 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 16 
1.1 
Background ................................................................................................................. 16 
1.2 
Rationale ..................................................................................................................... 17 
1.3 
Risk Assessment of Gemcabene ................................................................................. 18 
2 
STUDY OBJECTIVES and endpoints ............................................................................. 20 
2.1 
Objectives ................................................................................................................... 20 
2.1.1 Primary Objective ................................................................................................. 20 
2.1.2 Secondary Objectives............................................................................................ 20 
2.1.3 Exploratory Objectives ......................................................................................... 20 
2.2 
Endpoints .................................................................................................................... 20 
2.2.1 Primary Endpoint .................................................................................................. 20 
2.2.2 Secondary Efficacy Endpoints .............................................................................. 20 
2.2.3 Secondary Safety Endpoints ................................................................................. 21 
2.2.4 Exploratory Endpoints .......................................................................................... 21 
3 
STUDY DESCRIPTION .................................................................................................. 22 
3.1 
Summary of Study Design .......................................................................................... 22 
3.2 
Study Indication .......................................................................................................... 23 
4 
SELECTION AND WITHDRAWAL OF PATIENTS .................................................... 24 
4.1 
Inclusion Criteria ........................................................................................................ 24 
4.2 
Exclusion Criteria ....................................................................................................... 24 
4.3 
Withdrawal Criteria .................................................................................................... 26 
5 
STUDY TREATMENTS .................................................................................................. 28 
5.1 
Treatment Groups ....................................................................................................... 28 


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5.2 
Dose Rationale ............................................................................................................ 28 
5.3 
Randomization and Blinding ...................................................................................... 29 
5.4 
Drug Supplies.............................................................................................................. 29 
5.4.1 Study Drug Identification ..................................................................................... 29 
5.4.2 Formulation and Packaging .................................................................................. 30 
5.4.3 Study Drug Preparation and Dispensing ............................................................... 30 
5.4.4 Study Drug Administration ................................................................................... 30 
5.4.5 Treatment Compliance .......................................................................................... 30 
5.4.6 Storage and Accountability ................................................................................... 31 
5.5 
Prior and Concomitant Medications and/or Procedures ............................................. 31 
5.5.1 Permitted Medications and/or Procedures ............................................................ 31 
5.5.2 Excluded Medications and/or Procedures ............................................................. 31 
5.5.3 Restrictions and Dietary Guidelines ..................................................................... 32 
5.5.4 Documentation of Prior and Concomitant Medication Use .................................. 32 
6 
STUDY PROCEDURES .................................................................................................. 33 
6.1 
Informed Consent........................................................................................................ 33 
6.2 
Pre-Screening Visit ..................................................................................................... 33 
6.3 
Screening Visits .......................................................................................................... 33 
6.3.1 Screening Visit S1 (up to Day -28) ....................................................................... 34 
6.3.2 Screening Visit S2................................................................................................. 34 
6.4 
Treatment Period (Visit T1 through Visit T8) ............................................................ 34 
6.4.1 Visit T1 (Study Day 1) .......................................................................................... 34 
6.4.2 Visit T2 (Week 4) ................................................................................................. 35 
6.4.3 Visit T3 (Week 8) ................................................................................................. 35 
6.4.4 Visit T4 (Week 12) ............................................................................................... 35 
6.4.5 Visit T5 (Week 16) ............................................................................................... 35 
6.4.6 Visit T6 (Week 20) ............................................................................................... 35 
6.4.7 Visit T7 (Week 24) ............................................................................................... 35 
6.5 
Follow-up Visit 8 (Week 28; Telephone Call four weeks post-dose) ........................ 35 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................. 35 
7 
EFFICACY ASSESSMENTS .......................................................................................... 36 


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7.1 
Biomarker Assessments .............................................................................................. 36 
7.2 
Evaluation of NAFLD and NASH .............................................................................. 36 
7.2.1 Imaging and liver biopsy ...................................................................................... 36 
8 
RISK ASSESSMENT ....................................................................................................... 38 
8.1 
Known Potential Risks ................................................................................................ 38 
8.2 
Risks from the procedures in the protocol: ................................................................. 39 
8.3 
Known Potential Benefits: .......................................................................................... 39 
8.4 
Assessment of Potential Risks and Benefits ............................................................... 39 
9 
SAFETY ASSESSMENTS ............................................................................................... 40 
9.1 
Adverse Events ........................................................................................................... 40 
9.1.1 Adverse (Drug) Reaction ...................................................................................... 41 
9.1.2 Unexpected Adverse Drug Reaction ..................................................................... 41 
9.1.3 Assessment of Adverse Events by the Investigator .............................................. 41 
9.2 
Specific Safety Measures ............................................................................................ 42 
9.2.1 Hemoglobin decrease ............................................................................................ 42 
9.2.2 Creatinine increase ................................................................................................ 42 
9.2.3 Possible muscle and liver injury ........................................................................... 43 
9.2.4 Significantly elevated TG levels ........................................................................... 43 
9.2.5 Patients with Diabetes ........................................................................................... 43 
9.3 
Serious Adverse Events .............................................................................................. 43 
9.4 
Adverse Event Reporting − Procedures for Sponsor Investigator .............................. 44 
9.4.1 Non-serious Adverse Events ................................................................................. 44 
9.4.2 Serious Adverse Event Reporting ......................................................................... 44 
9.5 
Pregnancy Reporting ................................................................................................... 46 
9.6 
Expedited Reporting ................................................................................................... 46 
9.7 
Clinical Laboratory Evaluations ................................................................................. 46 
9.8 
Vital Signs ................................................................................................................... 47 
9.9 
Electrocardiograms ..................................................................................................... 47 
9.10 
Physical Examinations ................................................................................................ 47 
9.11 
Medical/Surgical History and Demographics ............................................................. 47 
9.12 
Reserve Samples ......................................................................................................... 47 


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9.13 
Dual Energy X-Ray Absorption Scan (DEXA) .......................................................... 47 
10 
STATISTICS .................................................................................................................... 49 
10.1 
Sample Size ................................................................................................................. 49 
10.2 
Analysis Populations ................................................................................................... 49 
10.2.1 Full Analysis Set ................................................................................................... 49 
10.2.2 Safety Analysis Set ............................................................................................... 49 
10.3 
Statistical Methods ...................................................................................................... 50 
10.3.1 Analysis of Efficacy .............................................................................................. 50 
10.3.1.1 
Primary efficacy analyses ................................................................................ 50 
10.3.1.2 
Secondary efficacy analyses ............................................................................ 50 
10.3.1.3 
Exploratory analysis ........................................................................................ 51 
10.3.1.4 
Missing Data .................................................................................................... 51 
10.3.2 Analysis of Safety ................................................................................................. 51 
11 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 52 
11.1 
Data Management ....................................................................................................... 52 
11.1.1 Data Handling ....................................................................................................... 52 
11.1.1.1 
Computer Systems ........................................................................................... 52 
11.1.1.2 
Data Entry ........................................................................................................ 52 
11.1.1.3 
Medical Information Coding ........................................................................... 52 
11.1.2 Data Validation ..................................................................................................... 52 
11.2 
Record Keeping .......................................................................................................... 52 
12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ............................. 53 
12.1 
Ethical Conduct of the Study ...................................................................................... 53 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 53 
12.3 
Informed Consent........................................................................................................ 53 
12.4 
Study Monitoring ........................................................................................................ 54 
12.5 
Data Safety Monitoring Board .................................................................................... 54 
12.6 
Disclosure of Data....................................................................................................... 54 
12.7 
Retention of Records................................................................................................... 54 
12.8 
Publication Policy ....................................................................................................... 55 
12.9 
Financial Disclosure.................................................................................................... 55 


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12.10 Insurance and Indemnity ............................................................................................. 55 
12.11 Legal Aspects .............................................................................................................. 55 
12.12 Definition of End of Study .......................................................................................... 55 
12.13 Sponsor Discontinuation Criteria ................................................................................ 56 
13 
STUDY ADMINISTRATIVE INFORMATION ............................................................. 57 
13.1 
Protocol Amendments ................................................................................................. 57 
13.2 
Address List ................................................................................................................ 57 
13.2.1 Sponsor ................................................................................................................. 57 
13.2.2 Drug Supplied By: ................................................................................................ 57 
13.2.3 Biological Specimens............................................................................................ 57 
14 
REFERENCES ................................................................................................................. 58 
APPENDIX A: SCHEDULE OF PROCEDURES ....................................................................... 61 
APPENDIX B: CLINICAL LABORATORY ANALYTES ........................................................ 64 
APPENDIX C: NEW YORK HEART ASSOCIATION CONGESTIVE HEART FAILURE 
CLASSIFICATION .......................................................................................................... 66 
APPENDIX D: Hematology, Renal, MUSCLE INJURY AND HEPATIC MONITORING ...... 67 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance model 
ANGPTL4 
Angiopoietin like 4 
Apo 
Apolipoprotein 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CK 
Creatine kinase 
CRA 
Clinical research associate 
CTA 
Clinical trial authorization 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
EC 
Ethic Committee 
ECG 
Electrocardiogram 
CRF 
Case report form 
EDC 
Electronic data capture 
ET 
Early Termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HbA1c 
Hemoglobin A1c 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
HIV 
Human immunodeficiency virus 
hsCRP 
High-sensitivity C-reactive protein 
IL-6 
Interleukin 6 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IWRS/IVRS 
Interactive web/voice response system 


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Abbreviation 
Definition 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein(a) 
LPL 
LSM 
MedDRA 
Lipoprotein lipase 
Least squares mean 
Medical Dictionary for Regulatory Affairs 
NCEP ATP-III 
National Cholesterol Education Program Adult Treatment Panel III 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NIMP 
Non-investigational medical product 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
OMG-3 
Omega-3 fatty acids 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetics 
PPS 
Per protocol set 
QD 
Once daily 
SAA 
Serum amyloid A 
SAE 
SE 
Serious adverse event 
Standard error 
SHTG 
SOP 
Standard Operating Procedure 
Severe hypertriglyceridemia  
TC 
Total cholesterol 
TG 
Triglyceride 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Gemcabene calcium is the monocalcium salt of a dialkyl ether dicarboxylic acid having 2 terminal 
gem dimethyl carboxylate moieties. Gemcabene has a dual mechanism of action that involves: (1) 
enhancing the clearance of very-low density lipoprotein cholesterol (VLDL); and (2) blocking the 
overall production of hepatic triglyceride (TG) and cholesterol synthesis.  
Gemcabene enhances the clearance of VLDL by decreasing the production of messenger RNA 
(mRNA) of the APOC3gene, thereby decreasing the production of the ApoC-III protein 1. This in 
turn unmasks apolipoprotein E (ApoE) which (1) enhances the clearance of the VLDL remnants 
via ApoE remnant receptors; (2) reduces the formation of low-density lipoprotein (LDL) particles; 
and (3) enhances lipoprotein lipase mediated TG lipolysis allowing increased delivery of fatty 
acids to muscle and adipose tissue.  
Gemcabene may also block the overall production of hepatic TG and cholesterol. Given its 
structural similarities to long-chain fatty acid, gemcabene may act as an inhibitor of acetyl CoA 
acetytransferase (ACC), subsequently leading to a decrease in hepatic TG production 2. 
Gemcabene may also inhibit one or more enzymes in the cholesterol synthesis pathway leading to 
less cholesterol in the cell, thereby upregulating LDL receptors in the liver. 
In inflammatory states, cytokines, such as interleukin-6 (IL-6) and interleukin 1-beta (IL1-b), 
activate nuclear hormone receptors (NHRs), such as C/EPB-b, C/EPB-d and nuclear factor kappa 
B (NF-kB), and lead them to bind to the C-reactive protein (CRP) promoter and increase CRP 
mRNA production. Based on preclinical studies, gemcabene may inhibit the interaction of these 
NHRs on the CRP promoter and therefore reduce CRP mRNA production 3.  
Taken together, gemcabene’s mechanism of action should lower the full range of atherogenic 
particles (VLDL, IDL, and LDL) resulting in decreases in atherogenic particle number (ApoB), 
particle cholesterol (non-HDL-C) and TG (when elevated); with concomitant lowering of hsCRP.  
As such, the effects of gemcabene were explored in a pre-clinical model of NAFLD (STAM mice). 
Overall, gemcabene showed an anti-fibrotic effect, as well as demonstrating anti-NASH and 
hepatoprotective effects on the liver pathology in this model. Treatment with middle and high 
doses of Gemcabene reduced the mRNA expression levels of inflammation related genes (TNF-α, 
Monocyte chemotactic protein-1 (MCP-1), Macrophage inflammatory protein-1 (MIP-1β), CCR5, 
CCR2, NF-kβ), supporting hepatoprotective property. Gemcabene decreased plasma CRP levels, 
which was in agreement with human data 4. The preclinical data is supportive of the potential for 
gemcabene to elicit beneficial effects in hepatic steatosis. 
Gemcabene-calcium rapidly converts to gemcabene free acid when in contact with the gastric 
fluid. Gemcabene is rapidly absorbed following oral administration. It distributes to the liver where 
it has its effect as the active molecule, with exposure increasing approximately linearly with dose. 
Steady state concentrations are achieved within six days of repeated dose administration, with an 
average half-life from 32 to 41 hours. Gemcabene's primary route of metabolism and elimination 
is renal, predominantly as a gemcabene glucuronide formed in the kidney. 


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1.2 
Rationale  
Patients with typical Familial Partial Lipodystrophy Disease (FPLD) have a marked loss of 
subcutaneous fat from the extremities and trunk accompanied by a variable amount of excess fat 
deposition in the nonlipodystrophic areas such as the face, chin, back, and intraabdominal regions 
5-7. Dietary fat restriction and other lifestyle changes are first line therapy to avoid weight gain, 
critical for effective management of metabolic complications in patients with lipodystrophy. 
However, despite lifestyle changes and conventional hypoglycemic and hypolipidemic therapies, 
some FPLD patients continue to have extreme hypertriglyceridemia, hepatic steatosis, and poorly 
controlled diabetes 8,9. 
Hypertriglyceridemia is a common condition of FPLD and serum triglyceride levels of 250–1999 
mg/dL, classified as moderate to severe hypertriglyceridemia, indicate risk for development of 
very severe hypertriglyceridemia, causative of pancreatitis and hepatic steatosis 10,11. In patients 
such as those with FPLD with severe or very severe hypertriglyceridemia, fibrates, omega-3 fatty 
acids (OMG-3) and occasionally niacin are first-line therapy.  
Fibrates decrease TG levels by 30–50% and sometimes increase HDL-C levels in patients with 
hypertriglyceridemia 12. In patients with high TG levels, LDL-C levels may increase during 
therapy, likely due to an increased conversion of VLDL to LDL. Side effects associated with 
fibrates may include elevated liver enzymes, increased CK, and hyperhomocysteinemia. Fibrates 
are contraindicated in patients with liver and gall bladder disease and should be used with caution 
in renal insufficiency 12. Omega-3 fatty acids are used in the treatment of patients with 
hypertriglyceridemia.  To achieve a TG reduction of 20–50%, administration of 3–4 g/d of EPA 
plus DHA given in multiple capsules is required 13. As with fibrates, with the reductions of TG 
levels there can be increased levels of LDL-C 12. Niacin lowers TG and increases HDL-C levels 
in patients with hypertriglyceridemia.  At doses of 500 to 2000 mg/d, niacin lowers TG by 10–
30%, increases HDL-C by 10–40%, and lowers LDL-C by 5–20% 14. Increased risk of flushing, 
diarrhea, nausea, vomiting, cough, and pruritus with niacin has tended to limit its use in general 
practice. Moreover, when co-administered with lovastatin or simvastatin, the risk of 
rhabdomyolysis and abnormal liver function is increased, particularly in the elderly and in patients 
with diabetes, CKD, or uncontrolled hypothyroidism 15.  Background statin therapy is increasingly 
common in patients with moderate1 to severe hypertriglyceridemia, however, patients with FPLD 
are often statin intolerant.  
NAFLD is often associated with FPLD. We reported the spectrum of NAFLD associated with 
FPLD which appears to be more frequent than what is seen in common Type 2 diabetes and appears 
more severe than common forms of NAFLD 16 and very often associated with NASH. The etiology 
for the latter is not clear, however, the fact that a mouse model of liver specific laminopathy 
develops NASH in a cell –autonomous manner suggests 17that the specific cellular defects seen in 
FPLD may play a role in the development of NAFLD/NASH.  Triglyceride content in the liver is 
regulated by fatty acid uptake as well as fatty acid and VLDL production rates. Derangements in 
these processes, such as excessive production of fatty acids and TGs that can occur with excessive 
carbohydrate consumption contribute to NAFLD 18. Patients with NAFLD compared to controls, 
present with an atherogenic dyslipidemic profile, characterized by increased serum levels of TGs, 
ApoB, VLDL-C, and LDL-C with a proportionally greater content of small dense LDL-C (sdLDL-
C) 18-20. NAFLD is also associated with aberrant nuclear receptor function and systemic 


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inflammation 21. NAFLD can progress to NASH. NASH is marked by hepatocyte ballooning and 
liver inflammation, which may progress to scarring and irreversible damage. Macro and 
microscopically, NASH is characterized by lobular and/or portal inflammation, varying degrees 
of fibrosis, hepatocyte death and pathological angiogenesis. At its most severe, NASH can 
progress to cirrhosis, hepatocellular carcinoma (HCC) and liver failure. It is estimated that 20-33% 
NAFLD patients will progress to NASH, with about 5% ultimately progressing to cirrhosis.  
Cirrhosis has a reported 7- to 10-year mortality of 12-25% 22-24.  
As NAFLD and NASH continue to be a growing epidemic, gemcabene’s clinical and preclinical 
data suggest that this novel agent may provide benefit to patients with the diagnosis of NAFLD 
and/or NASH. As such, further development of gemcabene may help meet an unmet medical need 
in these patient populations. 
In Phase 2 studies, gemcabene has shown TG lowering from 20 to > 50% based on dose and 
severity of hypertriglyceridemia and lowering in hsCRP of up to 50%.  Additionally, in animal 
and cell based models, gemcabene studies have provided evidence demonstrating: reduction in de-
novo lipogenesis, reduction in intrahepatic TG levels, modulation of inflammation and reduction 
of the NAFLD activity score, particularly related to hepatic ballooning, steatosis, fibrosis, and 
collagen accumulation.  As such gemcabene may have utility in hypertriglyceridemia of FLP and 
ultimately in the prevention or treatment of NASH in these patients.  
1.3 
Risk Assessment of Gemcabene 
The clinical program conducted to date has demonstrated that gemcabene is generally well 
tolerated. A total of 895 healthy adult volunteers and patients with various underlying conditions 
(including dyslipidemia, osteoarthritis, and hypertension) have been exposed to a minimum of at 
least one dose of gemcabene at doses ranging from 150 mg to 1500 mg once daily (QD). This 
includes 837 patients who received multiple doses of up to 900 mg for up to 12 weeks.  This also 
includes 292 patients (150 patients on high-intensity) on gemcabene in combination with a statin.   
Safety of these patients was evaluated by adverse event monitoring, clinical laboratory 
assessments, electrocardiograms (ECGs), physical examinations, and vital sign assessments. 
No significant drug-drug interactions have been observed with simvastatin (80 mg), atorvastatin 
(80 mg), or digoxin (0.25 mg). No clinically relevant effect on QTc or blood pressure has been 
observed.  
Across all clinical studies, the majority of treatment-emergent adverse events were mild to 
moderate in intensity. The most common adverse events reported included headache, asthenia 
(feeling of weakness), nausea, dizziness, dyspepsia (upset stomach), infection, abnormal bowel 
movements, myalgia, and abnormal kidney function tests. Ten patients (1%) reported a treatment-
emergent serious adverse event (SAE) across all previous studies. None of these SAEs were 
considered treatment-related. There were no deaths. 
Small mean increases in serum creatinine and blood urea nitrogen (BUN) have been observed in 
some studies. These changes appeared within the first two to four 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 patient. There were no significant changes 


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observed in urine protein, which seems to indicate that gemcabene does not cause tubular or 
glomerular injury. And, the increase was reversible with all creatinine values returning to baseline 
within approximately two weeks of cessation of gemcabene, suggesting a vascular effect and not 
renal injury.  
Based on a prospective analysis in a gemcabene monotherapy study (1027-04) in patients with 
mild-moderate hypertriglyceridemia (TG ≥ 200 mg/dL) and a retrospective meta-analysis of all 
studies that tested gemcabene monotherapy in patients with mild to severe hypertriglyceridemia 
(1027-04, 1027-14 [healthy, obese patients], and 4141001 [monotherapy arm of a study in 
hyperlipidemia patients +/- atorvastatin], we conclude that the 300 mg once daily (QD) dose is 
optimal based for gemcabene monotherapy.  The 600 mg dose will also be included for the 
following reasons: gemcabene has a U-shaped TG dose response curve in Type IV patients and 
including both 300 and 600 mg may further elucidate the mechanism; and although TG lowering 
is mitigated at gemcabene 600 mg in HTG patients, LDL-C was significantly lowered at the 600 
mg dose by a median % change of 17% (p=0.026).  In addition, those studies that evaluated hsCRP 
showed approximately a 50% lowering at gemcabene 600 mg. Therefore, we propose including 
the 300 mg and 600 mg dose to assess preliminary efficacy and safety in this preliminary study of 
FPLD patients. 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
The primary objective of this study is to assess the overall efficacy and safety of gemcabene (300 
mg once daily given for 24 weeks; or 300 mg once daily for 12 weeks followed by 600 mg once 
daily for 12 weeks) in up to eight patients with FPLD and a fasting TG value ≥ 250 mg/dL and 
hepatic quantifiable hepatic steatosis ≥10% (as determined by magnetic resonance proton density 
fat fraction [MRI-PDFF]). 
2.1.2 
Secondary Objectives 
The specific secondary objectives of this study are the following: 
• To assess the effect of gemcabene on TG and other lipid and apolipoprotein parameters;  
• To assess the effect on liver fat content as measured by MRI-PDFF; 
• To assess the effect on hepatic fibrosis as measured by MR-elastography. 
• To assess change in NAS including steatosis, lobular inflammation and hepatocyte ballooning;   
• To assess the effects of gemcabene on biomarkers of inflammation;   
• To assess the safety and tolerability of gemcabene 300 mg and 600 mg QD. 
2.1.3 
Exploratory Objectives 
The exploratory objectives are the following: 
• To assess changes in additional biomarkers of hepatic steatosis, lipid metabolism, obesity and 
diabetes; 
• To assess changes in quality of life (QOL) measures. 
2.2 
Endpoints  
2.2.1 
Primary Endpoint 
The primary endpoint of this study is the percent change from baseline to Week 12 in fasting serum 
TG.   
2.2.2 
Secondary Efficacy Endpoints 
The secondary endpoints are as follows: 
• Change and percent change in fasting serum TG from baseline to average of Weeks 6 and 12, 
and Week 24 and change in fasting serum TG from baseline to Week 12;  
• Change and percent change in liver fat content as determined by MRI-PDFF from baseline to 
Week 12 and Week 24; 


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• Change and percent change in liver fibrosis as determined by MR-elastography from baseline 
to Week 12 and Week 24; 
• Change and percent change in total cholesterol (TC), low-density lipoprotein cholesterol 
(LDL-C) (ultracentrifugation), HDL-C, apolipoprotein B (apo B), ApoA-1, ApoA-II, ApoA-
V from baseline to Weeks 12 and 24; 
• Change and percent change in high-sensitivity C-reactive protein (hsCRP), fibrinogen, 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) from baseline to Weeks 
12 and 24.  
2.2.3 
Safety Measures 
The safety variables include adverse events, safety laboratory parameters (chemistry, hematology, 
coagulation, and urinalysis) with particular attention to hepatic (e.g., ALT/AST, bilirubin, alkaline 
phosphatase, GGT, renal (e.g., blood urea nitrogen [BUN], serum creatinine, protein:creatinine 
ratio, albumin/creatinine ratio, urinalysis sediments, pH, electrolytes), and skeletal muscle 
toxicities (i.e., creatine kinase),  ketone bodies, 12-lead electrocardiograms (ECGs), physical 
examinations, and vital signs. 
2.2.4 
Exploratory Endpoints 
The exploratory efficacy endpoints are as follows:  
• Change and percent change in biomarkers of hepatic steatosis including AST/ALT ratio; γ-
glutamyl transpeptidase, (GGT); alkaline phosphatase; international normalized ratio (INR), 
albumin, total bilirubin from baseline to Week 12 and Week 24;   
• Liver mRNA levels which may include de novo cholesterol synthesis and lipogenesis, 
inflammation, LDL receptor, β-oxidation, and sulfatase from baseline to Week 24; 
• Change and percent change in leptin, adiponectin and fasting insulin levels, fasting plasma 
glucose (FPG), and hemoglobin A1c (HbA1c), non-high-density lipoprotein cholesterol (non-
HDL C), very low density lipoprotein cholesterol (VLDL-C), ApoC-II, ApoC-III, ApoE and 
Lp(a) from baseline to Week 12 and Week 24; 
• Change and percent change in interleukin-6 (IL-6), interleukin 1β (IL-1β), angiopoietin like 4 
transpeptidase (ANGPTL4), angiopoietin like 3 transpeptidase (ANGPTL3), fibrinogen, and 
serum amyloid A (SAA), from baseline to Weeks 12 and 24.  
• Change and percent change in NAS (NAFLD activity score)23 including steatosis, lobular 
inflammation and hepatocyte ballooning from baseline to Week 24; 
• Change and percent change in QOL measures including visual analog scale (VAS) of pain, 
short form-36 (SF-36), and Michigan Body Map from baseline to Weeks 12 and 24. 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
Although this is a pilot IND study, measures must be put in place to stabilize TG measures at 
baseline and concomitant TG-lowering therapies to ensure the collection of meaningful data during 
study conduct.  The study will consist of a six week Wash Out Period, up to a 28-day Screening 
Period, a 24 week Treatment Period, and a follow-on safety assessment four weeks post final dose. 
Below is a general description of each Period of the study. 
Pre-Screening Visit/Wash-Out Period 
A Pre-Screening Visit followed by a Wash-Out Period will be required for eligible patients taking 
fibrates, niacin ≥250 mg/day or over-the-counter fish oil or other products containing omega-3 
fatty acids (OMG-3), or thiazolidinediones (TZDs). For patients requiring a Wash-Out Period, the 
Pre-Screening Visit will be their first study visit and will occur prior to the Screening Visit based 
on the duration of the Wash-Out Period required.  
Patients currently taking fibrates, niacin ≥250 mg/day, prescription or over-the-counter fish oil or 
other products containing OMG-3, or TZDs must be able to safely discontinue therapy at 
screening. The Wash-Out Period will be six weeks. If patients are on metreleptin for 
investigational use, they should be washed out for four months and their leptin level must have 
returned to pre-metreleptin treatment state, which is indirect evidence that any binding antibodies 
may have decayed as well. 
Screening Period 
All eligible patients will participate in the Screening Visit up to 28 days prior to Day 1. For eligible 
patients taking stable, allowable, lipid-lowering therapy (statins, ezetimibe, proprotein convertase 
subtilisin/kexin type 9 [PCSK9] inhibitors, or other herbal products or dietary supplements with 
potential lipid-altering effects) for greater than six weeks and who do not require a Wash-Out 
Period, the Screening Visit will be their first study visit.  
At the end of the two-to four-week diet and lifestyle stabilization and TG qualifying period, eligible 
patients must have a fasting TG ≥ 250 mg/dL prior to their MRI-PDFF performed at Visit S2. The 
TG level for qualification will be based on Visit S1. If a patient's TG value from Visit S1 falls 
outside the required range for entry into the study, one additional sample for fasting TG 
measurement can be collected between Visits S1 and S2.   
During this Screening Period, potential patients must have hepatic steatosis of 10% based on the 
core imaging lab assessment of liver fat content (MRI-PDFF) to be eligible for enrollment on Day 
1 (Visit T1).   If the core imaging lab assessment of liver fat content is below the minimum range 
outlined in the protocol the patient will be ineligible and will not be eligible for re-screening.  A 
determination of hepatic fibrosis (MR elastography) will also be performed during Screening.    
Patients meeting screening criteria including TG and 10% liver fat will be offered an optional liver 
biopsy performed for the assessment of a baseline NAS.  
Open-Label Randomized Treatment Period 


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After confirmation of qualifying fasting TG values and MRI-PDFF confirmed hepatic steatosis 
≥10%, eligible patients will have a fasting liver biopsy performed, if they opt in, and enter the 
treatment phase to receive 300 mg gemcabene daily for 12 weeks starting on Day 1/Visit T1. Up 
to eight patients will be treated. After 12 weeks at visit T4, patients will be randomized 1:1 
according to a pre-generated randomization code to the remaining 12 -week treatment period:  
• Group 1: Gemcabene 300 mg QD for 12-24 weeks 
• Group 2: Gemcabene 600 mg QD for 12-24 weeks 
The primary evaluation of TG efficacy will be after 12 weeks of treatment.  The primary 
evaluation for the secondary parameters of liver fat (MRI-PDFF) and NAS (histology) will be at 
24 weeks.   
Safety Follow-Up Assessment 4 Weeks Post-Final Dose  
The Follow-up telephone call will occur four weeks (±3 days) after the last dose of study drug. 
3.2 
Study Indication 
Treatment with gemcabene is indicated as an adjunct to diet to reduce TG levels and indicators of 
nonalcoholic fatty liver disease (NAFLD) in adult patients with Familial Partial Lipodystrophy 
Disease (FPLD). 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
Patients who meet all the following criteria will be eligible to participate in the study: 
1. Male or female ≥ 18 years of age at time of consent with written and signed informed consent 
(by patient or legal guardian) prior to any study-specific procedure; 
2. Clinical diagnosis of lipodystrophy based on deficiency of subcutaneous body fat in a partial 
fashion assessed by physical examination, and at least one of the following MAJOR criterion 
(below): 
• Low skinfold thickness in anterior thigh by caliper measurement: men (≤ 10 mm) and 
women (≤ 22 mm); OR 
• Historic genetic diagnosis of Familial Partial Lipodystrophy Disease (e.g. mutations in 
LMNA, PPAR-γ, AKT2, or PLIN1 genes) as supported by source documentation.  
3. Hepatic steatosis (>10% – Stage 2 or 3) as demonstrated by MRI-PDFF; 
4. Alcohol intake of less than 20 g per day in females and 30 g per day in males; 
5. Mean fasting TG value ≥ 250 mg/dL mg/dL at Screening; 
6. Background lipid lowering therapy (statins, ezetimibe, PCSK9 inhibitors or other herbal 
products or dietary supplements with potential lipid-altering effects) must be stable for at least 
six weeks prior to the Screening Visit (S1);   
7. 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 
• 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 such as condom or occlusive cap (e.g. 
diaphragm or cervical/vault caps) plus spermicidal agent (e.g. foam, gel, film, cream, 
suppository).  
• Male patients must agree to use contraception by means of a condom and may not donate 
sperm throughout the duration of the study and for eight days after the last dose of study 
drug. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Weight < 50 kg;  
2. Body mass index (BMI) > 45 kg/m²; 


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3. Current, or history of, autoimmune diseases; 
4. Laboratory or other histologic findings highly suggestive of liver disease due to causes other 
than non-alcoholic steatohepatitis, such as chronic viral hepatitis, autoimmune hepatitis, 
primary biliary cirrhosis, biliary obstruction or genetic liver diseases such as Wilson's disease, 
hemochromatosis or alpha-1-antitrypsin deficiency; 
• Treatment with drugs associated with steatohepatitis, e.g., corticosteroids, high dose 
estrogens, methotrexate, amiodarone, tamoxifen, valproic acid, sulfasalazine, or oxacillin 
for more than two weeks in the six months prior to the study;  
• Abnormal liver function test at screening (aspartate aminotransferase or alanine 
aminotransferase > 3x ULN, total bilirubin or alkaline phosphatase greater than the ULN; 
Subjects with a history of Gilbert’s syndrome may be included if both direct bilirubin and 
the reticulocyte count do not exceed the ULN [reflexive direct bilirubin testing will be used 
to confirm Gilbert’s syndrome]); 
• Decompensated liver disease as evidenced by clinical features of hepatic failure (variceal 
bleeding, ascites, hepatic encephalopathy etc.) and laboratory investigations (prolonged 
prothrombin time with INR > 1.3 x ULN, platelet count < 150,000 cells/mm3, 
hypoalbuminemia with serum albumin less than 3.0 g/dL, direct bilirubin > 1.3 mg/dL, 
abnormal alkaline phosphatase) or presence of esophageal varices etc.; 
• Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml 
and/or liver mass on imaging study suggestive of liver cancer; 
• Use of drugs which can potentially decrease hepatic steatosis during previous three months; 
ursodeoxycholic acid, thiazolidinediones, high-dose vitamin E, betaine, acetylcysteine and 
choline; 
5. Other significant systemic or major illnesses, such as congestive heart failure (NYHA Class 
III or IV), cerebrovascular disease, respiratory failure, renal insufficiency, acute pancreatitis 
(within four weeks of Screening Visit), organ transplantation, serious psychiatric disease, and 
malignancy, that could interfere with the trial and adequate follow up;  
• Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, coronary 
artery bypass graft, or other major cardiovascular events resulting in hospitalization within 
three months of the Screening Visit. Patients with adequately treated stable angina, per 
Investigator assessment, may be included; 
• 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; 
• Uncontrolled hypertension, defined as sitting systolic blood pressure > 180 mmHg or 
diastolic blood pressure > 110 mmHg, and confirmed by repeat measurement;  
• Moderate to severe renal insufficiency defined as an estimated GFR < 60 mL/min/1.73m2 
(calculated using The Chronic Kidney Disease Epidemiology Collaboration equation) at 
the Pre-Screening Visit or the Screening Visit;  


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• Hematocrit of less than 30%;  
• Type 1 diabetes mellitus or uncontrolled diabetes mellitus (hemoglobin A1c [HbA1c] value 
≥ 9.5% based on results from the Pre-Screening Visit or the Screening Visit);  
6. Use of a fibrate, niacin ≥250 mg/day, prescription or over-the-counter fish oil or other products 
containing OMG-3, or TZDs within the last six weeks prior to Screening;  
7. If patients are on metreleptin for investigational use, they should be washed out for four months 
and their leptin level must have returned to pre-metreleptin treatment state which is indirect 
evidence that any binding antibodies may have decayed as well; 
8. Use of strong UGT inhibitors: amitriptyline, atazanavir, deoxyschizandrin, diclofenac, 
efavirenz, erlotinib, hecogenin, niflumic acid, nilotinib, probenecid, and valproic acid; 
9. Patients with hypersensitivity to or have a history of significant adverse reactions to fibrates; 
10. Patients on potent CYP3A4 inhibitors such as itraconazole or a macrolide antibiotic; 
11. Previously treated with gemcabene; participation in another clinical study of an investigational 
agent or device concurrently or within one month prior to the Screening Visit, or use of an 
investigational agent within one month or five half-lives (if known), whichever is longer, prior 
to the Screening Visit;  
12. Or 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 
Early Termination (ET) Visit. The reason for patient withdrawal must be documented in the Case 
Report Form (CRF) and on the source document(s). 


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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.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Up to eight patients will enter the treatment phase to receive 300 mg gemcabene daily for 12 weeks 
starting on Day 1/Visit T1. After 12 weeks of treatment, at visit T4, patients will be randomized 
1:1 according to a pre-generated randomization code to either of the following groups: 
  
Group 1: Gemcabene 300 mg QD for weeks 12-24 
 
Group 2:  Gemcabene 600 mg QD for weeks 12-24 
5.2 
Dose Rationale 
Based on a prospective analysis in a gemcabene monotherapy study (1027-04) in patients with 
mild-moderate hypertriglyceridemia (TG ≥ 200 mg/dL) and a retrospective meta-analysis of all 
studies that tested gemcabene monotherapy in patients with mild to severe hypertriglyceridemia 
(1027-04, 1027-14 [healthy, obese patients], and 4141001 [monotherapy arm of a study in 
hyperlipidemia patients +/- atorvastatin], we conclude that the 300 mg once daily (QD) dose is 
optimal. The 600 mg dose will also be included for the following reasons: gemcabene has a U-
shaped TG dose response curve in Type IV patients and including both 300 and 600 mg may 
further elucidate the mechanism; and although TG lowering is mitigated at gemcabene 600 mg in 
HTG patients, LDL-C was significantly lowered at the 600 mg dose by a median % change of 17% 
(p=0.026).  In addition, those studies that evaluated hsCRP showed approximately a 50% lowering 
at gemcabene 600 mg. Therefore, we propose including the 300 mg and 600 mg dose to assess 
preliminary efficacy and safety in this study of FPLD patients. 
Study 1027-04 
In a pre-specified analysis in patients with TG ≥ 200 mg/dL (Study 1027-04) gemcabene lowered 
TG by a median % change at 12 weeks of by 27% (p < 0.05), 39% (p < 0.01), 13% (p = 0.623), and 
9% (p = 0.952) at the 150 mg, 300 mg, 600 mg, and 900 mg doses, respectively, compared to a 5% 
lowering for placebo. The dose response curve was U-shaped with the maximum effect at 300 mg. 
There was a correlative decrease in ApoC-III of 24% (p < 0.05) and 31% (p < 0.01) at the 150mg 
and 300 mg doses, respectively.  There was also a statistically significant lowering of ApoE by 
37% (p < 0.01) at 300 mg.   
Similar to OMG-3 compounds and fibrates, gemcabene increases LDL-C in patients with isolated 
hypertriglyceridemia (Type IV) when TG levels are lowered.  Small non-significant increases in 
LDL-C at gemcabene 150 mg and 300 mg and significant lowering in LDL-C of 17% (p = 0.026) 
and 23% (p < 0.001) at gemcabene 600 mg and 900 mg, respectively; compared to an increase of 
0.4% on placebo were observed.  It is hypothesized that in this population treated patients are 
shifting from a pattern A to pattern B profile, whereby larger less atherogenic LDL particles are 
being formed.  This is supported by a moderate non-significant decrease in ApoB across all doses.  
Retrospective Meta-Analysis 
A retrospective meta-analysis of  the effect of gemcabene monotherapy on TG in patients exposed 
to drug for at least 50 days included studies 1027-04 (low HDL), 1027-14 (healthy obese) and 


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4141001 (hypercholesterolemic) all of which enrolled some patients with TG ≥ 200 mg/dL.  The 
effect of gemcabene in patients on background statin was also analyzed (1027-18). 
The sub-cut of gemcabene monotherapy patients with TG ≥ 200 mg/dL had a median % lowering 
in TG of 25% (p = 0.0192) and 32% (p = 0.0051) for gemcabene 150 mg (n = 22) and 300 mg (n = 
27), respectively, compared to a lowering of 3% for placebo (n = 31).   No significant differences 
were observed in TG levels at the 600 mg or 900 mg doses versus placebo.  Gemcabene in 
combination with statin had a median % lowering in TG similar to monotherapy: 38% (p = 0.0067) 
for gemcabene 300 mg + statin (n = 23), 46% (p = 0.0028) for gemcabene 600mg + statin (n = 13) 
compared to a lowering of 19% with statin alone (n = 26).   
5.3 
Randomization and Blinding 
Patients who have completed the Screening Visit and meet all inclusion and none of exclusion 
criteria will begin treatment on Study Day 1. At week 12 (Visit T4) subjects will be randomized 
to either 300 mg gemcabene or 600 mg gemcabene for the remiaing 12 weeks of study.  
Randomized treatment assignment and randomization numbers will be assigned by paper. 
Following randomization, study drug will be dispensed in an open-label manner. 
5.4 
Drug Supplies 
5.4.1 
Study Drug Identification 
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 or 6-(5-carboxy-5-methyl-
hexyloxy)-2,2-dimethylhexanoic acid calcium 
USAN Name 
Gemcabene calcium 
Parent Compound 
6,6’-oxybis (2,2-dimethylhexanoic acid) or 6-(5-
carboxy-5-methyl-hexyloxy)-2,2-
dimethylhexanoic acid 
USAN Name 
Gemcabene 
Molecular Formula 
Chemical Formula Calcium Salt: C16H28O5•Ca 
 
Chemical Formula Parent: C16H30O5 
Relative Molecular Mass 
Molecular Weight Calcium Salt: 340.48 
 
Molecular Weight Parent: 302.41 


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Formulation/amount 
Tablets/300 mg 
Manufacturer (drug substance) 
Corden Pharma Switzerland 
Manufacturer (drug product) 
Catalent Pharma Solutions 
Storage Requirements 
Room temperature (15-30°C) in a secured location 
(locked) with no access for unauthorized 
personnel.  
5.4.2 
Formulation and Packaging 
The drug product for oral administration is an immediate-release tablet containing the equivalent 
of 300 mg of gemcabene as its calcium salt, in a formulation comprising the following inactive 
ingredients: lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium magnesium 
stearate. The tablets are film coated with a blend of simethicone 30% emulsion and Opadry White 
YS 1-7040.  
Study drug will be prepared as a 30-day supply in bottles and dispensed based on the assigned 
treatment group. In accordance with 21 CFR §312.6 the packaging will bear a label with the 
statement “Caution: New Drug – Limited by Federal (or United States) law to investigational use.” 
Subjects will be instructed to take one (1- 300 mg tab) or two (2- 300 mg tabs) per day, based on 
treatment assignment.  
5.4.3 
Study Drug Preparation and Dispensing 
Study drug will be administered at the site on clinic visit days.  Patients will self-dose at all other 
times during the Treatment Period. The Investigator or designee will provide patients with 
sufficient study drug until the next scheduled study visit. 
5.4.4 
Study Drug Administration 
Patients will be instructed to take study drug at the same time in the morning either with or without 
food and with water.   Missed doses will be documented. If a patient misses a dose, two doses 
should not be taken the following day. 
5.4.5 
Treatment Compliance 
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 at each study visit post-enrollment 
during the Treatment Period and at the Early Termination Visit, if applicable, and recorded on the 
appropriate CRF and the drug accountability log.  
The Investigator or designee will remind patients at each visit of the importance of following the 
protocol-defined schedule for taking study drug. Reasons for not following the study drug 


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administration schedule as described in the protocol will be clearly recorded in the source 
documents. 
5.4.6 
Storage and Accountability 
The study drug will be stored at room temperature (15-30°C) in a secured location (locked) with 
access restricted to authorized personnel only. The storage temperature will be monitored and 
recorded.  
Upon receipt of study drug, the Investigator or designee will conduct a complete inventory of all 
study drug and ensure no damage occurred during shipment.  
The Investigator will maintain adequate records documenting the receipt, use, loss, or other 
disposition of study drug. Drug accountability logs will identify the study drug code number and 
account for the disposition on a 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 and Gemphire Therapeutics.  
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).  
5.5 
Prior and Concomitant Medications and/or Procedures 
5.5.1 
Permitted Medications and/or Procedures 
Patients are required to be on a stable, low-fat, low-cholesterol diet.  Patients should remain on 
previously prescribed background lipid-lowering therapy for the duration of the study, if started at 
least six weeks prior to the Screening visit. It is important that background lipid-lowering is stable 
with the same dose taken at the same time each day.  FPLD patients who receive pharmacologic 
treatment for their disease or any other chronic medical condition (i.e., diabetes) must be on a 
stable regimen for three months prior to signing informed consent and should remain on this 
regimen, if possible, during study conduct.  
5.5.2 
Excluded Medications and/or Procedures 
Patients are not permitted to receive treatment with a fibrate lipid-regulating agent, niacin ≥250 
mg/day, prescription or over-the-counter fish oil or other products containing OMG-3, or a TZD 
for at least six weeks prior to the Screening Visit. 
Patients are not permitted the use of tamoxifen, estrogens or progestins that have not been stable 
for greater than four weeks prior to Visit 1, nor permitted the use of oral or injected corticosteroids 
or anabolic steroids. If patients are on metreleptin for investigational use, they should be washed 
out for four months. 
Patients are not permitted the use of strong UGT inhibitors: amitriptyline, atazanavir, 
deoxyschizandrin, diclofenac, efavirenz, erlotinib, hecogenin, niflumic acid, nilotinib, probenecid, 
and valproic acid. 


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5.5.3 
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 blood testing.  
Patients are restricted from using alcohol 48 hours prior to study visits. Patients must not drink 
more than two units of alcohol per day.  A unit of alcohol is defined as 12 ounces (350 ml) of beer, 
5 ounces (150 ml) of wine, or 1.5 ounces (45 ml) of 80-proof alcohol for mixed drinks. 
Clinic visit assessments that require a patient to fast will be defined as no food or caloric beverage 
for at least eight hours prior to sample collection. Patients will be permitted to have water, tea or 
black coffee.  
Study drug should be taken at the same time in the morning either with or without food. 
Patients will maintain a stable, heart-healthy diet (as self-reported) throughout the study. 
5.5.4 
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 CRF and the source document. This includes medications 
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 
An overview of the visits is below with a tabular listing of the Schedule of Procedures located in 
Appendix A. Assessments that require a patient to fast will be defined as no food or caloric 
beverage (tea and black coffee are allowed) for at least eight 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 
Pre-Screening Visit 
Only patients with a history within the past year of TG ≥ 200 mg/dL on current TG-lowering 
therapy and requiring a Wash-Out Period will participate in the Pre-Screening Visit.  
A six-week Wash-Out Period will be required for eligible patients taking fibrates, niacin ≥250 
mg/day, prescription or over-the-counter fish oil or other products containing OMG-3, or TZDs.  
If patients are on metreleptin for investigational use, they should be washed out for four months 
and their leptin level must have returned to pre-metreleptin treatment state which is indirect 
evidence that any binding antibodies may have decayed as well. 
Refer to Appendix A for procedures that will be performed at the Pre-Screening Visit. 
6.3 
Screening Visits 
 
All eligible patients will participate in the Screening Period up to 28 days prior to Day 1. For 
eligible patients taking stable allowable, lipid-lowering therapy (statins, ezetimibe, niacin, PCSK9 
inhibitors, or other herbal products or dietary supplements with potential lipid-altering effects) for 
greater than six weeks and who do not require a Wash-Out Period, the Screening Visit will be their 
first study visit. To qualify for enrollment in the treatment period, the fasting TG measurement at 
Visit S1 must be ≥ 250 mg/dL (2.83 mmol/L).  If a patient's TG value from S1 falls outside the 
required range for entry into the study, one additional sample for fasting TG measurement can be 
collected prior to S2.  
At Visit S2 potential patients must have hepatic steatosis ≥10% based on the core imaging lab 
assessment of liver fat content (MRI-PDFF) to be eligible for enrollment on Day 1 (Visit T1).   If 
the core imaging lab assessment of liver fat content is below the minimum range outlined in the 
protocol the patient will be ineligible and will not be eligible for re-screening.  A determination of 
hepatic fibrosis (MR elastography) will also be performed at this visit.    
Patients meeting screening criteria including TG and 10% liver fat will be offered an optional liver 
biopsy performed for the assessment of a baseline NAS. If all of the inclusion criteria (Section 4.1) 
are met and the patient has none of the exclusion criteria (Section 4.2) the patient may be 
randomized into the 12-week treatment period. 


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6.3.1 
Screening Visit S1 (up to Day -28) 
Only patients with a history within the past year of TGs ≥ 250 mg/dL and NOT requiring 
wash-out from fibrates, prescription or over-the-counter fish oil or other products 
containing OMG-3, niacin ≥250 mg/day or TZDs may participate in Screening Visit 1.  
Patients may be receiving statins, ezetimibe, PCSK9 inhibitors, or other herbal products or 
dietary supplements with potential lipid-altering effects only if therapy is stable for greater 
than six weeks prior to Screening Visit 1.  
For patients determined as ineligible based on TG levels < 250 mg/dL at Visit S1 ONLY a 
fasting lipid panel for the measurement of TGs can be reassessed at an interim visit between 
Visits S1 and S2. 
For patients who required a wash-out period and completed the Pre-Screening Visit, the following 
Screening Visit procedures will not be repeated: informed consent, full physical examination, 
height, TSH, and serology (HBV, HCV, and HIV). Updates, as needed, will be made to 
medical/surgical history, demographics, and concomitant medications.   
Refer to Appendix A for procedures that will be performed at the Screening Visit S1 (up to Day -
28). 
6.3.2 
Screening Visit S2  
Patients with a qualifying TG level ≥250 mg/dL will have an assessment of liver fat content to 
determine eligibility as measured by MRI-PDFF.  If this core imaging lab assessment of liver fat 
is below 10% the patient will be ineligible for enrollment and will not be eligible for re-screening.  
A determination of hepatic fibrosis (MR elastography) will also be performed at this visit.    
Refer to Appendix A for all procedures that will be performed at the Screening Visit S2.  
6.4 
Treatment Period (Visit T1 through Visit T7) 
6.4.1 
Visit T1 (Study Day 1)  
Patients meeting screening criteria including TG and 10% liver fat will be offered an optional liver 
biopsy, which will be performed for the assessment of a baseline NAFLD Activity Score (NAS). 
If patients opt-out of the liver biopsy, they can still move to the treatment phase.  
Open-label, Treatment Period: After confirmation of qualifying fasting TG values and MRI-
PDFF confirmed hepatic steatosis ≥10%, eligible patients will have a fasting liver biopsy 
performed if they opt in and move to treatment phase with 300 mg daily for 12 weeks starting on 
Day 1/Visit T1. Up to eight patients will be treated.  
The T1 visit may occur over several days, but no more than 7 days.  
Refer to Appendix A for procedures that will be performed pre-dose at Visit T1 (Day 1). 


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6.4.2 
Visit T2 (Week 4) 
Refer to Appendix A for procedures that will be performed at Visit T2 (Week 4 ±3 days). 
6.4.3 
Visit T3 (Week 8) 
Refer to Appendix A for procedures that will be performed at Visit T3 (Week 8 ±3 days). 
6.4.4 
Visit T4 (Week 12) Randomized Treatment Period 
Refer to Appendix A for procedures that will be performed at Visit T4 (Week 12 ±3 days).  After 
12 weeks at visit T4, patients will be randomized 1:1 according to a pre-generated randomization 
code to the remaining 12 -week treatment period in a 1:1 ratio to one of the following: 
• Group 1: Gemcabene 300 mg QD for 12-24 weeks 
Group 2: Gemcabene 600 mg QD for 12-24 weeks 
6.4.5 
Visit T5 (Week 16)  
Refer to Appendix A for procedures that will be performed at Visit T5 (Week 16 ±3days). 
6.4.6 
Visit T6 (Week 20) 
Refer to Appendix A for procedures that will be performed at Visit T6 (Week 20±3 days). 
6.4.7 
Visit T7 (Week 24) 
Refer to Appendix A for procedures that will be performed at Visit T7 (Week 24±3days) 
6.5 
Follow-up Visit 8 (Week 28; Telephone Call four weeks post-dose) 
The Follow-up Visit will be conducted as a telephone call four weeks (±3 days) after the last dose 
of study drug, during which it will be assessed how the patient is doing with a body systems review, 
unless the patient requires a site visit due to an abnormal result at Week 24 (or the ET Visit, if 
applicable) or an ongoing treatment-related adverse event.  
Refer to Appendix A for procedures that will be performed at the Follow-up Visit (Week 28 ±3 
days) if done in person due to an adverse event. 
6.6 
Early Termination Visit and Withdrawal Procedures 
For patients who are withdrawn from the study prior to completion, refer to Appendix A for 
procedures that will be performed at the ET Visit.  
 


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7 
EFFICACY ASSESSMENTS 
7.1 
Biomarker Assessments 
The following efficacy assessments will be measured in order to obtain the primary, secondary, 
and exploratory endpoints.  Refer to Appendix A for procedures that will be performed at specific 
timepoints. 
• Fasting lipid panel which includes: TG, TC, HDL-C, non-HDL-C, VLDL-C, LDL-C 
(ultracentrifugation); 
• Fasting Apo B, ApoA-I, ApoA-II, ApoA-V, ApoC-II, ApoC-III, and ApoE;   
• hsCRP, SAA, IL-6, fibrinogen, IL-1β, ANGPTL4, and ANGPTL3;  
• Fasting insulin levels, FPG, HbA1c, leptin, adiponectin; 
• Change and percent change in biomarkers of hepatic steatosis including GGT; Alk Phos; AST 
and ALT ratio, AST/ALT ratio, INR, albumin, bilirubin from baseline to various timepoints; 
and  
• Change and percent change in liver mRNA levels which may include denovo cholesterol 
synthesis and lipogenesis, inflammation, LDL receptor, β-oxidation, and sulfatase from 
baseline to Week 24; 
•  
7.2 
Evaluation of NAFLD and NASH 
7.2.1 
Imaging and liver biopsy 
The magnetic resonance imaging–estimated proton density fat fraction (MRI-PDFF) is a novel 
imaging-based biomarker that allows fat mapping of the entire liver and is independent of the 
scanner’s manufacturer and magnet strength.   MRI-PDFF is emerging as the leading biomarker 
for assessing treatment response in NASH trials to monitor longitudinal changes in hepatic fat 25,26. 
MRI-PDFF is measured with advanced MRI techniques that minimize or correct the confounding 
factors (T1 bias, T2* bias, and multifrequency interference effects of fat and eddy currents) that 
corrupt fat fraction estimations with conventional MRI-by a previously described and validated 
protocol 27-30. The protocol uses a gradient echo sequence with a low flip angle to minimize T1 
bias, and it acquires multiple echoes in which the multiple spectral peaks of lipid at and water 
interfere with respect to each other. Once data are acquired at each echo of the echo times, they 
pass to a fitting algorithm that estimates and corrects T2* effects, models the fat signal, and 
estimates fat and water proton densities; then, the fat content is calculated 31,32.  
MRI-estimated PDFF has been validated against MRS as well as liver biopsy histological data. 
31,33,34. Hepatic fat quantification via MRI-PDFF has been utilized in NASH clinical trials for 
quantitative fat assessment 25,29,35-37.  
Based on the correlations to biopsy, the ease of conduct, the extensive availability of MRI-PDFF 
this is the imaging technique that will be utilized in this pilot study of FPLD. 


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MR-elastography will also be performed to assess tissue stiffness which has been shown to be 
associated with increased hepatic fibrosis42. 
Hepatic biopsy proven disease is the gold standard for diagnosis of NAFLD and NASH and for 
evaluation of treatment 38,39. However, hepatic biopsy has serious procedural related risks, e.g. 
bleeding, perforation and death, and consequently is not appropriate for frequent routine evaluation 
and follow-up in patients in the clinical setting.   
Although fat accumulation is generally considered diffuse in NAFLD and NASH, the distribution 
is non-uniform, which means any type of assessment that has limited spatial sampling may have 
high inter- and intra- observer variability 40-42. Therefore, there is still the need for continued 
development of surrogates (i.e., MRI-PDFF) for early and mid-stage clinical studies of potential 
therapies, as well as for following the treatment response in the clinical setting. 
A determination of NAS (NAFLD activity score) including steatosis, lobular inflammation and 
hepatocyte ballooning will be calculated from the liver biopsy if patients opted in for the liver 
biopsy.  In addition, markers of mechanism and effect will be assessed including syndecan.  


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8 
RISK ASSESSMENT 
8.1 
Known Potential Risks  
The safety and efficacy profile of gemcabene has been developed through 18 Phase 1 and 2 studies 
including 1278 healthy volunteers and patients.  
Common adverse events include:  
• Headaches 
• Asthenia (feeling of weakness) 
• Nausea 
• Dizziness 
• Dyspepsia 
• Abnormal bowel movements 
• Myalgia (muscle pain) 
• Increased BUN 
• Increased creatinine 
Identified and Potential Important Risks:  
 
Based on the non-clinical and clinical safety data collected, important potential risks are liver 
findings, hemoglobin decrease, BUN and creatinine increase and myalgia. Importantly, only one 
patient had a transaminase elevation >3x ULN after receiving gemcabene 600 mg and atorvastatin 
80 mg. While hemoglobin decrease was seen in non-clinical toxicity studies, only small decreases 
in hemoglobin have been observed clinically and were also seen with placebo (not statistically 
significant). Small increases in creatinine and BUN were observed in clinical studies with 
gemcabene. The increases appeared within the first two-to-four weeks of treatment and did not 
worsen over time.   
 
Other risks:  
• There is a possibility of rhabdomyolysis when combined with a statin. 
• Patients with a hypersensitivity to or who have a history of significant adverse reactions to any 
fibrate lipid lower agents should avoid gemcabene.  
• Patients on potent CYP 3A4 inhibitors such as itraconazole or a macrolide antibiotic should be 
excluded.  
• Based on non-clinical studies in rats, gemcabene should not be administered to pregnant 
women or women of childbearing potential not using effective methods to prevent pregnancy.  
• Gemcabene tests for carcinogenic activity are under review by the FDA with additional data 
requested for review prior to the initiation of studies greater than 6 months.  
 


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8.2 
Risks from the procedures in the protocol: 
Procedures in this protocol include 1) blood draws; 2) MRI; 3) IV placement for repeated blood 
draws; and 4) liver biopsy.  
8.3 
Known Potential Benefits:  
Three Phase 2 studies have demonstrated that gemcabene is efficacious in reducing TGs in 
hypertriglyceridemic patients and LDL-C in hypercholesterolemic patients. As many FPLD 
patients (and patients with NAFLD) have high TGs and may have high LDL-C, this is a potential 
benefit for the participants.  
Gemcabene has also been demonstrated to reduce ApoB and hsCRP, both associated with 
cardiovascular disease risk. This is also a potential benefit to the participants. Within the study, 
participants will benefit from receiving lifestyle counseling. They will also receive regular 
assessments of their liver disease including labs (ALT, AST and GGT) and MRI (hepatic 
steatosis).   
Long range benefits could include satisfaction from contributing to development of treatments for 
FPLD and FPLD with NAFLD.   
 
8.4 
Assessment of Potential Risks and Benefits  
The rationale for the necessity of exposing patients to the risks of participating in this study is that 
medications for FPLD are urgently needed.  
The value of the information to be gained outweighs the risks, because the risks are minimal and 
the information collected could be significantly valuable for the FPLD population.  Patients in the 
study will benefit from receiving standard of care lifestyle counseling and from state of the art 
measurements of their liver disease.   
 


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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 CRF. 
Adverse events, which include abnormal and clinically significant clinical laboratory test 
variables, will be monitored and documented from the time of first dose of study drug (Study Day 
1) until study participation is complete (the Follow-up Visit). 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 (Study Day 1), investigators should 
make updates to medical history and record any pre-existing medical condition or signs or 
symptoms that changes in severity, frequency, or seriousness in the medical history. Serious 
adverse events that occur prior to the first dose of study drug (Study Day 1) should be reported as 
an update to medical history as well as be reported on the appropriate adverse event CRF. 
Beginning with the first dose of study drug (Study Day 1), investigators should make an 
assessment for adverse events at each visit and record all adverse events, non-serious and serious, 
on the appropriate adverse event CRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the CRF. 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 CRF. 
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 CRF.  
Any medical condition already present prior to the patient taking the first dose of study drug (Study 
Day 1) should be reported in the medical history. Any SAEs occurring prior to the first dose of 
study drug (Study Day 1) should be reported as an update to medical history as well as an adverse 
event. Any pre-existing medical condition or signs or symptoms that changes in severity, 
frequency, or seriousness after the patient takes the first dose of study drug (Study Day 1) and 
through the Follow-up Visit should be reported as an adverse event. 
Clinically significant abnormal laboratory values or other examinations (e.g., ECG) that are 
detected at the time of the first dose of study drug (Study Day 1) and worsen during the study 
should be reported as adverse events. An abnormal laboratory result that is not verified by repeat 
testing does not necessitate reporting as an adverse event. The Investigator will exercise his or her 
medical, scientific, and clinical judgment in deciding whether an abnormal laboratory finding or 
other abnormal assessment is clinically significant. Clinically significant abnormal laboratory 
values occurring during the clinical study will be followed until repeat tests return to normal, 


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stabilize, or are no longer clinically significant. Any abnormal test that is determined to be an error 
does not require reporting as an adverse event. 
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 - 


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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) - 
Each report should be evaluated in the context of the natural history and course of the disease being 
treated and any other disease the patient may have. 
• Concomitant drug - 
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 - 
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 - 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
• The pharmacology and PKs of the study drug - 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of the 
study drug should be considered. 
9.2 
Specific Safety Measures 
The safety parameters will be reviewed every 3 months by an Independent Safety Monitor who 
will be Dr. James Shayman, a professor in the Department of Medicine, Division of Nephrology 
and Pharmacology at the University of Michigan. Dr. Shayman is an experienced clinical 
investigator and also an inventor of new drugs that have gained FDA approval.  
9.2.1 
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.  Refer to 
Appendix D for specific guidance.   
9.2.2 
Creatinine increase 
If, at any visit, a creatinine increase of > 0.3 mg/dL (27 µmol/L) from baseline is observed, a 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 


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make a clinical assessment of the significance of the finding. Refer to Appendix D for specific 
guidance. 
9.2.3 
Possible muscle and liver injury 
For muscle injury, CK, hepatic, and renal function laboratory data will be integrated with 
myopathy signs and symptoms. For management of CK elevations > 3  ULN, refer to 
Appendix D.  
 
For liver injury, laboratory data will be integrated with hepatic signs and symptoms. Monitoring 
and subsequent management of subject transaminase elevations is dependent upon 
baselinelevels, either < 2x ULN or ≥ 2x ULN at baseline.  Refer to Appendix D for specific 
guidance and/or discontinuation of study drug recommendations. 
 
9.2.4 
Significantly elevated TG levels  
In the event we see triglycerides>2000 mg/dL in a patient who did not have this high level at onset 
(many patients have very high triglycerides and no available therapy works for long term in the 
setting of the American diet and the social pressures, and this is one of the reasons why we want 
to undertake this study), we will contact the patient to review signs and symptoms of pancreatitis 
and we will evaluate diet information, have the patient meet with a dietician to manage adherence 
to a heart-healthy diet, counsel patients regarding restricted alcohol intake and diabetic control. 
We will repeat TG levels in 1 week. We will also measure lipase levels in the follow-up blood 
draw. 
9.2.5 
Patients with Diabetes 
In patients with diabetes, we will adjust concomitant medications to prevent hypoglycemia.  
However, given the short nature of the study, we will not add any new medications to rescue for 
hyperglycemia unless fasting glucose levels exceed 230 mg/dL and/or patients have symptoms. 
Both hypoglycemia and hyperglycemia, as defined as fasting glucose >230 mg/dL will be captured 
as lipodystrophy events. 
9.3 
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; 
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; 


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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. 
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 or 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. 
9.4 
Adverse Event Reporting − Procedures for Sponsor Investigator 
9.4.1 
Non-serious Adverse Events 
Each AE will be reported to the study investigator and the study investigator is responsible for 
completing and signing off on the AE reports.  Non-serious AEs will be reported to Gemphire in 
aggregate at the end of the study.  The sponsor investigator will review a summary of all AEs 
monthly and document this review.   
FPLD related events that are common in the study population (expected) and will be considered 
study endpoints include:  cardiac events, worsening abdominal pain requiring emergency room 
visits, urinary tract infections, acute pancreatitis in a patient with recurrent episodes of pancreatitis, 
hypoglycemia or hyperglycemia, DKA or hyperosmolar state. 
 
These and any other adverse events will be recorded on the CRF and monitored to resolution or 
30 days after end of the study.   
9.4.2 
Serious Adverse Event Reporting 
The sponsor investigator will report any qualifying Serious Adverse Event to MMS Holdings, 
Pharmacovigilance Department within 24 hours of learning of such event.   In addition to MMS 
Holdings, the Sponsor-Investigator may, at her discretion, report the SAE to any other required 
regulatory agencies, including the University of Michigan IRBMED according to IRBMED 
policy.Any serious adverse event (SAE), whether or not considered study intervention related, 


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including those listed in the protocol or investigator brochure and must include an assessment of 
whether there is a reasonable possibility that the study intervention caused the event.  
Study endpoints that are serious adverse events (e.g., FLP expected events) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between the 
study intervention and the event (e.g., death from anaphylaxis). All events must be reported to 
MMS Holdings Pharmacovigilance, on behalf of Gemphire, within 24 hours of learning of such 
event. 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the 
investigator deems the event to be chronic or the participant is stable.  
The study sponsor (Dr. Elif Oral) with assistance from the MICHR MIAP group, will be 
responsible for notifying the Food and Drug Administration (FDA) of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible, but in no case later than seven calendar 
days after the sponsor's initial receipt of the information.  Unexpected, suspected serious adverse 
events will be reported to the FDA within 15 calendar days after the sponsor’s initial receipt of the 
information.  In addition, Gemphire must notify FDA and all participating investigators in an 
Investigational New Drug (IND) safety report of potential serious risks, from clinical trials or any 
other source, as soon as possible, but in no case later than 15 calendar days after the sponsor 
determines that the information qualifies for reporting. 
All observed or volunteered SAEs regardless of treatment group or suspected causal relationship 
to the study drug will be reported as described below. If a SAE occurs, reporting to MMS Holdings 
Pharmacovigilance (Gemphire and Sponsor-Investigator’s Designee) must occur within 24 hours 
of learning of the event. Reporting to UM IRBMED will be done according to IRBMED reporting 
guidelines. 
All SAEs and follow-up information must be reported to Gemphire or designee within two weeks 
of awareness of the event as required by your local requirements by emailing or faxing a completed 
SAE report form to the following:  
Safety Contact Information: MMS Drug Safety 
Facsimile: +734 468 6352 
E-mail: GemphireDrugSafety@mmsholdings.com   
In particular, if the SAE if fatal or life-threatening, notification to Gemphire or designee must be 
made within one week, irrespective of the extent of available AE information. 
This timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE reports, initial and follow-up reporting of exposure in utero (EIU) cases, and any SAEs that 
the Investigator considers related to study drug occurring after the 30-day follow-up period. 


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The Investigator must continue to follow the subject as medically necessary until the SAE has 
subsided or until the condition becomes chronic in nature, stabilizes (in the case of persistent 
impairment), or the subject dies.   
9.5 
Pregnancy Reporting 
If a patient participating in the study becomes pregnant during the study or within 30 days of 
discontinuing study drug, the Investigator should complete the Exposure In Utero form and report 
the pregnancy within 24 hours to: 
Safety Contact Information: MMS Drug Safety 
Facsimile: +734 468 6352 
E-mail: GemphireDrugSafety@mmsholdings.com   
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The patient should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify MMS 
Drug Safety. At the completion of the pregnancy, the Investigator will document the outcome of 
the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as 
an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
9.6 
Expedited Reporting 
The Sponsor Investigator will report all relevant information about suspected unexpected serious 
adverse reactions that are fatal or life-threatening to the Food and Drug Administration (FDA) in 
accordance with 21 CFR 312.32 Information will also be submitted to the University of Michigan 
IRB (IRBMED) in accordance with IRBMED reporting guidelines. 
All other suspected unexpected serious adverse reactions will be reported to the FDA in accordance 
with 21 CFR 312.32 and the IRBMED in accordance with IRBMED reporting guidelines. 
A copy will be sent to Gemphire as agreed upon in the Clinical Trial Agreement. 
9.7 
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 site’s local laboratory for evaluation. 
Assessments that require a patient to fast will be defined as no food or caloric beverage for at least 
eight hours prior to sample collection. Patients will be permitted to have water.  
Local laboratory results that appear potentially misleading 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 
Principal Investigator prior to obtaining the new specimen. The clinical rationale for performing 
repeat testing of screening assessments should be thoroughly documented. 


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9.8 
Vital Signs 
Measurement of vital signs will include an assessment of pulse rate, blood pressure, respiration 
rate, and temperature. Vital signs will be measured according to the Schedule of Procedures 
(Appendix A). Blood pressure should be obtained in the seated position, after the patient has rested 
comfortably for at least five 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.   
9.9 
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 according to the Schedule of Procedures (Appendix A). 
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, or SAE, as applicable. All ECG traces will be kept as source data. 
9.10 
Physical Examinations 
A full physical examination will be performed according to the Schedule of Procedures (Appendix 
A). A full physical examination includes genitourinary examination per the Investigator’s 
discretion and does not include a rectal examination.  
A symptom-directed physical examination will be conducted at other visits.  See Schedule of 
Procedures (Appendix A). 
Height and weight will be measured according to the Schedule of Procedures (Appendix A).    
9.11 
Medical/Surgical History and Demographics 
Medical and surgical history and demographics will be recorded according to the Schedule of 
Procedures (Appendix A). 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 Study 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.  
9.12 
Reserve Samples 
Additional blood samples will be collected according to the Schedule of Procedures (Appendix A) 
to be available for analysis of exploratory biomarkers associated with lipid metabolism and FPLD 
and/or repeat or additional clinical laboratory and urine testing in the event of a safety issue.  
9.13 
Dual Energy X-Ray Absorption Scan (DEXA) 
DEXA (Dual X-ray absorptiometry) scan for total body composition: This involves using a dual 
X-ray absorptiometer (Hologic Inc., Bedford, MA) for estimation of fat and lean body mass. Its 


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validity has been shown in multiple studies with various groups of patients.  A DEXA scan will 
be performed according to the Schedule of Procedures (Appendix A). 


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10 
STATISTICS 
10.1 
Sample Size  
The sample size of eight patients (four per group) was empirically determined to provide 
expanded use proof of concept and initial safety and tolerance in the FPLD population.   
10.2 
Analysis Populations 
10.2.1 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized patients who received at least one dose 
of study drug, and have both a baseline and at least one post-baseline lipid value.  All efficacy 
summaries and analyses will be performed using the FAS. 
10.2.2 
Safety Analysis Set 
The safety analysis set (SAS) will include all randomized patients who receive at least one dose of 
study drug. All safety analyses will be conducted on SAS.  


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10.3 
Statistical Methods 
10.3.1 
Analysis of Efficacy 
10.3.1.1 
Primary efficacy analyses 
The primary efficacy endpoint is the percent change from baseline to Week 12 in fasting serum 
TG.  If the Week 12 TG value is missing, then the “Week 12” TG value will be imputed using 
last observation carried forward (LOCF).  
Baseline will be defined as the average of the pre-dose Day 1/Visit T1 value and the last 
qualifying screening visit.   
The primary efficacy endpoint will be summarized by treatment group and timepoint using the 
FAS. 
10.3.1.2 
Secondary efficacy analyses 
Secondary efficacy endpoints will also be summarized by treatment group and timepoint, using 
the FAS.  
The secondary TG efficacy endpoints are the change from baseline to Week 12 and change and 
percent change from baseline to the average of Weeks 6 and 12, and Week 24 in fasting serum 
TG.  Baseline will be defined as outlined above for the primary variable.  For the “average of 
Weeks 6 and 12” TG efficacy assessment, if only the Week 6 or Week 12 TG value is available, 
then that single value will be used.  If both the Week 6 and Week 12 TG values are missing, then 
the average “Week 6 and Week 12” TG value will be imputed using LOCF. For the “Week 24” 
TG efficacy assessment, if Week 24 values are missing, then the value will be imputed using 
LOCF. 
The change and percent change in all other secondary efficacy biomarkers will be summarized 
for Week 12 and Week 24 as described above.   
Baseline TC, HDL-C, and LDL-C are defined similarly to baseline for TG.  Baseline for fasting 
lipoproteins, hsCRP, SAA, IL-6, fibrinogen, IL-1β, ANGPTL4, ANGPTL3, are defined as the 
value from pre-dose Day 1/Visit T1.   
An additional secondary analysis is change and percent change from baseline to Week 12 and 
Week 24 in the percentage of hepatic steatosis (liver fat content) as measured by MRI-PDFF.  
Baseline liver fat content is defined as the value from Screening.  Missing percentage liver fat 
content at Week 24 will be imputed using last LOCF.   
Hepatic fibrosis as measured by MR elastography will be summarized as outlined above for liver 
fat content via MRI-PDFF. 
An additional secondary analysis in change and percent change from baseline to Week 24 in 
NAS as determined by histology.  


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10.3.1.3 
Exploratory analysis 
The exploratory variables will be summarized as described above.  Missing values will be 
imputed using LOCF. 
10.3.1.4 
Missing Data 
The primary analyses of the primary, secondary and exploratory (if measured and analyzed) 
outcome variables will use LOCF for missing value.   
In the case of the presence of a substantial amount of missing data, sensitivity analyses will be 
carried out to evaluate the possible impact of missing data and may include multiple imputation or 
other techniques that allow for missing not at random. 
To summarize laboratory variables, consecutive time windows will be created around each planned 
visit.  In the descriptive statistics of laboratory 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. 
10.3.2 
Analysis of Safety 
Safety will be assessed using the SAS.  The assessment of safety will include adverse events, 
clinical laboratory assessments, ECGs, physical examinations, and vital signs. 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 by treatment group at baseline, End of Treatment 
(Week 24), or the ET Visit, if applicable, and change from baseline to End of Treatment (Week 
24) or the ET Visit, if applicable. Frequency counts of new or worsening abnormalities will also 
be provided. 
 
 
 


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded directly into the Medrio EDC system. All corrections or changes made to 
any study data must be appropriately tracked in an audit trail in the EDC system. An CRF will be 
considered complete when all missing, incorrect, and/or inconsistent data are provided. Study data 
monitoring will be performed by Gemphire Therapeutics or its designee. 
11.1.1.1 
Computer Systems 
Data will be collected and processed using Medrio, a 21 CFR Part-11-compliant data capture 
system provided by Gemphire Therapeutics.  
11.1.1.2 
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. All passwords will be strictly confidential. 
11.1.1.3 
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 (WHO Drug) Dictionary for prior and concomitant 
medications. 
11.1.2 
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 sponsor investigator for resolution through data queries. 
The paper CRFs must be reviewed and signed by the Investigator. 
11.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, CRFs, inventory of study product, 
regulatory documents, and other 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 Trial Agreement. Prior to transfer or 
destruction of these records, the Drug Manufacturer 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, Informed Consent Form (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 patient 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. 


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12.4 
Study Monitoring  
To assure adequate protection of the rights of human subjects, per 21 CFR §312.50, 312.53, this 
study will be monitored by Gemphire Therapeutics or its designee in addition to the University of 
Michigan Institute for Clinical and Health Research (MICHR) (if needed). Routine monitoring 
will be scheduled at appropriate intervals, with more frequent visits occurring at the beginning of 
the study. An initiation visit will take place, followed by routine monitoring visits.  
Monitoring visits may be in the form of a site visit or a review of documents. During a monitoring 
visits, access to relevant hospital and clinical records must be given by the investigator to the 
Gemphire and the MICHR representative (if required) conducting the monitoring visit to verify 
consistency of data collected on the CRFs with the original source data. It is expected that the 
relevant investigational staff be available to facilitate the conduct of the visit, that source 
documents are available at the time of the visit, and that a suitable environment will be provided 
for review of study-related documents. Any issues identified during the site visits will be 
communicated with the investigator and an expected to be resolved in timely fashion. 
The established monitoring plan will ensure the quality and integrity of the data through pre-
investigation visits and periodic site visits to verify adherence to the protocol, completeness and 
accuracy of study data and samples collected, proper storage, dispensing and inventory of study 
medication, and compliance with regulations. 
12.5 
Data Safety Monitoring Board 
A Data Safety Monitoring Board will convene every quarter during study patient activity to 
review safety data for this study.   This board will consist of two physicians and a statistician.  
De-identified patient data will be provided with case numbers. In addition, the DSMB will 
review all the SAEs. If there is a reason to stop therapy in a particular patient, the DSMB will 
direct the Principle Investigator. Also, the DSMB may decide to halt this study if there is a 
pattern of SAEs.   
12.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, other regulatory bodies, 
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 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the study intervention. These 
documents should be retained for a longer period, however, if required by local regulations. It is 


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the responsibility of the sponsor to inform the investigator when these documents no longer need 
to be retained. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., CRFs and hospital records), all original signed ICFs, copies of all CRFs, 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 
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, University of 
Michigan and Gemphire 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. Sponsor Investigator is obligated to keep data 
pertaining to the study confidential. Gemphire and Investigator reserve 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 fulfill Sponsor 
obligations under 21 CFR §54. In addition, this information will be promptly updated if any 
relevant changes occur during the study and for a period of one year after the completion of the 
study. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Gemphire has taken out clinical trial 
insurance. This insurance provides coverage to the sites through Gemphire 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 will be submitted as an Investigator Initiated IND.  
The study will commence (i.e., initiation of study site) when the FDA authorization and favorable 
Ethics opinion have been received.  
12.12 
Definition of End of Study 
The End of Study for each patient is defined as the completion of the Follow-up Visit or the ET 
Visit, if applicable. 


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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 University of Michigan. In 
addition, Gemphire retains the right to discontinue development of gemcabene at any time.  
If the development of gemcabene is prematurely terminated or discontinued, Gemphire will 
promptly notify the Investigator. After notification, the Investigator must contact all participating 
patients within two weeks.  


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13 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
All protocol amendments will undergo the same review and approval process as the original 
protocol. A protocol amendment may be implemented only after it is approved by the IRB and 
submitted to the FDA, 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 five working 
days. 
13.2 
Address List 
13.2.1 
Sponsor 
Dr. Elif A.  Oral, MD 
University of Michigan 
Brehm Center for Diabetes 
Room 5313 
Ann Arbor, MI 48105 
Phone: (734) 615 0539 (Adam Neidert) 
Fax: (734) 232 8162 
 
13.2.2 
Drug Supplied By: 
Gemphire Therapeutics Inc.  
17199 N Laurel Park Drive 
Livonia, Michigan  
Telephone: +1-248-681-9815 
Facsimile: +1-734-864-5765 
 
13.2.3 
Biological Specimens 
University of Michigan Clinical Pathology Laboratories 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
 
Michigan Clinical Research Unit 
Cardiovascular Center 
1500 East Medical Center Drive 
Telephone:  734-936-8080 
 
Brehm Center for Diabetes 
1000 Wall Street 
Ann Arbor, MI  48105 
 


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14 
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Patel, J. et al. Association of noninvasive quantitative decline in liver fat content on MRI 
with histologic response in nonalcoholic steatohepatitis. Therap Adv Gastroenterol 9, 692-
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33 
Yokoo, T. et al. Estimation of hepatic proton-density fat fraction by using MR imaging at 
3.0 T. Radiology 258, 749-759, doi:10.1148/radiol.10100659 (2011). 
34 
Kang, G. H. et al. Reproducibility of MRI-determined proton density fat fraction across 
two different MR scanner platforms. J Magn Reson Imaging 34, 928-934, 
doi:10.1002/jmri.22701 (2011). 
35 
Patel, N. S. et al. Effect of weight loss on magnetic resonance imaging estimation of liver 
fat and volume in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 
13, 561-568 e561, doi:10.1016/j.cgh.2014.08.039 (2015). 
36 
Loomba, R. et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment 
by novel magnetic resonance imaging and magnetic resonance elastography in a 
randomized trial (MOZART trial). Hepatology 61, 1239-1250, doi:10.1002/hep.27647 
(2015). 
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Zarrinpar, A., Gupta, S., Maurya, M. R., Subramaniam, S. & Loomba, R. Serum 
microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and 
dizygotic twins: a prospective study. Gut 65, 1546-1554, doi:10.1136/gutjnl-2015-309456 
(2016). 
38 
Fonseca, J. et al. Comment to: "EASL-EASD-EASO Clinical Practice Guidelines for the 
management 
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doi:10.1016/j.jhep.2016.10.036 (2016). 
39 
Wilkins, T., Tadkod, A., Hepburn, I. & Schade, R. R. Nonalcoholic fatty liver disease: 
diagnosis and management. Am Fam Physician 88, 35-42 (2013). 
40 
el-Hassan, A. Y., Ibrahim, E. M., al-Mulhim, F. A., Nabhan, A. A. & Chammas, M. Y. 
Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features and 
influence on patient management. Br J Radiol 65, 774-778, doi:10.1259/0007-1285-65-
777-774 (1992). 
41 
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42 
Ratziu, V. et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. 
Gastroenterology 128, 1898-1906 (2005). 
 
 
 
 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Pre-
Screena 
Screening 
Period 
 
Treatment Periodb 
Follow-
Upc 
ET 
Study 
Day   -28 
Up to 
Day -3 
to Day 1 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24c 
 
Week 
28 
 
 
Visit 
S1 
Visit 
S2 
Visit T1 
Visit 
T2 
Visit 
T3 
Visit 
T4 
Visit 
T5 
Visit 
T6 
Visit 
T7 
FU8 
 
Informed consenta 
X 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriaa 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history and demographicsa 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Full physical examinationd 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
Symptom-directed physical examination 
 
 
 
X 
X 
 
X 
 
 
X 
Xe 
 
Initiate wash-out 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsf, heightg, and weight, BMI 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
Urinalysis; Protein:creatinine; 
albumin:creatinineh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
Serum/urine pregnancy testi 
X 
X 
 
X 
X 
 
X 
 
 
Xi 
Xe 
X 
Safety chemistry panel, coagulation, and 
hematologyj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
Xe 
X 
TSH and serology 
X 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panell LDL-C ultracentrifugation 
Xr 
Xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting apolipoproteinsm 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
hsCRP, SAA, IL-6 and fibrinogen 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Fasting insulin, FPG, HbA1c 
X 
X 
 
X 
 
 
X 
 
 
X 
 
X 
MRI-PDFF; MR elastography 
X 
 
 
 
X 
 
 
X 
 
X 
Liver Biopsyn 
 
 
 
X 
 
 
 
 
 
X 
 
 
QOL questionnaires 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
Randomization 
 
 
 
 
 
 
X 
 
 
 
 
 
Study drug administration 
 
 
 
X 
X 
 
X 
 
 
 
 
 
Compliance check 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary assessment (self-reported)o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGp 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 


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a. 
All eligible patients will participate in the Screening Visit up to 28 days prior to Day 1. Only patients with a history within the past year of TG ≥ 200 mg/dL on current 
TG-lowering therapy and requiring a Wash-Out Period will participate in the Pre-Screening Visit.  
b. 
Study assessments will be completed ±3 days for study visits with the exception of study visit T4 (Week 24) when assessments can be performed up to 3 days prior to 
Week 24, but not after Week 24. 
c. 
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 Week 24 or an ongoing treatment-related adverse event. 
d. 
A full physical examination includes genitourinary examination per the Investigator’s discretion and does not include a rectal examination. 
e. 
Only for patients who had an abnormal result at Week 24 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. The same machine should be used for the patient throughout the study. 
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, Week 6, Week 12 and Week 24, the Follow-up Visit (only for patients who had an abnormal result Week 24 [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, and the ET Visit, if applicable. A urine pregnancy test will 
be conducted at Day 1, Week 6, Week 12 and Week 24.  
j. 
See Appendix B for a list of analytes and description of when repeat or reflexive testing will be required.  
k. 
Thyroid-stimulating hormone and serology will be measured at the Screening Visit. Serology includes HBV, HCV, and HIV. HbA1c will be collected at Screening Visit, 
Week 12, and Week 24. 
l. 
Includes TG, non-HDL-C, TC, 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 total 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. 
Liver biopsy will be optional for subjects. 
o. 
Patients will self-report their adherence to a stable diet. 
p. 
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 CRF. 
r. 
LDL-C ultracentrification will not be performed at the Pre-Screening Visit.  
s. 
An addition fasting TG may be assessed at an “optional” visit between S1 and S2. 
Apo = apolipoprotein; ECG = electrocardiogram; ET = Early Termination; HBV = hepatitis B virus; HbA1c = hemoglobin A1c; HCV = hepatitis C virus; HDL-C = high-density 
lipoprotein cholesterol; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; non-high-density 
lipoprotein cholesterol = non-HDL-C; TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone; VLDL-C = very low-density lipoprotein cholesterol. 
 
Adverse events 
Xq 
Xq 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dual Energy X-ray Absorption Scan 
X 
 
 
X 
 
 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Reserve samples for exploratory measures  
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Reserve genotyping sample 
 
 
 
X 
 
 
 
 
 
 
 
 


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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. 
 
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 
Albumin 
 
 
 
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 Study Day 1 and Week 12, the Follow-up Visit (only for patients 
who had an abnormal result at Week 12  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 
 
 
Efficacy Parameters  
The following efficacy parameters will be assessed in this study: 
Apo A-I 
ApoA-II 
ApoB 
ApoA-V 
ApoC-II  
ApoC-III 
Triglycerides 
ApoE 
High-density lipoprotein cholesterol  
Low-density lipoprotein cholesterol  
Non-high-density lipoprotein cholesterol 
Very low-density lipoprotein cholesterol 
SAA 
Total cholesterol 
High-sensitivity C-reactive protein 
IL-6 
HbA1c 
Adiponectin 
Leptin 
HbA1c 
Fibrinogen 
FPG 
Insulin 
ANGPTL3 
 
IL-1β 
ANGPTL4 
 
 
 
 


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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: HEMATOLOGY, RENAL, MUSCLE INJURY AND 
HEPATIC MONITORING 
Hematology 
 
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.  If hemoglobin 
falls >3.0 g/dL without any clear cause, then the investigator should discontinue the investigational 
product and hemoglobin should be monitored until it returns to a level of no less than 1.0 g/dL 
below baseline. At this time the investigator can consider restarting the investigational product and 
recheck hemoglobin levels 1 and 2 weeks after re-initiation of investigational product. If 
hemoglobin levels decrease >3 g/dL again, investigational product should be discontinued and the 
subject should continue with all other study procedures.  
 
Hemoglobin should continue to be monitored until it returns to a level of no less than 1.0 g/dL 
below baseline. 
 
Renal 
 
Renal function and potential nephrotoxicity will be assessed via hematology and urinalysis 
throughout the study.  If, at any visit, a creatinine increase of > 0.3 mg/dL (27 μmol/L) from 
baseline or a > 30 urinary albumin:creatinine ratio mg/g is observed, a repeat chemistry/urinalysis 
will be performed within 1 week. 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.  
 
Patients with persistent serum creatinine changes of > 0.3 to < 0.5 mg/dL will be evaluated by the 
investigator to determine if the subject has any signs and symptoms of renal injury. If the 
investigator determines that the biomarkers along with the signs and symptoms are consistent with 
renal injury then investigational product should be discontinued and the subject should continue 
with all future protocol assessments. 
 
If, at any visit, there is a creatinine increase ≥0.5 mg/dL from baseline and > ULN, a repeat 
chemistry will be performed within one week. The subject’s pase medical history, concomitant 
medications (including over the counter drugs and herbal supplements0, 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. Clinically significant 
abnormal laboratory values occurring during the clinical study will be followed until repeat tests 
return to baseline or normal levels.  
 


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If at any time there is a doubling of serum creatinine or a decrease >50% in GFR from baseline, 
then investigational product should be discontinued immediately. The patient will be followed 
until renal parameters return to baseline or normal levels. The investigator can determine based on 
signs, symptoms and laboratory data whether or not to reinitiate investigational product and 
continue with scheduled monitoring. Regardless of whether or not investigational product is 
reinitiated subjects should continue with all future protocol assessments. 
 
 
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) 
within 1 week. Study drug should be temporarily discontinued, pending the results of an 
investigation into the cause of muscle injury and/or CK elevation returns to within normal 
range or to a level deemed acceptable by the Investigator, or until the abnormality is explained 
by an appropriate diagnosis. Any statin the patient is currently taking will be temporarily 
discontinued while the cause of the muscle injury is being investigated. The investigator can 
determine if it is appropriate to reinitiate study drug. If study drug is reinitiated, then CK 
assessments should be made with 7 days to ensure that recurrence is not seen. If there is 
recurrent elevations >5 x ULN after reinitiating study drug, then study drug should be 
permanently discontinued and the patient’s CK and renal function 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. If study drug is permanently 
discontinued the subject should continue with all future protocol assessments. 
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: Subjects with baseline transaminases < 2x ULN 
 
Subjects with hepatic enzyme elevations should be managed according to the standard of care, at 
the discretion of the Investigator. For subjects with signs or symptoms suggestive of hepatitis, an 
unscheduled visit and a chemistry panel should be performed. Subjects with an ALT or AST > 3 
× ULN should have an unscheduled visit. A repeat assessment should be performed as soon as 
possible (within 1 week) to confirm the finding. A clinical evaluation should be performed, 


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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. Non-study drug potential causes for transaminase elevations should 
be ruled out. The investigator may consider to temporarily suspend study drug and reassess liver 
function weekly 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.  
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: Baseline Transaminase < 2x ULN 
 
Study drug should be discontinued permanently if any 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 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
It is also recommended that statin regimen is discontinued if any of the above criteria is met. 
Abnormal values should be followed until they return within normal range or baseline range or to 
a level deemed acceptable by the Investigator, or until the abnormality is explained by an 
appropriate diagnosis. If study drug is permanently discontinued the subject should continue with 
all future protocol assessments. 
 
Hepatic Monitoring: Subjects with baseline transaminases ≥ 2x ULN 
 
If subjects with abnormal baseline liver indices develop elevations of AST or ALT >2x baseline 
or total bilirubin >1.5x baseline values during the study, repeat testing should be performed within 
48 -72 hours. If there are persistent elevations (ALT or AST >2x baseline or TBL >1.5x baseline 
values) upon repeat testing, then close observation (testing and physical examination 2-3 times per 
week) should be implemented and discontinuation of drug should be considered. Recommended 
Hepatic Discontinuation Criteria: Baseline Transaminase ≥ 2x ULN Study drug should be 
discontinued permanently if any one of the following occurs (as confirmed by repeat assessment) 
and if the event is without an alternative explanation: 
• If BLM ≥2x ULN but <5x ULN, discontinue if ALT or AST increases to >3x BLM 
• Discontinue if ALT or AST increase is >2x BLM AND the increase is accompanied by a 
concomitant increase in TBL to >2x BLM OR the INR concomitantly increases by >0.2 
• In any subjects with signs and symptoms of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
 


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