Clinical trial NCT03436420
Conditions: Non-Alcoholic Fatty Liver Disease
Keywords: Pediatrics Lipids Liver Diseases Obesity
Sponsor: Emory University
Start date: 2018-03-29; Completion date: 2019-08-27
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, prospective, open-label, Phase 2, proof of concept study to test preliminary efficacy and safety of gemcabene in children with established nonalcoholic fatty liver disease (NAFLD) incompletely treated by lifestyle changes. The hypothesis of the study is that 300 mg of gemcabene once a day for 12 weeks will reduce alanine aminotransferase (ALT), hepatic steatosis, dyslipidemia and down regulate de novo lipogenesis in children with NAFLD.

Detailed description:
Nonalcoholic fatty liver disease (NAFLD) has quickly become the most common liver disease in children in the US and is rising worldwide. While the true prevalence and incidence are not known, estimates have placed prevalence in the US as high as 7 million children. The prevalence varies greatly across race and ethnic groups with Hispanic, Asian and White children having increased rates compared to African American children. Lifestyle changes are the first line treatment, but many children fail to respond to these. Pharmaceutical treatments are needed for children that cure NAFLD and ideally also benefit the systemic features (dyslipidemia, insulin sensitivity, BMI). Gemcabene calcium (Gemcabene) is a promising therapeutic that may benefit pediatric NAFLD and early phase trials are needed to support further development for this indication. It has several mechanisms of action including enhancing the clearance of very-low-density lipoprotein (VLDL) and blocking the production of hepatic triglyceride and cholesterol synthesis. Gemcabene was previously tested in adults for treatment of dyslipidemia and has extensive safety data.

In this study, 40 children ages 12-17 years with histologically confirmed NAFLD or MRI based diagnosis and elevated ALT will receive 300 mg of gemcabene per day for 12 weeks. Study visits will occur at screening, baseline, week 2, week 6 and week 12. A follow up phone call will occur one month after the child stops taking the study medication.

Arms: arm 1: Children receiving 12 weeks of treatment with gemcabene
Interventions: intervention 1: Gemcabene
Intervention descriptions: intervention 1: Participants will take 300 milligrams (mg) of gemcabene, once per day for 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 Gemcabene for the Treatment of Pediatric NAFLD:  
A Phase 2a Study 
GEM-IIT-601 
Protocol Number: GEM-IIT-601 
 
 
NCT Number: NCT03436420 
 
Funded by: Gemphire Therapeutics Inc. 
Version Number:  v.4.0 
02OCT2018 
Version 3 (27FEB2018) was never implemented. 
 
 


  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 1 
2 
INTRODUCTION ............................................................................................................................................ 1 
2.1 
Study Rationale .................................................................................................................................... 1 
2.2 
Background........................................................................................................................................... 4 
2.3 
Risk/Benefit Assessment .................................................................................................................... 7 
2.3.1 
Known Potential Risks ..................................................................................................... 7 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 9 
3 
ENDPOINTS ................................................................................................................................................... 9 
4 
STUDY DESIGN ........................................................................................................................................... 10 
4.1 
Overall Design .................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design.............................................................................................. 10 
4.3 
Justification for Dose ......................................................................................................................... 11 
4.4 
End of Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATION ................................................................................................................................ 11 
5.1 
Inclusion Criteria ................................................................................................................................ 11 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Lifestyle Considerations .................................................................................................................... 13 
5.4 
Screen Failures .................................................................................................................................. 13 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 14 
6 
STUDY INTERVENTION ............................................................................................................................ 14 
6.1 
Study Intervention(s) Administration ............................................................................................... 14 
6.1.1 
Study Intervention Description ..................................................................................... 14 
6.1.2 
Dosing and Administration ............................................................................................ 15 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 15 
6.2.1 
Acquisition and accountability ...................................................................................... 15 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 15 
6.2.3 
Product Storage and Stability ....................................................................................... 16 
6.2.4 
Preparation ...................................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 16 
6.4 
Study Intervention Compliance ........................................................................................................ 16 
6.5 
Concomitant Therapy ........................................................................................................................ 17 
6.5.1 
Rescue Medicine ............................................................................................................ 17 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 17 
7.1 
Discontinuation of Study Intervention ............................................................................................. 17 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 17 
7.3 
Lost to Follow-Up ............................................................................................................................... 18 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 18 
8.1 
Efficacy Assessments ....................................................................................................................... 18 
8.2 
Safety and Other Assessments ....................................................................................................... 19 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 20 


  
 
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8.3.1 
Definition of Adverse Events (AE) ............................................................................... 20 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 21 
8.3.3 
Classification of an Adverse Event .............................................................................. 22 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 23 
8.3.5 
Adverse Event Reporting .............................................................................................. 24 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 24 
8.3.7 
Reporting Events to Participants ................................................................................. 25 
8.3.8 
Events of Special Interest ............................................................................................. 25 
8.3.9 
Reporting of Pregnancy ................................................................................................ 25 
8.3.10 
Drug-induced liver Injury clinical management plan ................................................. 25 
8.3.11 
Long-term safety follow-up ........................................................................................... 25 
8.4 
Unanticipated Problems .................................................................................................................... 26 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 26 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 26 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 27 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 27 
9.1 
Statistical Hypotheses ....................................................................................................................... 27 
9.2 
Sample Size Determination .............................................................................................................. 27 
9.3 
Populations for Analyses .................................................................................................................. 27 
9.4 
Statistical Analyses............................................................................................................................ 28 
9.4.1 
General Approach .......................................................................................................... 28 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 28 
9.4.3 
Analysis of the Secondary efficacy Endpoint(s) ........................................................ 28 
9.4.4 
Safety Analyses .............................................................................................................. 29 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 29 
9.4.6 
Planned Interim Analyses ............................................................................................. 29 
9.4.7 
Sub-Group Analyses ..................................................................................................... 29 
9.4.8 
Tabulation of Individual participant Data .................................................................... 30 
9.4.9 
Exploratory Analyses ..................................................................................................... 30 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 30 
10.1.1 
Informed Consent Process ........................................................................................... 30 
10.1.2 
Study Discontinuation and Closure ............................................................................. 31 
10.1.3 
Confidentiality and Privacy ........................................................................................... 33 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 33 
10.1.5 
Key Roles and Study Governance .............................................................................. 34 
10.1.6 
Safety Oversight ............................................................................................................. 34 
10.1.7 
Clinical Monitoring .......................................................................................................... 35 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 36 
10.1.9 
Data Handling and Record Keeping ............................................................................ 36 
10.1.10 
Protocol Deviations ........................................................................................................ 37 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 38 
10.1.12 
Conflict of Interest Policy .............................................................................................. 38 
10.2 
Additional Considerations ................................................................................................................. 38 
10.3 
Abbreviations ...................................................................................................................................... 38 
10.4 
Protocol Amendment History ........................................................................................................... 40 
11 
REFERENCES ............................................................................................................................................. 44 


  
 
iv 
Appendix A. Post Prandial Lipids and De Novo Lipogenesis Sub-Studies ...................................................... 47 
12 
Sub-Study SUMMARY................................................................................................................................. 47 
12.1 
Meal Challenge Sub-study & Deuterated WAter Tracer Sub-Study .......................................... 47 
13 
STUDY POPULATION ................................................................................................................................ 48 
13.1 
Inclusion Criteria * Additional Inclusion and Exclusion Criteria (in addition to the main study 
criteria) 
48 
13.2 
Exclusion Criteria * Additional Inclusion and Exclusion Criteria (in addition to the main study 
criteria) 
48 
14 
Methods ......................................................................................................................................................... 48 
14.1 
part 2: de novo lipogenesis .............................................................................................................. 49 
14.2 
Part 3: Cholesterol synthesis ........................................................................................................... 50 
15 
Adverse Event Reporting ............................................................................................................................ 51 
15.1 
Adverse Events and Serious Adverse Events ............................................................................... 52 
15.1.1 
Definition of Adverse Events (AE) ............................................................................... 52 
15.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 52 
15.1.3 
Adverse Event Reporting .............................................................................................. 52 
15.1.4 
Serious Adverse Event Reporting ............................................................................... 52 
16 
STATISTICAL CONSIDERATIONS .......................................................................................................... 52 
16.1 
Statistical Analysis ............................................................................................................................. 52 
Appendix B. PROMIS Questionnaires ................................................................................................................... 52 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and all applicable United States (US) Code of Federal Regulations 
(CFR. The Principal Investigator will assure that no deviation from, or changes to, the protocol 
will take place without prior agreement from the Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) sponsor, funding agency and documented approval from 
the Institutional Review Board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study.  All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Gemcabene for the Treatment of Pediatric NAFLD: A Phase 2a Study 
Study Description: 
This is a multicenter, prospective, open-label, Phase 2, proof of concept 
study to test preliminary efficacy and safety of gemcabene in children with 
established NAFLD incompletely treated by lifestyle changes who are ages 
12-17 years.   The hypothesis of the study is that 300 mg of gemcabene 
once a day for twelve weeks will reduce ALT, hepatic steatosis, 
dyslipidemia and down regulate de novo lipogenesis in children with 
NAFLD.     
 
Objectives: 
 
Primary Objective:  To evaluate safety and preliminary efficacy using 
multiple biomarkers of NAFLD (ALT, AST, GGT, hepatic steatosis) in 
children aged 12-17 years with established NAFLD not resolved by lifestyle 
changes.  
  
 
Secondary Objectives:  To assess indices demonstrating drug response and 
mechanism of action.  
 
Endpoints: 
Primary Endpoints:  
• 
Percent change in ALT from Baseline to Week 12  
 
 


Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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Secondary Endpoints:  
• 
Absolute change in ALT from Baseline to Weeks 6 and 12 
• 
Percent change in ALT from Baseline to Weeks 6 
• 
Percent change in ALT from Baseline to a mean of Week 6 and 
12 ALT 
• 
Absolute change and percent change in hepatic steatosis from 
Baseline to Week 12 as measured by MRI (volumetric fat 
fraction-HepaFat) 
• 
Absolute change and percent change in pancreatic fat from 
Baseline to Week 12 as measured by MRI (HepaFat) 
• 
Absolute change and percent change in AST from Baseline to 
Week 6 and Week 12 
• 
Absolute change and percent change in insulin sensitivity as 
assessed by fasting insulin, fasting glucose, and HOMA-IR from 
Baseline to Week 6 and Week 12 
• 
Absolute change and percent change in GGT from Baseline to 
Week 6 and Week 12 
• 
Absolute change and percent change in serum lipids including 
total cholesterol, non-HDL-C, HDL-C, VLDL-C, LDL-C, and 
triglycerides (TG) from Baseline to Week 6 and Week 12 
• 
Absolute change and percent change in apolipoproteins 
including apoA-1, apoB, apoC-II, apoE and apoCIII  
• 
Absolute change and percent change in inflammatory markers 
such as hsCRP, IL-1B, IL-6 and procollagen III.   
• 
Absolute change and percent change in lipoprotein particle 
sizes (VLDL, HDL, LDL, chylomicrons [NMR]) 
• 
Absolute change and percent change in post-prandial lipids 
(total cholesterol, non-HDL-C, HDL-C, VLDL-C, LDL-C, TG, 
lipoprotein particle size)  
• 
Absolute change and percent change in rate of de novo 
lipogenesis using stable isotope tracers 
• 
Absolute change and percent change in liver inflammation and 
fibrosis score (LIF and cT1) by MRI Liver MultiScan.  
• 
Change in body composition measures by AMRA from Baseline 
to Week 12  
• 
Absolute change and percent change in anthropometric 
measures including height, weight, body mass index, and waist 
circumference from Baseline to Week 12 
• 
Safety related endpoints including adverse events (AEs), vital 
signs, clinical labs, hematology and urinalysis 
• 
Treatment tolerance and compliance 
 
 
Study Population: 
40 enrolled (36 completers) boys and girls, aged 12-17 years, diagnosed 
with NAFLD  
 
Phase: 
2a 
 
 


Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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Sites/Facilities Enrolling 
Participants: 
Up to 3 US sites 
 
Study Intervention: 
 
300 mg gemcabene by mouth once a day  
 
Study Duration: 
 
12 months  
 
Participant Duration: 
22 weeks  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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1.2 
SCHEMA 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Day 1 
 
 
Visit 2 
Week 2 
 
 
Visit 3 
Week 6  
 
 
Visit 4 
Week 12 
 
 
Phone call 
Week 16 
 
 
Screen ~60:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, document. 
Perform baseline assessments. 
Administer initial study intervention.  
Final assessments of study endpoints and safety 
Follow-up assessments of study endpoints and safety 
Gemcabene 
~40 participants 
Follow-up Assessment 
Enroll 
Final assessments of study endpoints and safety 








Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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I – Liver Function panel includes: ALT, AST 
J – Diabetes Panel includes: Glu, INS, NEFA 
 
Note: If the ALT at screening is more than two times the historic value, or there is no historic value available, the subject will be asked to repeat the 
screening ALT after four weeks. If the repeat ALT is greater than 50% increased or decreased over the screening ALT a third ALT will be obtained. 
 
 
 




Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Nonalcoholic fatty liver disease (NAFLD) has quickly become the most common liver disease in children 
in the US and is rising worldwide1,2.  While the true prevalence and incidence are not known, estimates 
have placed prevalence in the US as high as 7 million children1.  The prevalence varies greatly across race 
and ethnic groups with Hispanic, Asian and White children having increased rates compared to African 
American children3,4.   
 
Similar to adults, NAFLD ranges widely in severity in children.  Cases of cirrhosis and end stage liver 
disease have been rarely reported.  Most children have some fibrosis present on liver biopsy, however 
the majority have mild fibrosis (stages 1-2) and advanced fibrosis is less common (found in 3-15%)5,6.  
Nonalcoholic steatohepatitis (NASH) is considered the more severe form of NAFLD and is a pathologist’s 
assessment that the biopsy has features of steatosis, inflammation and hepatocyte ballooning7.  NASH is 
seen less often in children because children rarely exhibit hepatocyte ballooning; thus even with 
substantial levels of inflammation, the threshold of NASH is not met8.  Children more often have a portal 
pattern of inflammation, called portal predominant or type 26,9.  This portal pattern disappears by late 
adolescence and is rarely seen in adults suggesting that it is simply a juvenile inflammatory response 
pattern10.  The type 2 portal pattern does not appear to be predictive of future histopathology or clinical 
course.  
 
ALT elevation is the most common screening test used for detecting NAFLD.  A normal ALT in boys and 
girls is <26 U/L and <23 U/L respectively11.  Similar to adults, very mild elevations in ALT or even normal 
ALT can be found in NAFLD12.  Children with a sustained ALT ≥ 80 U/L are twice as likely to have NASH8,13.  
The typical diagnosis algorithm is complicated because NAFLD is a diagnosis of exclusion and no single 
test can determine it.  Typically, serologic tests are sent to rule out other chronic liver diseases and 
including other causes of steatosis.  Ruling out chronic alcohol use is critical in adults but less relevant in 
a pediatric cohort.  After other chronic liver disease screening tests are performed, either an MRI or liver 
biopsy is used to detect the presence of steatosis in the liver.  Ultrasound is less useful because of its low 
sensitivity and specificity.  Magnetic resonance imaging (MRI) methods including MR spectroscopy and 
MR proton density fat fraction and MR volumetric fat fraction are all highly sensitive, specific and 
precise14,15.  Liver biopsy has been considered the gold standard but it is less accurate for measuring fat 
in the liver because of the small sample size and subjective nature of the pathologist’s estimate of 
steatosis.  Liver biopsy is the best method for detecting NASH because it demonstrates all the necessary 
criteria (steatosis, inflammation and hepatocyte ballooning)8.  Fibrosis is also best measured through 
liver biopsy at this time, although multiple non-invasive imaging methods are being developed in an 
attempt to replace it8.   
 
The pathophysiology of NAFLD is complex and mirrors the wide variety of clinical phenotypes.  There is 
clearly a genetic background that is the basis for developing NAFLD16,17.  However, presence of one of 
these polymorphisms is not sufficient to develop NAFLD.  There appears to be one or more 
environmental triggers that induce the phenotypes of NAFLD.  These environmental triggers are a 
subject of intense research effort.  One of the top suspects in the environment is the hypercaloric diet18.  
Others include environmental toxins such as plastics, air pollution, heavy metals etc.  Lastly, changes in 


Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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the nutrient content such as a high sugar diet or a diet low in antioxidant supply may contribute19,20.  
The timing of exposure may be critical and newer research points to the in utero time period as a critical 
time for triggering steatosis in the liver of children21.   
 
NAFLD is not simply a liver disease and in fact, the critical driver of NAFLD may be outside the liver.  The 
best evidence for this is the rapid reoccurrence of NAFLD after liver transplant, suggesting that the 
milieu that the new liver is placed into is still NAFLD-genic.  NAFLD appears to be a systemic lipid 
dysregulation with evidence of maladapted lipid flux throughout the body.  NAFLD occurs in the setting 
of both hepatic and whole-body insulin resistance22.  Adipose insulin resistance is strongly associated23.  
Within the liver, de novo lipogenesis (DNL) is inappropriately upregulated in NAFLD, resulting in 
increased synthesis of triglycerides from carbohydrates and other sources24.  Increased triglycerides are 
exported out of the liver on large, overloaded very low-density lipoprotein (VLDL) particles resulting in 
dyslipidemia and resultant atherosclerosis.  Increased visceral fat is closely linked to hepatic steatosis, 
although it appears that hepatic steatosis is more closely related to insulin resistance compared to 
visceral fat.  Adiponectin, a beneficial hormone secreted from healthy adipose tissue is deficient in 
NAFLD25.   
 
The long term natural history of NAFLD beginning in children is not yet known because the past and 
current cohorts of children have not been followed long enough to assess rates of liver outcomes such 
as cirrhosis, hepatocellular carcinoma and portal hypertension.  However, sufficient evidence exists to 
warrant concern.  For example, rates of liver transplant for NAFLD in young adults is rapidly increasing26.  
And importantly, the incidence of type 2 diabetes in children with NAFLD is 10 x the expected rate of 
diabetes onset in children27,28.  Type 2 diabetes may be the more important clinical outcome of NAFLD 
for children because pancreatic beta cell failure (diabetes) foretells a lifetime of morbidity including 
future health decline from kidney disease, vision loss, cardiovascular events and more.  In children, 
those with NASH are more likely to have diabetes28.  In adults with NAFLD, the most frequent cause of 
mortality is cardiovascular disease (CVD).  Because of this, any medication developed for children with 
NAFLD should have long term CVD safety and/or benefit on cardiovascular risk markers.   
 
The current standard of care for treating NAFLD in children is lifestyle changes8.  There are not specific 
recommendations for a best diet or exercise goals because of the lack of randomized controlled trials in 
children with NAFLD, so the approach is based on an accumulation of evidence from case series, small 
trials and studies in obese children (not necessarily with NAFLD).  Sugar reduction appears to be a 
potent and important component of diet improvement for treating NAFLD.  Other treatments with 
limited evidence including metformin and vitamin E.  Both were tested in a large RCT in children and did 
not meet the primary outcome of improved ALT, however both resulted in some significant histologic 
improvements in children with biopsy proven NASH29.  A more recent trial testing cysteamine bitartrate 
delayed release in children with NAFLD failed to meet the primary outcome of a 2-point improvement in 
NAFLD activity score (NAS) although improvement was seen in ALT, particularly in younger children30.   
 
One of the challenges in therapeutic development for NAFLD is the lack of validated surrogate markers 
of clinical benefit.  Because the natural history in children is not known, the target for clinical benefit is 
also not clear, although perhaps a case could be made for avoiding type 2 diabetes.  Most trials to date 
in both pediatrics and adults have focused on improvement in either liver histology (a surrogate for 
future cirrhosis) or improvement in ALT (surrogate for improvement in liver histology).  Both of these 
have substantial issues but have been accepted because of the lack of better alternative.  ALT is 
associated with hepatic inflammation and a substantial decrease in ALT is likely to represent 
improvement in NASH and fibrosis on liver biopsy (Figure 1).   


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Figure 1.  In 145 children who participated in the NIH sponsored “TONIC” trial testing metformin or 
vitamin E compared to placebo, there was significant association between improvement of ALT over 
time (from 0 to 96 weeks) and improvement in both NASH (1A) and Fibrosis (1B), p<.05 in both.  At week 
12, decreases in ALT of less than 20% were associated with failing to improve histology (progressed or 
stayed stable).  Data submitted for publication.   
 
MRI can be used to measure steatosis very precisely and is useful as a measurement in clinical trials in 
NAFLD.  However, decrease in steatosis alone is not clearly a useful because of the lack of association of 
steatosis with longer term outcomes.  Improvement in systemic metabolic measures such as insulin 
sensitivity, lipid levels, lipid particle sizes and adiponectin may be useful because of the close association 
of NAFLD with type 2 diabetes and CVD.   
 
In summary, the rationale for this trial is as follows.  NAFLD affects many children and is highly likely to 
lead to substantial morbidity and mortality, particularly from type 2 diabetes and cardiovascular disease.  
Lifestyle changes are the first line treatment, but many children fail to respond to these.  Pharmaceutical 
treatments are needed for children that cure NAFLD and ideally also benefit the systemic features 
(dyslipidemia, insulin sensitivity, BMI).  Gemcabene is a promising therapeutic that may benefit pediatric 
NAFLD and early phase trials are needed to support further development for this indication.   
 
 
 


Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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2.2 
BACKGROUND  
 
Introduction to Gemcabene: Gemphire Therapeutics Inc. (Gemphire) is developing gemcabene calcium 
(also denoted as CI-1027 or PD72953 and in this protocol referred to as gemcabene) for multiple 
indications including: 
1.) As an adjunct to diet and statin therapy for the treatment of patients with dyslipidemia who 
require additional low-density lipoprotein cholesterol (LDL-C) lowering such as patients with 
homozygous familial hypercholesterolemia (HoFH) and heterozygous FH (HeFH) and 
atherosclerostic cardiovascular disease (ASCVD).  
2.) To reduce triglycerides (TG) in patients with severe hypertriglyceridemia (TG ≥500 mg/dL),  
3.) To reduce or stop progression of hepatic steatosis in patients with nonalcoholic fatty liver 
disease (NAFLD)/nonalcoholic steatohepatitis (NASH).  
 
To date 18 clinical studies evaluating gemcabene have been conducted (17 completed and 1 terminated 
for business reasons) evaluating a total of 1278 healthy adult volunteers and participants with 901 
exposed to gemcabene providing extensive safety data and preliminary efficacy data for triglyceride 
reduction. No studies have previously been conducted in NAFLD populations.   
 
Brief Mechanism of Action Summarized from Investigator Brochure Version 2: Gemcabene is the 
monocalcium salt of a dialkyl ether dicarboxylic acid and is a new class of lipid-regulating compounds 
because it has 2 terminal gem-dimethyl carboxylate moieties.  It has several mechanisms of action 
including 1) enhancing the clearance of VLDL and 2) blocking the production of hepatic TG and 
cholesterol synthesis.   
 
The enhanced clearance of VLDL is through decreased apolipoprotein C-III, an apolipoprotein that when 
elevated can mask apoE on VLDL remnants and inhibit LPL mediated TG lipolysis.  Elevated apoC-III is 
associated with increased CVD risk.  Gemcabene decreases apoC-III through decreased expression of 
mRNA, likely decreasing protein production.  This leads to increased VLDL-remnant clearance and 
enhances LPL activity with the overall effect of lowering LDL-C and TG. 
 
Gemcabene also has effects within the hepatocytes.  In primary rat hepatocytes, gemcabene markedly 
blocked radiolabeled acetate incorporation into both TG and cholesterol.  AcetylCoA carboxylase (ACC1) 
is the rate limiting step in de novo lipogenesis (DNL).  Gemcabene may reduce ACC1 mRNA expression as 
well as inhibit ACC1 enzymatic activity, suggesting that it blocks the ACC1 step during DNL.   
 
Gemcabene may have other anti-inflammatory effects.  It reduces C-reactive protein (CRP), mRNA 
production and decreases CRP in animal models and in humans.  It down-regulates multiple markers of 
inflammation.  It may inhibit the activation of nuclear hormone receptors (NHR) including NF-κB.   
 
Gemcabene has a similar terminal gem-dimethyl carboxylate moiety to the widely used fibrate 
gemfibrozil and it also increases liver peroxisomal structures and enzymes in rodents, so it has been 
classified by the FDA as a peroxisome proliferator-activated receptor (PPAR) agonist.  However, in 3 
species (mice, rat, human) gemcabene has shown little or no direct agonist activity.  It has shown weak 
PPAR-α and weak PPAR-γ activity in vitro and in vivo.  In a 52-week safety study in monkeys no liver 
peroxisomal structures were noted in exposure of up to 4 times the exposure levels expected in the 
current study. 
 


Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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Summary of Pre-Clinical Data from Investigator Brochure Version 2:  
The full details of the comprehensive program evaluating the pharmacology, absorption, distribution, 
metabolism, excretion, toxicokinetics, safety pharmacology and toxicology of gemcabene is available in 
the investigator brochure including a tabular summary of the key non-clinical safety studies.  In animal 
models, gemcabene had the following actions: 
• 
In LDL receptor deficient mice, gemcabene significantly reduced total cholesterol and LDL-C. 
• 
In chow-fed Sprague-Dawley rats, gemcabene caused an increase in HDL-C and reduction of 
VLDL-C, LDL-C, ApoC-II, ApoC-III.   
• 
In female, obese Zucker rats, gemcabene increased HDL-C, ApoE and decreased TG and apo-
C-II.  
• 
In transgenic lipoprotein(a) mice, gemcabene significantly reduced total cholesterol, Lp(a) 
and ApoB-100.  
• 
In a mouse model of NASH, gemcabene showed anti-fibrotic effects at all tested doses and 
demonstrated anti-NASH and hepatoprotective effects on liver pathology of STAM mice.  
• 
In non-human primate models, gemcabene was shown to reduce Lp(a) and total cholesterol.  
• 
In several rodent models, gemcabene decreased inflammation and pain response.   
 
Safety pharmacology studies in mice, Wistar rats and beagle dogs demonstrated no adverse effect on 
central nervous system (CNS), respiratory or cardiovascular parameters.   
 
Oral bioavailability studies have been conducted in Wistar rats and in cynomolgus monkeys.  In all 
studies, gemcabene was rapidly absorbed following oral administration and primarily excreted in the 
feces of rats and in the urine of monkeys.   
 
Single and repeated dose toxicity studies were conducted in mice, rats and monkeys.  In rats, 
gemcabene was well tolerated up to 100 mg/kg/day.  Increased liver weight, increased hepatic 
peroxisomal enzymes, increased fine vacuolation of hepatocytes and hepatocellular hypertrophy were 
observed in rats at all doses in repeat dose studies of gemcabene.  In cynomolgus monkeys, 
administered gemcabene at oral doses of 10, 30 and 100 mg/kg/day or up to 52 weeks there were no 
gemcabene related deaths, clinical signs of toxicity or ophthalmologic findings, no effects on CK and no 
heart related changes.  Decreases in body weight gain were observed in males and females at 100 
mg/kg/day.  Mild, partially reversible changes in red cell mass were observed in all doses and correlated 
with decreased cellularity of sternal bone marrow in some animals.  Reversible mild increases in 
creatinine and BUN were seen at all doses but without histologic changes in the kidneys.  Dose related 
increases in liver weights were observed at 10mg/kg/day in males and >30mg/kd/day in females and 
were associated with histologic hepatocyte hypertrophy.  In the liver, in both sexes at 100 mg/kd/day 
there was some single cell necrosis, mild degeneration of centrilobular hepatocytes and some oval cell 
hyperplasia.  Findings in the liver were associated with mild to moderate increases in ALT.  These were 
reversible at the end of the 12-week recovery period except for the increase in liver weight.  Based on 
these findings, the no observed adverse effect level (NOAEL) at up to 52 weeks exposure is 30 
mg/kg/day.   
 
While most of the toxicity data was reassuring, there was toxicity seen in a 26 week, repeat dose oral 
toxicity study in rats.  Body weight decreased 25-46% and hemoglobin, hematocrit and reticulocyte 
count decreased at all dose levels (30-300 mg/kg/day).  There were increases of 85% to 4.5 fold in ALT 
activity at the higher doses of 100 and 300 mg/kg/day.  Liver weights were increased and liver 
pathologic changes were seen including hepatocellular hypertrophy and vacuolation.  In cynomolgus 


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monkeys, over 26 weeks at >30 mg/kg/day fatty changes were seen in the liver and kidneys.  
Carcinogenicity studies are ongoing in mice and rats. No mutagenic effects were seen in genetic toxicity 
studies. Developmental toxicity studies demonstrated abnormalities and teratogenicity at doses >10 
mg/kg/day in rats but none in rabbits.  
 
Summary of clinical studies with Gemcabene from the Investigator Brochure Version 2:  
Phase 1 PK studies have demonstrated that oral gemcabene is rapidly absorbed with exposure 
increasing approximately linearly with dose.  The primary route of elimination is renal.  There is no 
clinically relevant effect on QT interval.  There was a rapidly reversible increase in serum creatinine that 
is thought to be a hemodynamic change rather than a direct nephrotoxic effect because no change in 
protein to creatinine ration and no abnormal urine analysis was present.  No effect was observed on 
blood pressure.  There was an increase in the glucose disposal rate.   
 
Phase 2 Efficacy studies have demonstrated benefits.  In patients with dyslipidemia, monotherapy with 
300 – 900 mg significantly lowered LDL-C compared to placebo in three Phase 2 studies.   In patients 
with baseline TG ≥ 200 mg/dL (Study 1027-04), gemcabene lowered TG by 39% at the 300 mg dose 
compared with 5% lowering by placebo.   
 
Human safety data is drawn from this collection of 19 clinical studies.  The most frequent reported 
adverse events in healthy volunteers for single doses were headache, asthenia, nausea, dizziness and 
somnolence.  The most frequent adverse events for 4 weeks were headache, infection, nausea, 
asthenia, photosensitivity reaction, rhinitis, diarrhea, flatulence, dizziness and pharyngitis.  In patients 
with dyslipidemia treated for 8 weeks, headache, asthenia, dizziness and pain were more frequent with 
gemcabene compared to placebo at doses from 300-900 mg.  Nausea, dyspepsia and flatulence were 
more frequent with gemcabene compared to placebo.  In 1272 healthy adult volunteers and patients, 
only 17 discontinued due to gemcabene related adverse events.  There were no treatment related 
serious adverse events and no deaths.  
 
Important Literature and Data Relevant to the Trial 
There are two publications reporting trials using gemcabene.  The first was published in 2003 and 
reported the efficacy and tolerability of gemcabene in 161 patients with low HDL and high serum TG31.  
In this study, patients underwent a 6-week placebo, dietary lead in period and then were administered 
either 150, 300, 600 or 900 mg once daily for twelve weeks.  At the 150 mg dose, HDL significantly 
improved and at both the 150 mg and 300 mg doses, TG significantly decreased compared to baseline.  
Gemcabene was well tolerated with adverse event rates similar to placebo.  The second reported trial 
was published in 2016 and reported gemcabene as an additive therapy to statins in 61 stable 
hypercholesterolemic patients32.  This was an 8 week, double-blind, placebo controlled, randomized, 
phase 2 study in men and post-menopausal women and tested Gemcabene at doses of both 300 and 
900 mg.  Gemcabene as an add-on to stable statin therapy demonstrated additional statistically 
significant reductions in LDL-C and CRP compared to placebo.   
 
Context of the Trial 
At this time, there is not yet an FDA approved medication for NAFLD in either children or adults.  There 
have been two large, randomized controlled trials in children testing metformin, vitamin E and 
cysteamine bitartrate and both were negative for the primary outcomes.  There is consensus in the 
NAFLD field that while patients respond to lifestyle treatment, it is not effective for all patients and may 
not cure or resolve the more severe forms including NASH and NAFLD with fibrosis33,34.  Thus, 
medications are being sought that will not only improve the histologic features of progressive disease 


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(inflammation, ballooning, fibrosis) but will also improve the systemic dysmetabolic features associated 
with NAFLD that lead to type 2 diabetes and to cardiovascular disease.  The combination of these two 
effects is especially important for children because simply “curing” the liver expression of the disease 
may not provide sufficient long term clinical benefit if the subsequent consequences are in the form of 
type 2 diabetes and cardiovascular disease.   
 
Importance of this Trial and Relevance  
Gemcabene is a novel therapeutic with substantial safety data in humans for treatment up to twelve 
weeks at doses as high as 900 mg daily.  The mechanisms of action are highly relevant in NAFLD 
including reduction of de novo lipogenesis, the key lipid malfunction in NAFLD, decrease in circulating TG 
and LDL-C and decrease in systemic inflammation.  All of these mechanisms are altered in NAFLD and 
Gemcabene has the potential to ameliorate hepatic steatosis, the inflammatory response to the hepatic 
steatosis as well as systemic inflammation and the associated dyslipidemia.  The proposed trial is a 
phase 2a, preliminary efficacy and safety trial in children because it has not previously been tested in 
children and because it has not previously been tested in patients with NAFLD.  This trial will provide 
support for future phase 2b and phase 3 trials to prove efficacy and longer term safety in this 
population.  Critical questions to be answered in this trial include the tolerability of gemcabene at 300 
mg in a pediatric population, the effect on ALT (a biomarker of hepatic inflammation), the effect on 
hepatic steatosis volume and the effect on circulating lipid levels.  Additional mechanistic questions 
remain including what happens to the excess acetyl coA after interruption of the de novo lipogenesis 
pathway and so exploratory studies are planned to test effect of Gemcabene on DNL, ketogensis (the 
likely pathway for diverted acetyl CoA metabolites) and to test changes in whole body metabolite 
patterns (metabolomics).   
 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 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 
transaminase elevation > 3x ULN after receiving gemcabene 600 mg and atorvastatin 80 mg and the 


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percentage of transaminase elevations overall is similar to placebo.  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 
have been observed in clinical studies with gemcabene.  The effects were mild and appeared within the 
first 2-4 weeks of treatment, did not worsen over time and were not persistent and generally resolved 
within 10-14 days after discontinuation of gemcabene.   
 
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.  
• 
The safety and effectiveness of gemcabene has not been established in children and juvenile 
toxicity studies are underway but not yet completed.  
• 
2-year carcinogenicity studies are ongoing and therefore potential for carcinogenic activity is 
still not known.   
 
Risks from the procedures in the protocol: 
Procedures in this protocol are minimized and include 1) blood draws 2) MRI and 3) IV placement for 
repeated blood draws.  To minimize risk to the participants, all blood draws and IV placements will be 
performed by pediatric experience staff in the research centers.  All MRI’s will be without contrast and 
without any sedation as these are the two primary risks of MRI.   
 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Three Phase 2 studies have demonstrated that gemcabene is efficacious in reducing LDL-C in 
hypercholesterolemic patients.  As many NAFLD patients have high LDL-C, this is a potential benefit for 
the participants.  
 
Gemcabene has also been demonstrated to reduce TG, LDL-C, ApoB and hsCRP, all associated with 
cardiovascular disease risk.  This is also a potential benefit to the participants.  
Within the study, participants will benefit from receive lifestyle counseling, the current standard of care 
for pediatric NAFLD. They will also receive regular assessments of their liver disease including labs (ALT, 
AST and GGT) and hepatic steatosis (MRI).   
 
Long range benefits could include satisfaction from contributing to development of treatments for 
NAFLD.   
 
 
 
 


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2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The rationale for the necessity of exposing participants to the risks of participating in this study is that 
medications for NAFLD in children are needed.  Risks to children in this study are being minimized by 
using a low dose of the medication that has proven to be safe over twelve weeks in studies in adults.  
Further, risk is being minimized by using non-invasive measurement of the liver (MRI) as well as using 
pediatric experienced staff for the blood draws.  
 
The value of the information to be gained outweighs the risks because the risks are minimal based on 
the data from the studies in adults and the potential value to improve NAFLD in children is high.  
Children in the study will benefit from receiving standard of care lifestyle counseling and from state of 
the art measurements of their liver disease.   
 
 
3 
ENDPOINTS 
 
Primary Endpoint:  
• 
Percent change in ALT from Baseline to Week 12  
Secondary Endpoints:  
• 
Absolute change in ALT from Baseline to Weeks 6 and 12 
• 
Percent change in ALT from Baseline to Week 6 and the mean of Week 6 and Week 12 
• 
Absolute change and percent change in hepatic steatosis from Baseline to Week 12 as 
measured by MRI (volumetric fat fraction-hepafat) 
• 
Absolute change and percent change in pancreatic fat from Baseline to Week 12 as 
measured by MRI (HepaFat) 
• 
Absolute change and percent change in AST from Baseline to Week 6 and Week 12 
• 
Absolute change and percent change in insulin sensitivity as assessed by fasting insulin, 
fasting glucose, and HOMA-IR from Baseline to Week 6 and Week 12 
• 
Absolute change and percent change in GGT from Baseline to Week 6 and Week 12 
• 
Absolute change and percent change in serum lipids including total cholesterol, non-HDL-C, 
HDL-C, VLDL-C, LDL-C, and triglycerides (TG) from Baseline to Week 6 and Week 12 
• 
Absolute change and percent change in apolipoproteins including apoA-1, apoB, apoC-II, 
apoE and apoCIII  
• 
Absolute change and percent change in inflammatory markers such as hsCRP, IL-1B, IL-6 and 
procollagen III.   
• 
Absolute change and percent change in lipoprotein particle sizes (VLDL, HDL, LDL, 
chylomicrons [NMR])  
• 
Absolute change and percent change in post-prandial lipids (total cholesterol, non-HDL-C, 
HDL-C, VLDL-C, LDL-C, TG, lipoprotein particle size)  
• 
Absolute change and percent change in rate of de novo lipogenesis using stable isotope 
tracers 
• 
Change in body composition measures by AMRA from Baseline to Week 12  
• 
Absolute change and percent change in liver inflammation and fibrosis (LIF and cT1) scores 
by MRI (Liver MultiScan).   
• 
Absolute change and percent change in anthropometric measures including height, weight, 
body mass index, and waist circumference from Baseline to Week 12 


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• 
Safety related endpoints including adverse events (AEs), vital signs, clinical labs, hematology 
and urinalysis 
• 
Treatment tolerance and compliance 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
Hypothesis 
Gemcabene (300mg a day) for twelve weeks will be safe and will decrease ALT and percent hepatic 
steatosis by MRI in children with NAFLD.   
 
Type of trial 
• 
Phase 2a open label trial  
• 
Multicenter, prospective, open label trial in 40 children (36 who complete the study) with 
NAFLD  
 
Treatment group 
• 
Gemcabene 300 mg once a day  
 
Number of clinical centers 
• 
3 pediatric sites 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The scientific rationale for this phase 2a, open label trial in children with NAFLD is based on critical 
factors emanating from both the disease and the investigational product.  NAFLD trials are challenging 
because of the large placebo response rate, estimated to be from 20-40%.  The placebo response is 
likely in part due to response to lifestyle changes (improved diet and increased exercise) which is co 
administered in most trials.  A placebo-controlled trial would require a much larger sample size (~140 
subjects) in order to test response of ALT in gemcabene compared to placebo.  Because this is the first 
study in children, a smaller study design was selected – an open label single arm study.  The problem of 
placebo response is managed in two ways.  First, the sample size was made large enough to allow 
detection of a greater than historical placebo response rate.  Second, there will be a 4-6 week dietary 
lead in period between screening and initiation of gemcabene (baseline).  This will moderate the effects 
of the dietary and exercise changes in response to counseling.   
 
Children ages 12 years and older were selected for this study because there is not yet juvenile toxicity 
data to support testing in younger children.   
 
Children diagnosed with NAFLD by either liver biopsy or by MRI will be included because routine clinical 
practice is quickly moving away from the use of liver biopsies with the advent of easily accessible and 
accurate MRI based hepatic fat measurement.  To ensure that very mild cases of NAFLD are not 


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included, children must have an elevated ALT 2 x ULN (≥ 54 U/L for boys and ≥46 U/L for girls) at the 
time of screening (demonstrating increased likelihood of ongoing inflammation in the liver). To assess 
inflammation change in historical ALT (within three months prior to screening) will be obtained (if 
available). If the ALT at screening is more than two times the historic value, or there is no historic value 
available, the subject will be asked to repeat the screening ALT after four weeks. If the repeat ALT is 
greater than 50% increased or decreased over the screening ALT a third ALT will be obtained. If a third 
ALT is not within 50% of the previous value the subject may be re-screened at a later date. 
 
ALT and hepatic steatosis have been selected as the two non-invasive biomarkers of response of NAFLD 
to gemcabene because they are non-invasive and are generally accepted as representing improvement 
in liver histology, which has been linked to clinical outcomes35,36.   Importantly, both ALT and hepatic 
steatosis are related to NAFLD biology and are sensitive to change.   
 
 
4.3 
JUSTIFICATION FOR DOSE 
 
The dose of 300 mg daily was selected because this was the most efficacious dose for TG reduction in 
adults. The drug is oral, once a day based on the previous studies. Most children in this study will be >70 
kg. A minimum weight of 60 kg will be set to eliminate children receiving a higher dose/kg than 
intended.   
 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study through week 12.  The end of the study is defined as completion of the last visit or procedure 
shown in the SoA in the trial for all enrolled participants.   
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
  
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form  
2. Provision of signed and dated assent, if indicated   
3. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
4. Children aged 12-17 years at the time of informed consent 
5. History of clinical diagnosis of NAFLD including a, b and c below: 
a. Medical history eliminating, other chronic liver diseases (for example mitochondrial 
diseases, hepatotoxic drugs, anorexia nervosa) 
b. Laboratory studies: negative testing for hepatitis C and normal ceruloplasmin 
c. Either liver biopsy confirming NAFLD or MRI > 10% steatosis within the past three years 
6. ALT ≥ 54 U/L for boys or ≥ 46 U/L for girls and ≤ 250 U/L at screening visit and within past three 
months (prior to screening). If ALT at screening is more than two times the historic value (or a 
historic value is not available), the subject will be asked to repeat the ALT after four weeks. If 


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the repeat ALT is more than 50% increased or decreased over the screening ALT a third ALT may 
be obtained. If a third ALT is not within 50% of the previous value then the subject is ineligible, 
but may be rescreened at a later date. 
7. Body weight ≥ 60 kg at the time of screening 
8. Able to take oral medication and be willing to adhere to the GEM-IIT-601 regimen 
9. Minimum of three months of attempted lifestyle modification to treat the NAFLD and 
agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration 
 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias) 
2. Seizure disorder 
3. Active coagulopathy (INR > 1.4) 
4. Renal dysfunction with an estimated glomerular filtration rate (eGFR) <60ml/min/1.73 
calculated using Schwartz Bedside GFR calculator for children   
5. History of active malignant disease requiring chemotherapy or radiation  
6. History of significant alcohol intake (AUDIT questionnaire) or inability to quantify alcohol 
consumption 
7. Use of new medications or supplements with the intent to treat NAFLD/NASH during the 30 
days prior to screening, including statin therapy.  Medications or supplements (including 
metformin and vitamin E) that they have been on and are on a stable dose are acceptable   
8. History of bariatric surgery or planning to undergo bariatric surgery during study duration 
9. Clinically significant depression  
10. Any girl nursing, planning a pregnancy, known or suspected to be pregnant, or who has a 
positive pregnancy screen 
11. Non-compensated liver disease defined as cirrhosis and any one of the following hematologic, 
biochemical, and serological criteria on entry into protocol: 
o Hemoglobin < 10 g/dL; 
o White blood cell (WBC) < 3,500 cells/mm3; 
o Neutrophil count < 1,500 cells/mm3; 
o Platelets < 150,000 cells/mm3; 
o Total bilirubin > 1.3 mg/dL unless due to Gilbert’s syndrome (subjects with a history of 
Gilbert’s syndrome may be included if both direct bilirubin and the reticulocyte count do 
no exceed the ULN [reflexive direct bilirubin testing will be used to confirm Gilbert’s 
syndrome]) 
o Albumin < 3.2 g/dL 
o International normalized ratio (INR) > 1.3 
o Abnormal alkaline phosphatase 
o Any history of ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular 
carcinoma (HCC) 
12. Poorly controlled diabetes mellitus (hemoglobin A1c (HbA1c) > 8%) or requiring insulin 
13. Patients with type I diabetes mellitus  
14. Chronic liver disease other than NAFLD 
15. Patients on CYP 3A4 inhibitors such as itraconazole or macrolide antibiotics are excluded 
16. Patients who are on thiazolidinediones, fibrates or fish oils are excluded 


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17. Patients who are on daily prescription medications are excluded except for allergy medications, 
ADHD medications, asthma medications, or any other acceptable medication in the opinion of 
the investigator   
18. Abnormal creatinine kinase levels at screening (may be repeated if the elevation is thought to be 
exercise related) 
19. Sexually active female participants of childbearing potential and Tanner stage ≥ 4 or 
menstruating unwilling to utilize two acceptable forms of contraception from screening through 
completion of the study or unwilling to complete pregnancy tests throughout the study 
20. Currently enrolled in a clinical trial or who received an investigational study drug within 90 days 
of screening 
21. Participants who are not able or willing to comply with the protocol or have any other condition 
that would impede compliance or hinder completion of the study, in the opinion of the 
investigator 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
All participants will be required to have attempted lifestyle changes as a treatment for their NAFLD.  This 
will include attempting a dietary improvement and physical activity.  Because of the highly variable 
success with this, no specific requirement for weight loss will be set.  
 
Within the trial, all children will be given standardized lifestyle-based treatment at the Baseline visit.  
These will consist of the American Heart Association recommended healthy eating pattern for children 
(http://www.heart.org/HEARTORG/HealthyLiving/Dietary-Recommendations-for-Healthy-
Children_UCM_303886_Article.jsp#.WZx7NOmQwaY).   
 
It is important that participants are instructed to not undertake any form of strenuous physical 
activity for at least 24 hours prior to blood testing. 
 
All clinic visit assessments except screening require the children to fast overnight. This is defined as no 
food or caloric beverages for a minimum of eight hours prior to sample collection. They will be 
permitted to have water and it will be encouraged in the evening and in the morning before the visit to 
promote good hydration.  
 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a low 
ALT, body weight too low, other medication use or failure to meet inclusion or do meet exclusion criteria 
may be rescreened if in the view of the investigator there is a high likelihood that they would qualify on 
the rescreening. Rescreened participants will get the same screening number.    




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Manufacturer (drug substance):  
 
 
Gemcabene Tablets 
 
 
 
 
 
 
 
Primary Packaging 
 
 
 
6.1.2 DOSING AND ADMINISTRATION 
 
The dose is 300 mg orally once a day.  
 
The first dose of study drug will be administered at the research site on Study Day 1. On days with a 
scheduled office visit with blood sample collection, subject will remain fasted and should not take 
gemcabene until after the blood samples are collected at the site. On all other days, the subject will self-
dose: taking study drug at the same time in the morning with a full glass (8 ounces) of water either with 
or without food. If a subject misses a dose prior to 6:00 PM, then the subject should take their dose. 
However, if past 6:00 PM, the subject should not dose and then count the dose as a “missed dose.” The 
subject will resume normal dosing the next day (i.e., do not take two doses the following day). 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The IP will be dispended to each site at study initiation.  IP will be monitored and stored by the research 
pharmacy at each site.  The research pharmacist will dispense to the study participants or study 
investigator at Baseline and at Week 6.  At the end of the study, expired or unused product will be 
destroyed.    
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
 
 
 
 
 
Study drug will be prepared in bottles with 30 days of dosing contained within each bottle. The subjects 
will be asked to take one tablet per day.  A 6-week supply (two bottles) will be dispended at Baseline 


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and at the Week 6 visit.  This will include an extra 2 weeks of additional drug as a backup supply to 
account for visit windows. 
 
 
6.2.3 PRODUCT STORAGE AND STABILITY  
 
The study drug will be stored at controlled room temperature (15 to 30°C) in a secured location (locked) 
with access restricted to authorized personnel only. Storage temperature will be monitored and 
recorded. 
 
Upon receipt of study drug, the Investigator or designee will conduct a complete inventory of all study 
drug and ensure no damage occurred during shipment.  
 
The Investigator will maintain adequate records documenting the receipt, use, loss, or other disposition 
of study drug. Drug accountability logs will identify the study drug code number and account for the 
disposition on a subject-by-subject basis, including specific dates and quantities. The drug accountability 
logs will be signed by the individual who dispenses the study drug and copies will be provided to the 
Sponsor. 
 
 
 
6.2.4 PREPARATION 
 
No preparation is necessary.   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
This is an open label, unblinded early phase study so there are no measures for blinding.   
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Subjects will be instructed to take study drug daily according to the protocol and return used and 
unused packaging to the site at each subsequent study visit.   
 
Compliance with administration of study drug will be assessed at each study visit during the Treatment 
Period and at the Early Termination Visit, if applicable, and recorded on the appropriate eCRF and the 
drug accountability log. 
 
The Investigator or designee will remind subjects at each visit of the importance of following the 
protocol-defined schedule for taking study drug. Reasons for not following the study drug administration 
schedule as described in the protocol will be clearly recorded in the source documents. 
 
Adherence will be verified through pill counts of returned bottles, phone calls and asking parents/legal 
guardians.  Participants will be encouraged to use a cell phone or watch alarm to remind them to take 
the pill each day.   
 


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6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
  
 
6.5.1 RESCUE MEDICINE 
 
N/A 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from gemcabene does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation (Early Termination Visit) will 
include the following: 
• 
Blood tests  
• 
MRI  
• 
Vital signs, physical measurements, and a physical examination 
• 
Questionnaires (Food Frequency Questionnaire, PROMIS Questionnaires, Beverage 
Questionnaire, Physical Activity Assessment) 
• 
Urine collection and pregnancy test (in WOCBP) 
• 
Adverse event and concomitant medication review  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 


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• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive gemcabene for ≥ 14 days.  
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form, receive the study 
intervention for > 4 weeks, and subsequently withdraw, or are withdrawn or discontinued from the 
study, will not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Study Procedures: 
 
Central Lab Tests 
The primary and secondary outcomes listed below will be batched and measured at a central lab.  At 
each indicated study visit (see SOA), plasma will be collected, aliquotted and frozen within 2 hours of 
collection and shipped to the Cardiovascular Research Lab at the Atlanta VA.  After all study visits are 
completed and samples are obtained for all participants, the following tests will be measured:  
• 
Lipid panel (TG, CHOL, HDLc, LDLc) 
• 
Apolipoprotein panel (apoA-1, apoB, apoC-II, apoC-III, apoE) 
• 
hsCRP 
• 
Liver function panel (AST, ALT) 
• 
Diabetes panel (GLU, INS, NEFA) 
• 
Pharmacokinetics (Week 2, Week 6, Week 12 and in sub-study participants at Emory 0, 2, 4 and 
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Local (safety) labs 
In order to assure the safety of participants at the time of their participation in the study, the labs listed 
below will be performed locally at the time of the visits and reviewed by the study staff.  For those labs 
that are measured by the local lab and by the central lab (ALT, AST, Glu, Lipids) the central lab 
measurements will be used for outcome analysis.  In the case that a central lab is missing, this will be 
noted and if the local lab is available it will be used.  (also see SOA). 
• 
CMP (includes Glu, BUN, Creatinine, Lytes, Calcium, Total Protein, Albumin, Alk Phos, AST, ALT, 
Total Bilirubin)  
• 
CBC (includes WBC, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, PLT) 
• 
GGT 
• 
CPK 
• 
Lipid profile (includes cholesterol, triglycerides, HDL, LDL, and VLDL) 
• 
HbA1c 
• 
UA (includes chemical analysis, blood, nitrites, leukocyte esterase, protein) 
• 
PT/INR 
 
Imaging:  
Limited MRI (no contrast) of the abdomen to measure percent hepatic steatosis and the liver multiscan.  
The Resonance Health (HepaFat) scan will be used for liver fat and pancreatic fat and the Perspectum 
Liver Multiscan (LIF and cT1 scores) will be used for inflammation and fibrosis. Body composition will be 
assessed by AMRA Medical AB (AMRA).  
 
Patient reported outcomes:  
PROMIS questionnaires fatigue, anxiety and depression (see Appendix B) 
 
Study Procedures by Visit:  
Please refer to Section 1.3 Schedule of Activities for additional visit details 
 
Unscheduled Visits: 
- 
Repeat MRI or labs 
- 
Rescreening Visit 
- 
Repeat ALT (for screening) 
- 
Early Termination Visit 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Specific Safety Measures: 
Hemoglobin decrease 
For a hemoglobin decrease of > 1.5 g/dL from baseline during the study, repeat hematology studies 
and reflexive evaluation of reticulocyte count will be performed. The subject’s past medical history, 
concomitant medications (including over the counter drugs and herbal supplements), and any recent 
symptoms (e.g., bleeding, shortness of breath, fatigue) will be reviewed to determine a potential 
etiology and make a clinical assessment of the significance of the finding. 
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If, at any visit, a creatinine increase of > 0.3 mg/dL (27 µmol/L) from baseline, a GFR decrease of >15 
mL/min from baseline is observed, a repeat chemistry/urinalysis will be performed within seven days. 
The subject’s past medical history, concomitant medications (including over the counter drugs and 
herbal supplements), and any recent symptoms (e.g., fatigue, malaise, polyuria/oliguria, or 
palpitations) will be reviewed to determine a potential etiology and make a clinical assessment of the 
significance of the finding. 
Possible muscle and liver injury 
For muscle injury, CPK, hepatic, and renal function laboratory data will be integrated with myopathy 
signs and symptoms.  
For liver injury, laboratory data will be integrated with hepatic signs and symptoms. Alanine 
aminotransferase increases > 2 × baseline with symptoms of hepatitis or > 3 × baseline with or without 
symptoms of hepatitis will be evaluated and managed according to guidelines for studies in patients 
with pre-existing liver disease. This includes a repeat assessment as soon as possible to confirm the 
findings and a clinical evaluation.  If the participant has signs or symptoms of hepatitis or ALT > 5x 
baseline, the study drug will be temporarily discontinued. 
 
Data to be provided to the participants – At a minimum, the locally run clinical labs and MRI liver fat 
result from baseline will be provided to each patient at the end of the study and reviewed with them by 
a study investigator.  This includes the CMP, CBC, GGT, hemoglobin A1c, insulin, glucose and fasting 
lipids.  The investigator may choose to share other locally run clinical labs from other time points with 
the participant.   
 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
   
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
An adverse event is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. All 
adverse events, including observed or volunteered problems, complaints, or symptoms, are to be 
recorded on the appropriate eCRF.  
 
Adverse events, which include abnormal and clinically significant clinical laboratory test variables, will be 
monitored and documented from the time of first dose of study drug (Study Day 1) until study 
participation is complete (the Follow-up Visit). Subjects should be instructed to report any adverse event 
that they experience to the Investigator. Beginning with the signing of the informed consent until the 
time of the first dose of study drug (Study Day 1), Investigators should make updates to medical history 
and record any pre-existing medical condition or signs or symptoms that changes in severity, frequency, 


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or seriousness in the medical history. Serious adverse events that occur prior to the first dose of study 
drug (Study Day 1) should be reported as an update to medical history as well as be reported on the 
appropriate adverse event eCRF. Beginning with the first dose of study drug (Study Day 1), Investigators 
should make an assessment for adverse events at each visit and record all adverse events, non-serious 
and serious, on the appropriate adverse event eCRF.  
 
Wherever possible, a specific disease or syndrome rather than individual associated signs and symptoms 
should be identified by the Investigator and recorded on the eCRF. However, if an observed or reported 
sign or symptom is not considered a component of a specific disease or syndrome by the Investigator, it 
should be recorded as a separate adverse event on the eCRF. Additionally, the condition that led to a 
medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion) should be 
recorded as an adverse event, not the procedure. Concomitant procedures should be recorded as such 
on the appropriate eCRF.  
 
Any medical condition already present prior to the subject taking the first dose of study drug (Study Day 
1) should be reported in the medical history. Any SAEs occurring prior to the first dose of study drug 
(Study Day 1) should be reported as an update to medical history as well as an adverse event. Any pre-
existing medical condition or signs or symptoms that changes in severity, frequency, or seriousness after 
the subject takes the first dose of study drug (Study Day 1) and through the Follow-up Visit should be 
reported as an adverse event.  
 
Clinically significant abnormal laboratory values or other examinations (e.g., ECG) that are detected at 
the time of the first dose of study drug (Study Day 1) and worsen during the study should be reported as 
adverse events. An abnormal laboratory result that is not verified by repeat testing does not necessitate 
reporting as an adverse event. The Investigator will exercise his or her medical, scientific, and clinical 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Clinically significant abnormal laboratory values occurring during the clinical study will be 
followed until repeat tests return to normal, stabilize, or are no longer clinically significant. Any 
abnormal test that is determined to be an error does not require reporting as an adverse event.  
 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than specified 
in the protocol and higher than known therapeutic doses. Overdoses with associated symptoms are 
always handled as AEs and reported as such. Overdoses without associated symptoms are not reported 
as AEs but are documented in [specify e.g., CRF] in order to collate information for the IB regarding the 
level of excess dosage taken or administered without adverse effects. An overdose will be reported 
irrespective of outcome even if toxic effects were not observed. 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected 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, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant 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 


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requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using Related/Not Related. In a clinical trial, the 
study product must always be suspect.  
 
No (unlikely related, unrelated, not related, no relation) – The time course between the 
administration of study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (e.g., medical history, concomitant drugs, therapies, and complications) 
is suspected. 
Yes (possibly related, related) – The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship and no other 
cause (e.g., medical history, concomitant drugs, therapies, and complications) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the study 
drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
• 
The temporal sequence from study drug administration - 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• 
Underlying, concomitant diseases (medical history) - 


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o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
• 
Concomitant drug - 
o The other drugs the subject is taking or the treatment the subject receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• 
Known response pattern for this class of study drug - 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a class 
effect. 
• 
Exposure to physical and/or mental stresses - 
o The exposure to stress might induce adverse changes in the recipient and provide a 
logical and better explanation for the event. 
• 
The pharmacology and PKs of the study drug - 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The study investigators will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
 
The expected adverse events are listed in the Investigators Brochure (IB).   
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 


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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study coordinators will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Adverse event reporting will include the following.  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 the sponsor within 30 days.  The sponsor will review a summary of all AEs 
monthly.  A summary of AEs will be provided to the DSMB as part of the quarterly reports.   
 
NAFLD related events that are common in the study population (expected) include:  
- 
Abdominal pain 
- 
Hyperglycemia 
- 
High blood pressure 
- 
Diabetes 
 
These and any other adverse events will be recorded on the CRF and monitored to resolution or 30 days 
after end of the study.   
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the sponsor and MMS Pharmacovigilance, per the SAE 
reporting form, any serious adverse event, whether or not considered study intervention related, 
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., all-cause mortality) 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). In that case, the investigator must immediately report the 
event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by Emory University/
 or MMS Pharmacovigilance and 
should be provided as soon as possible. 
 
The study sponsor (Emory) 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 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor 
must notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 


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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. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A  
 
8.3.9 REPORTING OF PREGNANCY  
 
If a participant becomes pregnant, the study drug will be discontinued immediately while continuing to 
carry out safety follow-up.  Permission will be requested to follow the pregnant women to pregnancy 
outcome.  All pregnancies should be reported as an adverse event and the reporting mechanisms under 
that apply.   
 
 
8.3.10 DRUG-INDUCED LIVER INJURY CLINICAL MANAGEMENT PLAN 
 
If subjects develop elevations of AST or ALT >2x baseline or total bilirubin >1.5x baseline values during 
the study, repeat testing will be performed within 48 -72 hours. If there are persistent elevations (ALT or 
AST >2 X baseline or TBL >1.5 X baseline values) upon repeat testing, then close observation (testing and 
physical examination 2-3 times per week) will be implemented and discontinuation of drug will be 
considered.  
 
A decision to discontinue or temporarily interrupt the study drug will be based on factors that include 
how much higher than baseline ALT and AST were relative to the upper limit of normal (ULN) and how 
much the on study ALT and AST levels have increased relative to baseline, in addition to whether there is 
concomitant elevation of bilirubin or INR.  
 
The study drug will be discontinued or temporarily interrupted:  
o If baseline measurements (BLM) were <2 X ULN, discontinue if ALT or AST increases to >5 X 
BLM. 
o If BLM ≥2 X ULN but <5 X ULN, discontinue if ALT or AST increases to >3 X BLM.  
o Discontinue if ALT or AST increase is >2 X BLM AND the increase is accompanied by a 
concomitant increase in TBL to >2 X BLM OR the INR concomitantly increases by > 0.2. 
o In any subjects with signs and symptoms of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  
 
If a patient lives in a remote area, laboratory testing will be performed locally and the results will be 
promptly communicated to the investigator site. 
 
8.3.11 LONG-TERM SAFETY FOLLOW-UP 
 


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For long-term safety follow-up of subjects there will be a Week 24, Week 36, and Week 60 safety follow-
up visit. The same study procedures will be conducted at all three visits, as outlined in Table 1 (Schedule 
of Activities). The Month 3 Safety Follow-up Visit (Week 24 Visit) will take place 12 weeks after the Week 
12 or ET visit with a two week visit window. The Month 6 Safety Follow-Up Visit (Week 36 visit) will take 
place 24 weeks after the Week 12 or ET visit with a two week visit window. The Month 12 Safety Follow-
up Visit (Week 60) will take place a year from the Week 12 or ET visit. 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator 
). The UP 
report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 7 calendar days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 7 calendar days of 
the investigator becoming aware of the problem.  


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• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 30 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
  
 
9.1 
STATISTICAL HYPOTHESES 
 
The primary end-point of the study and on which the statistical power is based is the percent change in 
ALT from Baseline to Week 12.  
 
The hypothesis being tested is that treatment with gemcabene for twelve weeks will result in a clinically 
meaningful reduction in ALT, in pediatric NAFLD participants. 
  
9.2 
SAMPLE SIZE DETERMINATION 
The sample size for this study is 36 completed participants.  A percent change from baseline of 
approximately 20% is considered to be clinically meaningful.  Assuming a two-sided test at the 5% 
significance level, 36 completed participants will provide 81% power to detect a percent change from 
baseline of 20% (effect size = 0.5), if the standard deviation is 40%.  Additionally, assuming a drop-out 
rate of 10%, a total of 40 participants is needed for enrollment into the study to ensure an adequate 
number of subjects complete the trial. Power was calculated using a two-sided Wilcoxon test with a 0.05 
significance level using PASS v. 14.0.8 (Kaysville, UT). 
 
9.3 
POPULATIONS FOR ANALYSES 
 
• 
Intention-to-Treat (ITT) Analysis Set: all enrolled participants.  All efficacy summaries and 
analyses will be performed using the ITT. 
• 
Modified Intention-to-Treat Analysis (mITT) Set: all enrolled participants who took at least one 
dose of study intervention and have liver enzymes performed at Baseline and Week 12.  
Confirmatory efficacy analyses will be performed using the mITT.   
• 
Safety Analysis Set (SAS): all enrolled participants who took at least one dose of study 
intervention.  All safety summaries will be performed using the SAS.   
• 
Per-Protocol Analysis Set (PPAS): the subset of the participants in the full analysis (ITT) set who 
complied with the protocol sufficiently (e.g., took at least 80% of study intervention for 80% of 
the days within the 12-week period) and did not have any major protocol deviations.  
Confirmatory efficacy and safety analyses will be performed using the PPAS. 
 


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9.4 
STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
Statistical significance will be assessed at the 0.05 level, unless otherwise noted.  
 
Descriptive statistics will be calculated for all variables of interest and include means and 
standard deviations or medians and ranges (for continuous measures) or counts and 
percentages (for categorical measures), as appropriate. Continuous data will be assessed for 
normality using histograms and normal probability plots and statistically tested using the 
Anderson-Darling test and/or the Shapiro Wilk test for normality. Non-normal data will be 
presented using medians accompanied by 25th and 75th. All analyses will be conducted using SAS 
v. 9.4 (Cary, NC) or CRAN R v. 3.3 (Vienna, Austria).  
 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
For the primary efficacy endpoint, we will use the ITT population. The entire population, regardless of 
whether or not they took the study medication, will be used in the analysis.  
• 
Percent change in ALT  
Changes in our primary continuous outcome measures (ALT) from Baseline to the primary 
endpoint (Week 12), will be examined as percentage change.  
൬ቀ
(𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑣𝑣𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎−𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣)
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
 ቁ𝑥𝑥 100൰.  Statistically, percent change from Baseline to Week 
12 will be tested against the null hypothesis of no change (i.e., percent change = 0) using a one-
sample two-sided t-test or a Wilcoxon signed-rank test, in the event that the percent change is 
non-normally distributed.  Output from the t-test will include the mean percent change, its 95% 
confidence interval and the p-value.   If the data are non-normally distributed, the median 
percent change value and the 25th and 75th percentiles will be presented, along with the p-value 
from the Wilcoxon signed-rank test.   
 
• 
Patients with no week 12 measurements will be excluded from the primary efficacy analysis 
(only observed case data will be used).   In a sensitivity analysis, for subjects with missing week 
12 data, we will carry forward their week 6 measurements and re-assess the primary outcomes. 
Similar analyses will be used to examine the mITT and the PPAS datasets.  
 
 
 
9.4.3 ANALYSIS OF THE SECONDARY EFFICACY ENDPOINT(S) 
For each secondary efficacy endpoint: 
 
Similar to the primary endpoints described above, we will examine percent change in all 
continuous secondary outcomes measures. In addition, we will also calculate raw change from 
baseline (raw change = (postbaseline value – baseline value). Raw change and percent change in 
each continuous endpoint will be calculated in a manner analogous with described above for the 


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primary endpoint. Raw changes in measures from baseline will be assessed using a paired t-test 
or a Wilcoxon signed-rank test when data are non-normally distributed.   Output for each 
endpoint will include the mean, its 95% confidence interval and the p-value if a t-test is 
performed.   If the endpoint is not normally distributed, median values, and the 25th and 75th 
percentiles will be presented, along with the p-value from the Wilcoxon signed-rank test. 
 
Similar analyses will be performed to examine interval changes in continuous measures from 
Baseline to Week 6 (when applicable).  
 
Growth data collected during the study will be summarized descriptively at each time point and 
converted to age-sex specific z-scores using normative data. Raw changes in BMI and weight as 
well as Z-scores will be examined using the methods described above.  
 
• 
 Patients with no week 12 measurements will be excluded from the secondary efficacy analyses 
(observed case data only will be used).  In a sensitivity analysis, for subjects with missing week 
12 data, we will carry forward their week 6 measurements and re-assess the primary outcomes. 
Similar analyses will be used to examine the mITT and the PPAS datasets. 
 
 
 
 
9.4.4 SAFETY ANALYSES 
 
Each AE will be counted once only for a given participant in each summary table, and will be presented 
based on severity, frequency, and relationship of AEs to study intervention by System Organ Class (SOC) 
and preferred term groupings.  For each AE, the severity, relationship, expectedness, outcome, and 
duration will be presented in a table.  Adverse events leading to premature discontinuation from the 
study intervention and serious treatment-emergent AEs will be presented either in a table or a listing.  
AEs will be tabulated and described using counts and percentages with associated 95% confidence 
intervals. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Descriptive statistics (e.g., means standard deviations, medians, counts, and percentages), will be used 
to describe the study cohort. No inferential statistical testing will be performed.  
 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
No interim analysis is planned.   
 
 
9.4.7 SUB-GROUP ANALYSES 
 
The primary and secondary endpoints will be analyzed by sex and by presence or absence of select 
NAFLD genes which may alter response to the IP. Differences in the primary outcome (% change in ALT 
from Baseline to Week 12) will be compared among sexes and genetic subgroups using two-sample t-


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tests or Wilcoxon rank sum tests, as applicable. Percent change for other continuous measures will be 
analyzed similarly. For subgroups with more than two levels, we will test for differences in percent 
change from baseline using analysis of variance (ANOVA) models with a Tukey-Kramer post-hoc multiple 
comparison procedure or a Kruskal Wallis test with a Dwass, Steel, Critchlow-Fligner multiple 
comparison procedure. 
 
For raw changes in continuous measures (ALT, AST, etc.) subgroup analysis will be conducted using 
analysis of covariance (ANCOVA) models. Specifically, for each outcome of interest, we will compare the 
12-week outcome measure between subgroups (e.g., sex) controlling for the baseline value of the 
outcome measure. Initial models will include the interaction between subgroup and baseline value to 
assess the homogeneity of slope assumption. If the assumption is met, the interaction will be removed 
and least square means with associated 95% confidence intervals will be provided for each subgroup. 
Differences in subgroup means will be reported and accompanied by 95% confidence intervals. If the 
assumption of homogeneity of slopes is violated, an alternative approach such as the Johnson-Neyman 
procedure, will be utilized.  
 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
N/A 
 
 
9.4.9 EXPLORATORY ANALYSES 
Exploratory analyses are planned as described in the sub-study (appendix A).   
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
   
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent and assent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol.  
 
The following questionnaires and handouts will be submitted with the IRB submission:  
• 
AUDIT questionnaire 
• 
Block physical activity questionnaire 
• 
Bev Q survey 
• 
Food frequency questionnaire 
• 
TANNER screener 


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• 
PROMIS Questionnaires (Fatigue, Anxiety, Depression) 
• 
AHA Healthy Children Handout 
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  The DSMB will review all AEs and SAEs and may suspend or terminate the study for safety 
concerns.  AEs will be reviewed quarterly and for any SAE, an ad hoc meeting of the DSMB will be 
convened within 10 business days to review the event.   
 
Written notification, documenting the reason for study suspension or termination, will be provided by 
the suspending or terminating party to study participants, investigators, Gemphire, the Investigational 
New Drug (IND) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 


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Patient-specific trial stopping rules include: 
 
• 
In any patient who develops an AE of grade 3 that is probably or possibly related to study drug and 
any patient who develops a grade 4 or higher CTCAE regardless of causality assessment, 
investigational product will be discontinued.  
 
• 
Hemoglobin will be assessed by central laboratory evaluation.  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 one and two 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. 
 
• 
If, at any visit, a creatinine increase of > 0.3 mg/dL (27 µmol/L) from baseline, a GFR decrease of 
> 15 mL/min from baseline, or a > 30 urinary albumin:creatinine ratio mg/g is observed, a repeat 
chemistry/urinalysis will be performed within one 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 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. 


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10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Emory University. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by the Emory University research staff will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived at the Emory University. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at Emory University. After the study is 
completed, the de-identified, archived data will remain at Emory and will be made available for use by 
other qualified researchers including those outside of the study with the consent of the steering 
committee and Gemphire. Permission to transmit data to the outside investigators for the purpose of 
improving human health will be included in the informed consent.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at Emory with the same goal as the sharing of data. These 
samples may be shared with other qualified researchers after permission from the steering committee 
and Gemphire.   
 


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During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
Steering Committee:  
 
  
 
 
 
 
  
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including pediatric hepatology, pediatric nephrology and 
pediatric endocrinology. Members of the DSMB are independent from the study conduct and free of 
potential/perceived conflict of interest with Gemphire, 
 and the study investigators.  The DSMB 
will meet at least quarterly to assess summary safety and efficacy data for the study. If requested, the 
summary data tables may be shared with regulatory agencies.  The DMSB will operate under the rules of 
an approved charter that will be written and reviewed at the organizational meeting of the DSMB. At 
this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB will 
provide its input to
 and the steering committee. 
 
DSMB Members:  
 
 
 
 
  


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DSMB Statistician:  
 
 
  
 
 
 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
• 
Monitoring for this study will be performed by an appointed CRA on behalf of Gemphire. The 
study monitor will perform on-site monitoring every 4-8 weeks, or as needed, depending on 
data quality, enrollment and other factors. 100% SDV will be performed, with particular 
attention of monitoring time to eligibility and safety assessments. 
• 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same 
time, the Sponsor in the maintenance of complete, legible, well organized and easily 
retrievable data. Before the enrollment of any subject in this study, the Sponsor or their 
designee will review with the Investigator and site personnel the following documents: 
protocol, Investigator’s Brochure, eCRFs and procedures for their completion, informed 
consent process, management of investigational product, and the procedure for reporting 
adverse events such as SAEs. 
• 
A detailed follow-up letter will be provided to the Principal Investigator following visits and will 
be acknowledged and filed in the Trial Master File. 
• 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, 
at what level of detail monitoring will be performed, and the distribution of monitoring reports. 
• 
Independent audits may be conducted by QACV Consulting or a similar vendor to ensure 
monitoring practices are performed consistently across all participating sites and that monitors 
are following the CMP. 


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• 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are 
satisfactory. During the monitoring visits, information recorded on the CRFs will be verified 
against source documents and requests for clarification or correction may be made. After the 
CRF data is entered by the site, the CRA will review the data for safety information, 
completeness, accuracy, and logical consistency. Computer programs that identify data 
inconsistencies may be used to help monitor the clinical study. If necessary, requests for 
clarification or correction will be sent to Investigators. The Investigator and his/her staff will be 
expected to cooperate with the monitor and provide any missing information, whenever 
possible. 
 
 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   


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Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into a 21 CFR Part 11-compliant data capture system 
provided by Gemphire Therapeutics Inc. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
 
 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
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 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., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, source 
documents, and detailed records of treatment disposition. The records should be retained by the 
Investigator according to specifications in the ICH guidelines, local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer. The Investigator must obtain written permission from 
Gemphire before disposing of any records, even if retention requirements were met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, Emory University 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. 
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  


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It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working days of 
the scheduled protocol-required activity.  All deviations must be addressed in study source documents, 
reported to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements.  
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
Publication Policy 
Following completion of the study, the data will be considered for publication in a scientific journal or 
for reporting at a scientific meeting. Each Investigator is obligated to keep data pertaining to the 
study confidential. The Investigator must consult with Emory University before any study data are 
submitted for publication. The Sponsor reserves the right to deny publication rights until mutual 
agreement on the content, format, interpretation of data in the manuscript, and journal selected for 
publication are achieved.   
 
Insurance and Indemnity 
In accordance with the relevant national regulations, 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. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  All study group 
members will disclose all conflicts of interest every 12 months during the study and the sponsor (Emory 
University) will establish a mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 


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CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 


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SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 
Summary of changes from previous version of protocol. 
Version 4.0 02OCT2018 
 
Section(s) Affected by Change 
Description of Change  
Brief Rationale 
1.1 Synopsis 
3. Endpoints 
8.1 Efficacy Assessments 
Addition of cT1 score by Liver Multiscan as 
secondary endpoint 
LIF score is a categorical descriptor 
of cT1 measurements. This was 
inadvertently left out of the original 
protocol. Both measures will be 
included as secondary endpoints. 
1.3 Schedule of Activities 
Removed description of MRI details in the 
table. 
These procedures are detailed later 
in the protocol.  
10.1.6 Safety Oversight 
Change cardiology to endocrinology 
Correction of initial error regarding 
DSMB member specialty 
14. Sub-study Methods 
Added Week 12 only for PK collection 
Clarification that PK was only 
collected at Week 12 during the 
sub-study (not during baseline) 
1.3 Schedule of Activities 
Updated Table 1, 2, and 3 to reflect details 
of the three additional long-term safety 
visits. 
To clarify which study procedures 
will take place at the additional 
three long-term safety follow-up 
visits.  
8.3.11 Long-term safety 
follow-up 
Addition of long-term safety follow-up 
visits 
To clarify the long-term safety 
follow-up plan 
 
Summary of changes from previous version of protocol. 
Version 3.0 – 31JUL2018 
 
Section(s) Affected by Change 
Description of Change  
Brief Rationale 
1.2 Synopsis 
3. Endpoints 
8.1 Efficacy Assessments 
Addition of cT1 score by Liver Multiscan as 
secondary endpoint 
LIF score is a categorical descriptor 
of cT1 measurements. This was 
inadvertently left out of the original 
protocol. Both measures will be 
included as secondary endpoints. 
1.1 Synopsis 
4.1 Overall Design 
5.5 Strategies for Recruitment 
and Retention 
10.1 Key Roles and Study 
Governance 
Study population increased from 40 to 50 
subjects due to the addition of a 4th site. 
Addition of UCSD (PI: Dr. Jeff 
Schwimmer) to increase the study 
population by 10 subjects.  
1.3 Schedule of Activities 
Removed description of MRI details in the 
table. 
These procedures are detailed later 
in the protocol.  


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Table 2. Specimen Collection 
Schedule 
Table 3. Blood Volume Chart 
Addition of clinical lipid profile at Baseline, 
Week 2, Week 6, and Week 12 
To get clinical lipid profiles run in 
real time for investigator review 
5.1 Inclusion Criteria 
Changed language regarding historic ALT 
requirement to be within 50% of the 
screening visit ALT but not necessarily 
within the other set range of girl ≥ 46 boy 
≥ 54 but < 250. 
To improve clarity surrounding 
historic ALT requirements 
5.2 Exclusion Criteria 
Addition of timing criteria of taking fish oil, 
fibrates, or thiazolidinediones – must be at 
least 30 days prior to screening 
To improve clarity for subjects 
previously taking these medications 
8.3.10 Drug-Induced Liver 
Injury Clinical Management 
Plan 
Changed definition of close observation 
from 2-3 times weekly to at least weekly 
To give more flexibility to subjects 
in scheduling multiple unscheduled 
visits 
10.1.6 Safety Oversight 
Change cardiology to endocrinology 
Correction of initial error regarding 
DSMB member specialty 
12.1 Meal Challenge Sub-
study and Deuterated Water 
Tracer Sub-study 
Changed until 10 have completed sub-
study 
To improve clarity 
14. Methods 
Clarified that PK labs are only to be drawn 
at Week 12 in the sub-study and not at 
baseline 
To improve clarity and consistency 
throughout protocol 
14. Methods 
Clarified when drug is administered at the 
Week 12 visit for the substudy. 
To improve clarity 
 
 
Summary of changes from previous version of protocol. 
Version 2.0 – 27FEB2018 
 
Section(s) Affected by Change 
Description of Change  
Brief Rationale 
Section 1.1 Synopsis  
 
Section 3 Endpoints 
Added “absolute change and percent 
change in pancreatic fat from Baseline to 
Week 12” 
Pancreatic fat protocol added to 
Hepafat scan (MRI) 
Section 1.1 Synopsis  
 
Section 3 Endpoints 
Added “change in body composition 
measures by AMRA from Baseline to Week 
12” 
Addition of body composition 
acquisition (MRI) 
Section 1.3 Schedule of 
Activities (Table 1) 
Moved standardized lifestyle counseling 
from Screening to Baseline 
Correction of an oversight on the 
timing of the counseling  
Section 1.3 Schedule of 
Activities (Table 1) 
Added visit window for Baseline Visit 
activities (+/- 2 days) 
Allow for flexibility in scheduling 
the baseline MRI and completing 
other visit activities 
Section 1.3 Schedule of 
Activities (Table 1) 
Added Early Termination Visit 
To improve clarity of study 
procedures for an ET visit 
Section 1.3 Schedule of 
Activities (Table 1) 
Moved “Metabolomics” from Table 1 to 
Table 2 
To improve clarity 
Section 1.3 Specimen 
Collection Schedule (Table 2) 
Added specimen collection details for 
Early Termination visit 
To improve clarity of study 
procedures for an ET visit 


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Section 1.3 Specimen 
Collection Schedule (Table 2) 
Clarified which labs are included within 
CMP, CBC, and Lipid Profile 
To improve clarity 
Section 1.3 Specimen 
Collection Schedule (Table 2) 
Added note regarding the possibility of an 
additional lab draw during screening for 
subjects with no historic ALT available 
To improve clarity 
Section 1.3 Blood Volume 
Chart (Table 3) 
Updated entire table to reflect the blood 
volume changes from switching vendors 
and combining draw tubes. 
To reflect the changes made to the 
labs 
Section 7.1 Discontinuation of 
Study Intervention 
Defined which activities will take place at 
the Early Termination visit 
To improve clarity 
Section 7.2 Participation 
Discontinuation/Withdrawal 
from the study 
Clarified the timing of when subjects 
should be replaced 
To improve clarity 
Section 8.1 Efficacy 
Assessments 
Added pancreatic fat and body 
composition 
To reflect additional MRI protocols 
Section 8.1 Efficacy 
Assessments 
Added to Unscheduled visits: repeat ALT 
during screening and the Early 
Termination visit 
To improve clarity 
Throughout protocol 
Renaming “12 weeks” and “6 weeks” to 
“Week 12” and “Week 6” 
To improve clarity 
Throughout protocol 
Minor changes to format and correction of 
typographical errors 
To improve clarity 
 
 
 
Summary of changes from previous version of protocol. 
Version 1.1 – 01DEC2017 
 
Section(s) Affected by Change 
Description of Change  
Brief Rationale 
Title Page 
Removed NCT number and summary of 
changes 
To avoid need for future 
amendment and redundancy 
Table 1. Schedule of Activities 
Added calculated BMI at each visit 
To address request by FDA 
Table 1. Schedule of Activities  
Added footnote C in regards to obtaining 
physical measurements 
To improve clarity 
Table 1. Schedule of Activities 
Added ECG to Baseline and Week 2 visits 
To address request by FDA 
Table 1. Schedule of Activities 
Added pregnancy test at Week 2 and 
Week 6 visits 
To improve safety 
Table 2. Specimen Collection 
Schedule 
Added urinalysis and urine collection for 
storage 
To improve clarity 
Table 2. Specimen Collection 
Schedule 
Added pharmacokinetic studies 
To address request by FDA 
Table 2. Specimen Collection 
Schedule 
Added CBC at Week 12 
To address request by FDA 
Table 3. Blood Volume Chart 
Added Table 3 to show blood volume 
amounts throughout study 
To address request by FDA 


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Section 4.2 Scientific Rationale 
for Study Design 
 
Section 5.1 Inclusion Criteria 
Added language regarding assessment of 
inflammation change in ALT at screening: 
obtain historical and/or repeat ALT 
measure 
To address request by FDA 
Section 5.1 Inclusion Criteria 
Added inclusion criteria of ALT ≤ 250 at 
screening 
To address request by FDA 
Section 5.1 Inclusion Criteria 
Entry criteria clarification of clinical 
diagnosis of NAFLD  
To address request by FDA 
Section 5.1 Inclusion Criteria 
Added inclusion requirement of 
attempted lifestyle modification to treat 
NAFLD for at least three months  
To address request by FDA 
Section 5.2 Exclusion Criteria 
Entry criteria clarification regarding 
Gilbert’s syndrome lab requirements 
To address request by FDA 
Section 5.2 Exclusion Criteria 
Addition of abnormal alkaline 
phosphatase to exclusion criteria 
To address request by FDA 
Section 5.2 Exclusion Criteria 
Addition of any history of ascites, variceal 
bleeding, hepatic encephalopathy, or 
hepatocellular carcinoma (HCC) to 
exclusion criteria 
To address request by FDA 
Section 5.2 Exclusion Criteria 
Changed HbA1c exclusion criteria to < 8% 
at screening 
To address request by FDA 
Section 5.2 Exclusion Criteria 
Addition of exclusion criteria for patient 
with type 1 diabetes mellitus 
To address request by FDA 
Section 5.2 Exclusion Criteria 
Change in exclusion of elevated creatinine 
kinase elevations to allow for repeat test if 
thought to be related to exercise  
To address request by FDA 
Section 5.3 Lifestyle 
Considerations 
Fasting requirement changed from 12 
hours to 8 hour minimum, clarified that 
fasting is not required for the screening 
visit  
To make fasting requirements 
easier on participants 
Section 8.2 Safety and Other 
Assessments 
Addition of 7 day window for obtaining 
repeat creatinine levels 
To improve clarity 
Section 8.3.10 Drug-Induced 
Liver Injury Clinical 
Management Plan 
Addition of Section 8.3.10 Drug-Induced 
Liver Injury Clinical Management Plan 
To address request by FDA 
Section 10.1.2 Study 
Discontinuation and Closure 
Addition of Patient-specific trial stopping 
rules 
To address request by FDA 
Section 10.1.6 Safety 
Oversight 
Addition DSMB Statistician 
To improve clarity 
Appendix B. PROMIS 
Questionnaires 
Addition of PROMIS questionnaires to 
protocol 
To address request by FDA 
Throughout protocol 
Minor changes to format and correction of 
typographical errors 
To improve clarity 
 
 
 


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11 REFERENCES  
 
1. 
Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among 
United States adolescents, 1988-1994 to 2007-2010. J Peds 2013;162:496-500. 
2. 
Pacifico L, Nobili V, Anania C, Verdecchia P, Chiesa C. Pediatric nonalcoholic fatty liver disease, 
metabolic syndrome and cardiovascular risk. World journal of gastroenterology : WJG 2011;17:3082-91. 
3. 
Schwimmer JA, McGreal N, Deutch R, Finegold MJ, Lavine JE. Influence of gender, race and 
ethnicity on suspected fatty liver in obese adolescents. Pediatrics 2005;115:e561-e5. 
4. 
Louthan MV, Theriot JA, Zimmerman E, Stutts JT, McClain CJ. Decreased prevalence of 
nonalcoholic fatty liver disease in black obese children. J Pediatr Gastroenterol Nutr 2005;41:426-9. 
5. 
Suzuki A, Abdelmalek MF, Schwimmer JB, et al. Association between puberty and features of 
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10:786-94. 
6. 
Patton HM, Lavine JE, Van Natta ML, et al. Clinical correlates of histopathology in pediatric 
nonalcoholic steatohepatitis. Gastroenterology 2008;135:1961-71.e2. 
7. 
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty 
liver disease: practice guideline by the American Gastroenterological Association, American Association 
for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 
2012;142:1592-609. 
8. 
Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis 
and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert 
Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology 
and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr 2017;64:319-34. 
9. 
Schwimmer JA, Behling C, Newbury R, et al. Histopathology of Pediatric Nonalcoholic Fatty Liver 
Disease. Hepatology 2005;42:641-9. 
10. 
Brunt EM, Kleiner DE, Wilson LA, et al. Portal chronic inflammation in nonalcoholic fatty liver 
disease (NAFLD): A histologic marker of advanced NAFLD-Clinicopathologic correlations from the 
nonalcoholic steatohepatitis clinical research network. Hepatology (Baltimore, Md) 2008. 
11. 
Schwimmer JB, Dunn W, Norman GJ, et al. SAFETY study: alanine aminotransferase cutoff values 
are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology 
2010;138:1357-64. 
12. 
Molleston JP, Schwimmer JB, Yates KP, et al. Histological abnormalities in children with 
nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. The 
Journal of pediatrics 2014;164:707-13.e3. 
13. 
Schwimmer JB, Newton KP, Awai HI, et al. Paediatric gastroenterology evaluation of overweight 
and obese children referred from primary care for suspected non-alcoholic fatty liver disease. 
Alimentary pharmacology & therapeutics 2013:doi 10. 


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14. 
Manning P, Murphy P, Wang K, et al. Liver histology and diffusion-weighted MRI in children with 
nonalcoholic fatty liver disease: A MAGNET study. J Magn Reson Imaging 2017. 
15. 
Middleton MS, Heba ER, Hooker CA, et al. Agreement Between Magnetic Resonance Imaging 
Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies 
From Adults With Nonalcoholic Steatohepatitis. Gastroenterology 2017. 
16. 
Sookoian S, Pirola CJ. Genetic predisposition in nonalcoholic fatty liver disease. Clinical and 
molecular hepatology 2017;23:1-12. 
17. 
Umano GR, Martino M, Santoro N. The Association between Pediatric NAFLD and Common 
Genetic Variants. Children (Basel, Switzerland) 2017;4. 
18. 
Neuschwander-Tetri BA. Lifestyle modification as the primary treatment of NASH. Clin Liver Dis 
2009;13:649-65. 
19. 
Vos MB. Nutrition, nonalcoholic fatty liver disease and the microbiome: recent progress in the 
field. Current opinion in lipidology 2013. 
20. 
Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology 2013. 
21. 
Wesolowski SR, Kasmi KC, Jonscher KR, Friedman JE. Developmental origins of NAFLD: a womb 
with a clue. Nat Rev Gastroenterol Hepatol 2017;14:81-96. 
22. 
Manco M. Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics. Children 
(Basel, Switzerland) 2017;4. 
23. 
Bril F, Barb D, Portillo-Sanchez P, et al. Metabolic and histological implications of intrahepatic 
triglyceride content in nonalcoholic fatty liver disease. Hepatology 2017;65:1132-44. 
24. 
Jin R, Welsh JA, Le NA, et al. Dietary fructose reduction improves markers of cardiovascular 
disease risk in Hispanic-American adolescents with NAFLD. Nutrients 2014;6:3187-201. 
25. 
Louthan MV, Barve S, McClain CJ, Joshi-Barve S. Decreased serum adiponectin: an early event in 
pediatric nonalcoholic fatty liver disease. J Pediatr 2005;147:835-8. 
26. 
Alkhouri N, Hanouneh IA, Zein NN, et al. Liver transplantation for nonalcoholic steatohepatitis in 
young patients. Transpl Int 2016;29:418-24. 
27. 
Cioffi CE, Welsh JA, Cleeton RL, et al. Natural History of NAFLD Diagnosed in Childhood: A Single-
Center Study. Children (Basel, Switzerland) 2017;4. 
28. 
Newton KP, Hou J, Crimmins NA, et al. Prevalence of Prediabetes and Type 2 Diabetes in 
Children With Nonalcoholic Fatty Liver Disease. JAMA Pediatr 2016;170:e161971. 
29. 
Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of 
nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. 
JAMA : the journal of the American Medical Association 2011;305:1659-68. 
30. 
Schwimmer JB, Lavine JE, Wilson LA, et al. In Children with Nonalcoholic Fatty Liver Disease, 
Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but does not Reduce Disease Activity 
Scores. Gastroenterology 2016. 


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31. 
Bays HE, McKenney JM, Dujovne CA, et al. Effectiveness and tolerability of a new lipid-altering 
agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am J Cardiol 
2003;92:538-43. 
32. 
Stein E, Bays H, Koren M, Bakker-Arkema R, Bisgaier C. Efficacy and safety of gemcabene as add-
on to stable statin therapy in hypercholesterolemic patients. J Clin Lipidol 2016;10:1212-22. 
33. 
Banini BA, Sanyal AJ. Nonalcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, Natural 
History, Diagnosis, and Current Treatment Options. Clinical medicine insights Therapeutics 2016;8:75-84. 
34. 
Issa D, Wattacheril J, Sanyal AJ. Treatment Options for Nonalcoholic Steatohepatitis - A Safety 
Evaluation. Expert opinion on drug safety 2017. 
35. 
Sanyal AJ, Neuschwander-Tetri BA, Tonascia J. End Points Must Be Clinically Meaningful for Drug 
Development in Nonalcoholic Fatty Liver Disease. Gastroenterology 2016;150:11-3. 
36. 
Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but no Other Histologic Features, 
Associates with Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology 2015. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A. POST PRANDIAL LIPIDS AND DE NOVO LIPOGENESIS SUB-STUDIES 
Purpose and Background 
While fasting lipids reflect steady state and remnants from the previous day’s diet, the patterns of lipids 
following a meal reflects important aspects of metabolic health (or dysfunction) especially in patients 
with NAFLD.  Gemcabene is proposed to improve postprandial lipids in several ways.  First, it is a dual 
inhibitor of both cholesterol synthesis and fatty acid synthesis.  In addition, it decreases plasma levels of 
apoC-III, which then leads to increased clearance of VLDL particles, lowering circulating TG levels.  The 
mechanism of apoC-III lowering is thought to be through inhibition of the expression of apoC-III.   
12  
SUB-STUDY SUMMARY 
12.1 MEAL CHALLENGE SUB-STUDY & DEUTERATED WATER TRACER SUB-STUDY 
Title: 
Meal Challenge Sub-Study 
 
Study Description: 
Provides measurement of postprandial lipids in 10 participants 
 
Endpoints: 
Primary Endpoint:  
• 
Incremental area under the curve for TG concentration in 
plasma, chylomicrons and VLDL 
 
Secondary Endpoint:  
• 
Incremental AUC for apoB and apoC-III in plasma, chylomicrons 
and VLDL 
 
 
Title: 
Deuterated Water Tracer Sub-Study  
 
Study Description: 
 
Provides measurement of postprandial lipids and will be performed 
simultaneously in the same 10 participants who are participating in the 
Meal Challenge Sub-Study 
 
Endpoints: 
 
Primary Endpoint:  
• 
Change in fractional hepatic De Novo Lipogenesis (DNL) and 
fractional cholesterol synthesis (DNC) after twelve weeks of 
gemcabene 
 
Secondary Endpoint:  
• 
Change in absolute hepatic De Novo Lipogenesis (DNL) and 
absolute cholesterol synthesis (DNC) after twelve weeks of 
gemcabene 
 
Study Population: 
The sample for this study will include n=10 participants with NAFLD (~50% 
boys and ~50% girls) who are participating in the GEM-IIT-601 study.  The 


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sub-study will only be conducted at Emory.  All Emory site participants will 
be invited to participate in the sub-study until 10 have been enrolled . 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
 
Emory University 
 
Description of Study 
Intervention: 
 
No intervention; only blood collection will occur  
 
Study Duration: 
 
12 months  
 
Participant Duration: 
12 weeks  
 
 
13 STUDY POPULATION 
The sample for this study will include n=10 participants with NAFLD (~50% boys and ~50% girls) who are 
participating in the GEM-IIT-601 study.  The sub-study will only be conducted at Emory.  All Emory site 
participants will be invited to participate in the sub-study until 10 have been enrolled.   
 
13.1 INCLUSION CRITERIA * ADDITIONAL INCLUSION AND EXCLUSION CRITERIA (IN 
ADDITION TO THE MAIN STUDY CRITERIA) 
 In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
10. Willing to participate in the sub-study and complete all sub-study procedures at Baseline and 
Week 12 visits 
11. History of hypertriglyceridemia 
 
 
13.2 EXCLUSION CRITERIA * ADDITIONAL INCLUSION AND EXCLUSION CRITERIA (IN 
ADDITION TO THE MAIN STUDY CRITERIA) 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
22. Food allergies including gluten sensitivities 
23. Known reaction to deuterated water 
 
14 METHODS 
After consent and assent to the main study, participants at Emory University will be informed of the sub-
study at the Screening visit.  Consent and assent for the sub-study will be obtained through providing 
details of the sub-study and procedures and through discussion.  The postprandial lipid study will take 
place at the Baseline and Week 12 visit.  Prior to the day of the visit, the participants will have a 
standardized meal provided for their evening meal.  They will be asked not to consume any sugar 


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containing beverages including juice. The meal will be identical at Baseline and Week 12 and will consist 
of a commercially prepared frozen dinner that can be microwaved at the time of consumption.  It will be 
shipped frozen to the participant’s home along with instructions.   
Deuterated water: De novo lipogenesis and cholesterol synthesis can be studied by measuring the 
incorporation of deuterium from deuterated water into VLDL-TG palmitate and plasma free cholesterol. 
Two 60 ml bottles of deuterated water (D, 70%) will be provided the evening prior to the DNL and DNC 
assessments.  One bottle will be consumed with the standardized evening meal and one bottle 3 hours 
later around bedtime.   
No food or flavored drinks will be allowed after 7 pm the day prior to the visit to ensure 8 hours of 
fasting.  Participants will be asked to consume one glass of water in the morning prior to driving to the 
research center to ensure good hydration at the time of the sub-study.   
On the morning of the visit, at the pediatric research unit, participants will have an IV placed during the 
initial blood draw to make repeated blood draws more comfortable.  After fasting labs are completed, a 
standardized breakfast will be provided (approximately 30% fat [~12% polyunsaturated, 8% saturated, 
and 10% monounsaturated], 15% protein and 55% carbohydrates consumed in combination with a juice 
beverage).  The standardized breakfast will be enriched with fructose to stimulate DNL and will be 
identical at Baseline (Week 0) and Week 12 assessments.  It will be a fixed meal and not calorie-adjusted 
for body weight.     
Blood samples will be drawn at 0, 2, 4, and 6 hours to assess the biological measures of interest.  At each 
timepoint, 14 mL of blood will be collected in spray-dried K2 EDTA vacutainers and immediately placed 
on ice.  Blood samples will be transported to the lab within 30 minutes, spun and the plasma aliquoted.  
At each blood collection timepoints, four (4) mL of plasma will be stored at 4◦C and transported to the 
Biomarker Core Laboratory, Atlanta VAMC (Dr. Ahn Le’s lab) on the same day for lipoprotein 
fractionation by density ultracentrifugation.  Two (2) plasma aliquots from each timepoint will be stored 
at -80 ◦C.   
 
Timepoint 
(hours)  
0 
2 
4 
6 
Total amount 
of blood per 
assessment 
K2 EDTA  
14 ml 
14 ml 
14 ml 
14 ml 
56 ml 
PK Sampling (Week 
12 only) 
3 ml 
3 ml 
3 ml 
3 ml 
12 ml 
 
 
 
 
14.1 PART 2: DE NOVO LIPOGENESIS 
 
Study Subjects: 
10 adolescents (as described above)  


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Study Design: 
 
Hepatic de novo lipogenesis will be measured in the fasting state (0 HR) 
and during the fructose enriched meal challenge (0, 2, 4 and 6 HRS) before 
Gemcabene treatment begins (Week 0) and after treatment is complete 
(Week 12). 
 
 
Sample Collection and 
Processing:  
(1) VLDL (Sf20-400) particles will be isolated from 1 mL of plasma at 
the Biomarker Core Laboratory, split in two equal VLDL aliquots 
(one primary and one back-up sample), frozen at -80 oC and 
shipped to Metabolic Solutions, Inc. for triglyceride isolation and 
deuterium enrichment of VLDL-TG palmitate by IRMS.   
 
(2) Plasma (250 µL) will be collected at 0, 2, 4 and 6 HRS and frozen at 
-20 oC for body water enrichment analyses (Metabolic Solutions, 
Inc.).  Spray-dried K2 EDTA vacutainers will be used to collect 
plasma for body water enrichment analyses. 
 
(3) VLDL-TG palmitate concentration 
 
Data Analysis: 
Deuterium enrichment in VLDL-TG palmitate and plasma water will be 
determined by IRMS.  Fractional DNL will be calculated from body water 
and VLDL-TG-palmitate deuterium enrichment using precursor-product 
relationships.  Absolute DNL will be calculated as Fractional DNL x VLDL-TG 
palmitate pool size. 
 
 
 
 
Endpoints: 
Primary Endpoint:  
• 
Fractional hepatic DNL in the fasting state (0 HR) and during 
meal stimulation (2 HR, 4 HR, 6 HR) 
 
Secondary Endpoint:  
• 
Absolute hepatic DNL in the fasting state (0 HR) and during 
meal stimulation (2 HR, 4 HR, 6 HR) 
 
 
 
 
14.2 PART 3: CHOLESTEROL SYNTHESIS 
 
Study Subjects: 
10 adolescents (as described above)  
Study Design: 
Cholesterol synthesis will be measured in the fasting state (0 HR) and 
during the meal challenge (6 HR) before Gemcabene treatment begins 
(Week 0) and after treatment is complete (Week 12). 


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Sample Collection and 
Processing:  
(1) Plasma (250µL) will be collected at 0, and 6 HRS and frozen at -20 
oC for deuterium enrichment analyses of free cholesterol 
(Metabolic Solutions, Inc.) by IRMS.   
(2) Plasma free cholesterol concentration 
Data Analysis: 
Deuterium enrichment in plasma free cholesterol and plasma water will be 
determined by IRMS.  The fraction of newly synthesized cholesterol (DNC) 
will be calculated from body water and cholesterol deuterium enrichment 
using precursor-product relationships.  Absolute cholesterol synthesis will 
be calculated as DNL (%) x plasma (free) cholesterol concentration. 
 
 
 
 
Endpoints: 
Primary Endpoint:  
• 
Fractional cholesterol synthesis in the fasting state (0 HR) and 
during meal stimulation (6 HR) 
 
Secondary Endpoint:  
• 
Absolute cholesterol synthesis in the fasting state (0 HR) and 
during meal stimulation (6 HR) 
 
Measurements for DNL and DNC endpoints: 
Measurement  
0 HR 
2 HR 
4 HR 
6 HR 
Deuterium enrichment in VLDL-TG palmitate (1 
mL of plasma to isolate VLDL-TG for IRMS 
analyses) 
X (in 
duplicate) 
x 
 x 
x  
Deuterium enrichment in plasma water (0.25 
mL of plasma for IRMS or Cavity Ringdown 
Spectrometer analyses) 
x 
x 
x 
x 
Deuterium enrichment in plasma free 
cholesterol  
(0.25 mL of plasma for IRMS analyses) 
x 
 
 
x 
VLDL-TG palmitate concentration 
(GCMS) 
x 
 
 
x 
Plasma free cholesterol concentration 
(Enzymatic Method) 
x 
 
 
x 
 
 
15 ADVERSE EVENT REPORTING 


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15.1 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
   
 
15.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Please refer to the main protocol. 
 
 
15.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
Please refer to the main protocol. 
 
 
15.1.3 ADVERSE EVENT REPORTING  
 
Please refer to the main protocol.   
 
 
15.1.4 SERIOUS ADVERSE EVENT REPORTING  
 
Please refer to the main protocol. 
 
 
16 STATISTICAL CONSIDERATIONS  
  
16.1 STATISTICAL ANALYSIS 
Data will be examined to identify missing data from one or more timepoints. Paired-sample t-tests will 
be conducted for comparison between Baseline and Week 12, and p-values will be considered as 
significance when < 0.05.  Missing data imputation methods will be used for the small number of missing 
data points (< 1%).   If there is a clear linear pattern, the mean of the previous and subsequent data 
points will be used.  If there is a lack of linear pattern over time, the average change plus the average 
mean of the outcome at its adjacent timepoints will be used to replace the missing data.  For lipid and 
glucose metabolism variables, comparisons of the 6-hour response will be made using the incremental 
area under the curve (IAUC) using the trapezoidal method and paired analysis comparing individual 
timepoints at Baseline (0 hour, fasting) and post-prandially.  Since the response variables will be 
measured repeatedly throughout the 6-hr period, the linear mixed model analysis will be utilized to 
compare the effects of the two different beverages, as well as the influence of sex.  Specifically, a 
random intercept model will be assumed for each individual to incorporate the within-subject 
correlation with those random effects representing the influence of the repeated observations from the 
same subject. 
APPENDIX B. PROMIS QUESTIONNAIRES 


Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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Protocol GEM-IIT-601                                                                                                                                                                        Version 4.0 
 
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