Clinical trial NCT02430077
Conditions: Familial Partial Lipodystrophy
Keywords: Hepatic Steatosis
Sponsor: Abhimanyu Garg
Start date: 2016-06-01; Completion date: 2022-12-01
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Lipodystrophies are rare disorders characterized by selective loss of adipose tissue and predisposition to insulin resistance and its metabolic complications. Hepatic steatosis is a common complication in patients with partial and generalized lipodystrophies.Despite aggressive management of diabetes and hyperlipidemia, hepatic steatosis and its complications present a therapeutic challenge in many patients. Due to this large disease burden, it is important to assess the efficacy and safety of novel therapies for hepatic steatosis in patients with lipodystrophies.There are, however, no systematic studies evaluating various therapeutic interventions for reducing hepatic steatosis in patients with lipodystrophies. A variety of drugs have been investigated in nonlipodystrophic patients with non-alcoholic hepatic steatosis and steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). Recent data support the activation of the farnesoid X receptor (FXR, NR1H4), a nuclear hormone receptor regulated by bile acids, for treatment of NASH and NAFLD. FXR activates transcription of several genes particularly the atypical nuclear receptor small heterodimer partner (SHP, NR0B2) and thus can influence triglyceride metabolism within hepatocytes.Both cholic acid (CA) and chenodeoxycholic acid (CDCA) are ligands for FXR, however, UDCA which is the 7 hydroxy β-epimer of CDCA, does not activate FXR. Obeticholic acid (OCA) is a first-in-class selective FXR agonist which has approximately 100 fold greater FXR-agonistic activity in the nanomolar range, as compared to CDCA .It therefore appears that FXR modulation offers interesting therapeutic possibilities in treating hepatic steatosis. This study is primarily designed to study efficacy of OCA, a strong FXR ligand, in reducing hepatic triglyceride levels in patients with hepatic steatosis and Familial Partial Lipodystrophy (FPLD). If proven to be effective, it may reduce morbidity and mortality as a result of sequelae of hepatic steatosis in patients with lipodystrophies.

Detailed description:
This study will be a randomized, placebo-controlled cross-over trial. Patients who are considered eligible for the study will undergo screening evaluation to determine their eligibility for the trial. For those who are found to be eligible, during the baseline period, they will continue their usual diet and other lifestyle measures without changing any medications for 1 month in order to establish a baseline state. Three blood samples will be obtained during this period at the Clinical and Translational Research Center. Following the baseline period, the patients will receive obeticholic acid (OCA) or an identical placebo in the dose of 25 mg/day for a period of 4 months and then will receive the other treatment (OCA or placebo) for 4 months. There will be a wash-out period of 4 months in-between the two study periods.

Patients will be educated to maintain their usual physical activities and diet during the study. The subjects will be admitted to the Clinical and Translational Research Center for the baseline evaluations (at the beginning of the two study periods), and at the end of four months during each study period.

Arms: arm 1: Patient will receive obeticholic acid (OCA) in the dose of 25 mg/day for a period of 4 months. arm 2: Patient will recieve placebo in the dose of 25 mg/day for a period of 4 months.
Interventions: intervention 1: Obeticholic Acid intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules of obeticholic acid (OCA) or an identical placebo in the dose of 25 mg/day for a period of 4 months . intervention 2: Identical to Obeticholic Acid - placebo drug

Protocol documents:
Prot_SAP_000.pdf: 
STUDY PROTOCOL & STATISTICAL ANALYSIS PLAN 
 
Official title: Phase 2 Study of Obeticholic Acid 
for Lipodystrophy patients. 
 
 
NCT number: NCT02430077  
IRB Approved date:08-02-2019 


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Title: Phase 2 Study of Obeticholic Acid for Lipodystrophy patients. 
Name of Principal Investigator: Dr. Abhimanyu Garg. 
Funding Sponsor: National Institutes of Health. 
IND number: 117441 
Version number: 1 
1. Introduction and Purpose:
Lipodystrophies are rare disorders characterized by selective loss of adipose tissue and predisposition to 
insulin resistance and its metabolic complications (1, 2).  Hepatic steatosis is a common complication in 
patients with partial and generalized lipodystrophies (1,3,4). Advanced cirrhosis resulting in portal 
hypertension, hepatic encephalopathy, and hepatocellular carcinoma resulting in death (4, 5) or requiring 
hepatic transplantation (6) have be reported in patients with lipodystrophies possibly due to long-standing 
hepatic steatosis. Despite aggressive management of diabetes and hyperlipidemia, hepatic steatosis and its 
complications present a therapeutic challenge in many patients. A recent report of hepatic pathology in 50 
patients with various types of lipodystrophies by Safar Zadeh et al. from the NIH, NIDDK (5), revealed mild to 
moderate perisinusoidal and periportal fibrosis (Fibrosis score 1A-1C) in 24%, periportal and perisinusoidal 
fibrosis (Score 2) in 20%, bridging fibrosis (Score 3) in 26% and cirrhosis (Score 4) in 16%. In some patients, 
especially those with generalized lipodystrophies, hepatic fibrosis and cirrhosis has been reported as early as 
during infancy (7) and early childhood (8, 9). In the NIH study (5), 9 out of 10 patients with congenital 
generalized lipodystrophy (CGL), type 2 (an autosomal recessive disorder), age 8-18 years, had bridging 
fibrosis or cirrhosis. These data point to the increased prevalence, early onset and severity of nonalcoholic 
hepatic steatosis and steatohepatitis and its complications in patients with lipodystrophies. Due to this large 
disease burden, it is important to assess the efficacy and safety of novel therapies for hepatic steatosis in 
patients with lipodystrophies. 
There are, however, no systematic studies evaluating various therapeutic interventions for reducing hepatic 
steatosis in patients with lipodystrophies. We and others reported efficacy and safety of recombinant leptin 
therapy in improving hepatic steatosis in severely hypoleptinemic patients with generalized lipodystrophies (5, 
10-16). Recently, metreleptin was approved by the FDA for treating metabolic complications in patients with 
generalized lipodystrophy. However, the reduction of liver volume or hepatic triglyceride (TG) concentrations in 
response to metreleptin therapy in hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan 
variety (FPLD), an autosomal dominant disorder due to heterozygous missense mutations in lamin A/C 
(LMNA) gene,  has been variable (17, 18). Furthermore, many patients with FPLD are not hypoleptinemic and 
some may even have normal or high serum leptin levels (see preliminary data). Therefore, there remains a 
need to develop other therapies for treatment of hepatic steatosis especially for patients with FPLD, many of 
whom are also predisposed to develop hepatic fibrosis (5).
A variety of drugs have been investigated in nonlipodystrophic patients with non-alcoholic hepatic steatosis 
and steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). Most of these patients have obesity 
and/or type 2 diabetes as a concomitant condition. Previously, ursodeoxycholic acid (UDCA) (19-25), insulin 
sensitizers (metformin and thiazolidinediones) (26-30), fibrates (gemfibrozil and fenofibrate) (20, 31), vitamin E 
(30, 32), betaine (33), and probucol (34) have been tried in studies in non-lipodystrophic subjects with NASH or 
NAFLD. The trials with fibrates have reported inconsistent results in patients with NAFLD (20, 31). As 
compared to other agents, UDCA has been studied more extensively (19-25). However, a large multicenter 
trial showed that UDCA is not effective in reducing hepatic steatosis (35). Thus far, only vitamin E has been 
shown to improve histology in patients with hepatic steatosis (30). However, these results have not yet been 
replicated and concerns related to an increase in mortality with vitamin E (36) have limited its use. 
Recent data support the activation of the farnesoid X receptor (FXR, NR1H4), a nuclear hormone 
receptor regulated by bile acids, for treatment of NASH and NAFLD (37).  FXR activates transcription of 
several genes particularly the atypical nuclear receptor small heterodimer partner (SHP, NR0B2) and thus can 
influence triglyceride metabolism within hepatocytes (38). FXR-deficient mice exhibit a hepatic phenotype 
similar to NASH patients with significant hepatic TG accumulation, hepatic inflammation and injury and 
development of hepatocellular carcinoma (39, 40).  
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Both cholic acid (CA) and chenodeoxycholic acid (CDCA) are ligands for FXR, however, UDCA which is 
the 7 hydroxy β-epimer of CDCA, does not activate FXR (38, 41). Obeticholic acid (OCA) is a first-in-class 
selective FXR agonist which has approximately 100 fold greater FXR-agonistic activity in the nanomolar range, 
as compared to CDCA (42, 43).  Interestingly, a recent study showed that giving 0.5% CA for 3 weeks reduced 
hepatic triglyceride content by over 50% in KK-Ay mice (a model for diet- induced hypertriglyceridemia) fed 
chow or high fat diet  (44). Furthermore, WAY-362450, another potent, selective and orally active synthetic 
FXR agonist has been shown to protect against NASH in mice fed a methionine and choline deficient diet (45). 
This hepatoprotection by WAY-362450 is abolished in FXR-deficient mice, demonstrating the requirement for 
functional FXR (45).  
In apolipoprotein E-deficient mice, OCA resulted in reduced expression of SREBP1c, the master 
transcription factor that regulates TG synthesis, and reduced hepatic TG and cholesterol content and 
ameliorated hyperlipidemia (46). OCA treatment further reversed insulin resistance and NAFLD in Zucker fa/fa 
rats (47). FXR activation alters the hepatic expression of many genes involved in lipid metabolism. While 
ApoC-I, ApoC-II, Apo-CIV, ApoE, FAS, PPARα are upregulated; ANGPTL3, ApoA-1, ApoC-III, SREBP-1c are 
downregulated.  Increased expression of ApoC-II, a lipoprotein lipase (LPL) activator (48), and reduced 
expression of angiopoietin-like protein 3 (ANGPTL3) which inhibits LPL activity (44), may increase LPL activity 
upon FXR activation. All these changes may lead to reduction of hepatic and serum TG upon FXR activation.  
In a double-blind, placebo-controlled trial in 64 subjects with Type 2 diabetes and NAFLD, OCA 25 or 50 
mg once daily for 6 wk, significantly improved peripheral glucose disposal rates in euglycemic, glucose clamp 
study as well as alanine aminotransferase and gamma glutamyl transpeptidase levels (49). However, hepatic 
insulin sensitivity or steatosis was not directly assessed in this trial.  
 Preliminary data from the Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis 
Treatment (FLINT) trial reveal that OCA significantly improved nonalcoholic steatohepatitis as determined by 
liver 
biopsy 
in 
patients 
with 
NAFLD 
and 
the 
trial 
has 
been 
halted 
in 
January 
2014 
(http://www.interceptpharma.com/nash.php). Even though patients with lipodystrophies were not excluded from 
the FLINT trial, the likelihood of including enough lipodystrophy patients among 283 participants to provide 
informative data is very small given the estimated population prevalence of lipodystrophies to be < 1 in a 
million (1, 2). In a similar trial, Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic 
patients with non-alcoholic steatohepatitis (PIVENS), 247 patients with NASH with a mean ± SD triceps 
skinfold thickness of 33 ± 13 mm and body fat of 39 ± 9% were recruited. In comparison, our adult patients with 
FPLD have triceps skinfold thickness of 5.8 ± 2.1 mm (n=59) and body fat of 21.5 ± 5.3% (n=44). Patients with 
generalized lipodystrophy have much lower body fat than those with FPLD. Thus, there is extremely low 
likelihood of including lipodystrophy patients in trials of patients with NASH/NAFLD, who are usually obese. 
Furthermore, there is high likelihood of missing the diagnosis of lipodystrophy, if the investigators were not 
asked to specifically ascertain it.  
It therefore appears that FXR modulation offers interesting therapeutic possibilities in treating hepatic 
steatosis (37). This study is primarily designed to study efficacy of OCA, a strong FXR ligand, in reducing 
hepatic triglyceride levels in patients with hepatic steatosis and FPLD. If proven to be effective, it may reduce 
morbidity and mortality as a result of sequelae of hepatic steatosis in patients with lipodystrophies.  
2. Background:
This study is aimed at developing a novel intervention for therapy of severe hepatic steatosis in patients 
with FPLD. The intervention, OCA, is a strong FXR activator and there is emerging evidence of the role of FXR 
agonists in improving hepatic steatosis from the data obtained in experimental animals and in obese patients 
with NASH or NAFLD. Thus, this will be the first proof-of-concept study to ascertain the role of OCA in 
improving hepatic steatosis in patients with FPLD. We will use the state of the art technology of measuring 
hepatic fat content by proton magnetic resonance spectroscopy. We will also measure plasma FGF19 levels 
as marker of FXR activation and assess hepatic insulin sensitivity using the robust two-step, euglycemic, 
hyperinsulinemic glucose clamp technique along with infusion of stable isotope of glucose for measuring 
glucose turnover.  
We are aware of the preliminary data from the FLINT trial of OCA for NASH treatment. However, the 
mechanisms of hepatic steatosis in patients with lipodystrophies are quite different than those in obese 
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patients with NASH who usually have high circulating levels of free fatty acids and marked upregulation of 
sterol regulatory element binding protein-1c (SREBP-1c) along with increased de novo lipogenesis (50, 51). On 
the other hand, in a mouse model of CGL, type 1 due to Agpat2 deficiency, Mgat1 was markedly upregulated in 
the steatotic liver indicating that hepatic triglyceride synthesis was occurring through an alternative pathway; and a 
marked increase in hepatic de novo lipogenesis occurred without any upregulation of SREBP-1c (52). Similar 
observations were made in the steatotic livers of CGL, type 2 mice with seipin ablation where the expression of 
SREBP1c did not change despite increased expression of lipogenic genes such as fatty acid synthase (53). 
Furthermore, in both the models of CGL, serum levels of free fatty acids were not elevated or were in fact 
lower than those in the wild type mice (52-54). The transgenic mouse model of FPLD overexpressing the 
human p.R482Q LMNA mutation also develops hepatic steatosis without any increase in basal lipolysis (55). 
However, the investigators did not study the molecular changes underlying hepatic steatosis in the FPLD 
mouse model.  
Preliminary Studies: The PI has been involved in studying fatty liver disease in patients with lipodystrophies 
for many years. For the last few years, we have been evaluating patients with various types of lipodystrophy to 
characterize their physical and biochemical features. We have noted hepatomegaly and abnormal liver function 
tests in many of these patients and have also performed 1H Magnetic Resonance Spectroscopy in some of 
them to measure intrahepatic lipid content. Data from some representative adult patients with FPLD are shown 
in Fig. 1.   Hepatic fat content ranged from 0.5-61%.  Although traditionally, hepatic steatosis is defined as 
hepatic triglyceride content exceeding 5.0%, studies by Drs. Szczepaniak and Browning (co-investigator) in a 
large population based sample found the 95th percentile of hepatic triglyceride concentration in 345 subjects 
from the Dallas Heart Study without any risk factors for hepatic steatosis 
was 5.56% (56). Even considering a higher cut-off value (>5.6%) to define 
hepatic steatosis, it appears that 74% of the FPLD patients had hepatic 
steatosis. Thus, these data reveal high prevalence of hepatic steatosis in 
patients with FPLD (1, 57). 
Fig. 1 Hepatic triglyceride content in adult patients with FPLD. Each symbol represents 
data from one patient. The interrupted line represents 5.6% liver fat. Thus, both males and 
females have increased prevalence of hepatic steatosis.  
Fig. 2 Reduction of hepatic triglyceride concentrations measured using 
proton MRS in severely hypoleptinemic (serum leptin < 4 ng/mL) and 
moderately hypoleptinemic (serum leptin 4-7 ng/mL) female patients 
with FPLD in response to leptin therapy.  
We have also reported marked reduction in hepatic triglyceride content with recombinant leptin therapy in 
patients with generalized lipodystrophy and severe hypoleptinemia (10, 11). In an open-label trial of human 
recombinant leptin in three patients with generalized lipodystrophy, 8 – 10 months of therapy resulted in a 
STU062014-033, Garg, Form A, Mod_8, 08-02-19
Protocol version number 1, 08042014 
Female
Hepatic triglyceride content (%)
0
10
20
30
40
50
60
70
Male


Page 4 of 24 
STU062014-033, Garg, Form A, Mod_8, 08-02-19
Protocol version number 1, 08042014 
mean decline in intrahepatic lipid content by about 80% (11). Compared to baseline, the intrahepatic lipid 
content decreased in the three patients from 14.9% to 1.2%, 5.7% to 2.2% and 11.1% to 1.5%, respectively.  
In another recent study from our group (18) in 24 women with FPLD, although overall, metreleptin 
replacement therapy resulted in significant lowering of hepatic TG levels from a median baseline value of 
10.2% to 5.9% - 8.2%, after 3 months and 6 months, respectively (p<0.0001).  However, the response was 
quite heterogeneous and especially many female patients with moderate hypoleptinemia (serum leptin 4-7 
ng/mL) did not respond to metreleptin (Fig. 2). Due to heterogeneity of response to metreleptin in our study as 
well as in previous studies (17), FDA did not approve this therapy for partial lipodystrophies. Furthermore, 
many FPLD patients do not have severe hypoleptinemia (serum leptin <4 ng/mL in females and <1.5 ng/mL in 
males), which can justify leptin replacement therapy (Fig. 3). In fact, their serum leptin levels may be normal or 
even high.  
Figure 3: Serum leptin concentrations in patients with FPLD. The horizontal red line 
indicates serum leptin concentrations of 4 ng/mL in females, and 1.5 ng/mL in males, 
which correspond to 7th percentile of population. As shown, many FPLD patients have 
normal or even high levels of serum leptin. These normoleptinemic FPLD are not 
candidates for leptin replacement therapy.  
Most recently, we evaluated the efficacy and safety of cholic acid 
for reducing hepatic steatosis in patients with lipodystrophies using a 
randomized, 
double-blind, 
placebo-controlled, 
crossover 
design. 
Eighteen patients with genetic or autoimmune lipodystrophies, and 
elevated hepatic TG content participated. Cholic acid (15 mg/kg/day) 
was compared with placebo for a period of 6 months each. Compared 
to placebo, cholic acid did not reduce hepatic TG content [median 
(interquartile range) 14.8% (9.4-19.0%) vs. 15.9% (10.5-26.5%), 
respectively; p = 0.42] (Fig. 4). Cholic acid therapy also did not change 
AST, ALT or GGT levels. Two patients developed diarrhea and excessive flatus while taking CA and these 
symptoms resolved after reducing the dose of cholic acid. It is likely that failure to reduce hepatic TG content 
with cholic acid may be due to relatively weak agonistic activity of cholic acid for FXR. Therefore, in the current 
protocol, we want to study more potent FXR agonist, obeticholic acid, which is ~100 times more potent than 
CDCA.  OCA may prove to be efficacious in treating hepatic 
steatosis.  
Fig.  4 Hepatic triglyceride content during the cholic acid study. 
Connected open circles represent the 12 subjects who completed both 
the six month study periods. For three subjects with incomplete data, 
filled symbols represent subjects with placebo data only; inverted 
triangles represent 3 month data. Median values for each phase are 
shown as horizontal bars. 


Page 5 of 24 
3. Concise Summary of Project:
This study will be a randomized, double-blind, placebo-controlled, cross-over trial (Fig. 5). Patients who are
considered eligible for the study will undergo screening evaluation to determine their eligibility for the trial. For
those who are found to be eligible, during the baseline period, they will continue their usual diet and other
lifestyle measures without changing any medications for 1 month in order to establish a baseline state. Three
blood samples will be obtained during this period at the Clinical and Translational Research Center. Following
the baseline period, the patients will receive obeticholic acid (OCA) or an identical placebo in the dose of 25
mg/day for a period of 4 months and then will receive the other treatment (OCA or placebo) for 4 months.
There will be a wash-out period of 4 months in-between the two study periods. The dose of OCA is chosen
based upon several considerations: a. In a previous study of patients with type 2 diabetes mellitus and hepatic
steatosis, this dose resulted in significant improvement in insulin-mediated glucose disposal and reduction in
ALT and GGT (49). b. This dose is generally well-tolerated with negligible side effects. If there are intolerable
side effects which are considered probably or possibly related to OCA/placebo, the dose of OCA/placebo will
be reduced to 25 mg every other day. If the side effects persist despite reduction of the dose, the medication
will be stopped but the subject will continue to participate and complete the trial (as per intent to treat protocol).
Fig. 5 : Study design and time points 
for determination of variables. Wash 
out period will be for 4 months. 
Patients will be educated to maintain their usual physical activities and diet during the study. The subjects 
will be admitted to the Clinical and Translational Research Center for the baseline evaluations (at the 
beginning of the two study periods), and at the end of four months during each study period.  In some subjects, 
unable to visit CTRC at the end of 2 months, we will provide kits to them for mailing the blood and urine 
samples using courier service.  We have done such collections successfully in our previous trials of leptin 
therapy in patients with lipodystrophies.  
Justification for the choice of design: 
We considered both the randomized, parallel design and the 
cross-over design.  In view of the rare prevalence of FPLD, we decided to use the cross-over design. This 
allows us to achieve more power with fewer patients compared to the parallel design. We do not expect carry 
over effects of OCA on hepatic triglyceride levels given that there will be a four month wash-out period 
between the two study periods and an additional 4 month time before determining the end point variable during 
the second study period. We will attempt to keep the drop-outs to as minimum as possible to achieve 
maximum out of this design. Our choice of study design was guided by Lagakos’s editorial entitled, “Clinical 
Trials and Rare Diseases” (58). 
Primary and Secondary Endpoint Variables: The primary end-point variable will be the reduction in the liver 
TG content on 1H MRS. Reductions in the levels of serum alanine and aspartate aminotransferases, gamma-
glutamyl transpeptidase, triglycerides, insulin and suppression of hepatic glucose output during the low-dose 
and high-dose insulin infusions during the euglycemic clamp study (measure of hepatic insulin sensitivity) will 
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be the secondary end-points of the study. Complete blood counts and serum chemistries will be performed for 
safety considerations. As an evidence of FXR activation, fasting serum FGF19 levels will be measured. We will 
also measure liver size using magnetic resonance imaging. These additional tests will be performed at 
baseline and after 2 and 4 months of therapy.   
Lundasen et al. (59) reported 250% increase in serum FGF19 levels after 2-3 wk of feeding 15 mg/kg/d of 
chenodeoxycholic acid, an FXR ligand. Meyer-Gerspach et al. (60) have further shown a dose dependent 
increase in plasma FGF19 levels 60 min after intraduodenal infusion of chenodeoxycholic acid.  Recently, 
Mudaliar et al. (49) reported  marked 92% and 223% increase in plasma FGF19 levels with 25 mg and 50 mg 
of OCA administration, respectively; compared to only 8% increase with placebo (Fig. 6). Thus, there is strong 
evidence supporting the use of plasma FGF19 levels as markers of FXR activation.  
Fig. 6  Increased plasma FGF19 levels in patients with diabetes and NAFLD after treatment 
with OCA. Data are presented as mean ± SEM. **P < .01, ***P < .001. Statistical 
significance is based on comparisons of absolute change from baseline between the OCA 
treatment groups and placebo. From Mudaliar et al. (49) 
Patients:  
We are currently following a large number of patients with FPLD harboring heterozygous missense LMNA 
mutations including 128 affected adult women and 40 affected adult men. Of these, 50 women and 30 men are 
nondiabetic and the diabetes status of 20 FPLD patients was unclear. We will inform the eligible subjects of the 
availability of the study and from amongst these patients, a total of 20 patients who satisfy the following 
inclusion and exclusion criteria will be enrolled. They will be instructed not to change their medications during 
the study without consulting the investigators.  
Based on analysis of our database of FPLD patients with LMNA mutations, diabetes as an exclusion criteria 
posed a challenge since >50% of female FPLD patients have diabetes. Therefore, we have revised our 
exclusion criteria and will consider enrolling patients with diet-controlled diabetes or those on metformin . We 
will also enroll FPL patients with  disease-causing variants in PPARG and other FPL genes.  We are in the 
process of identifying additional potential subjects from our large Lipodystrophy database who will be willing to 
take part in the study.  We have identified 55 females and 35 males with LMNA variants and 4 females with 
PPARG variants with FPLD who may be eligible to take part in the study.  
4. Study Procedures:
Demographic Characteristics, Health History, and Physical Examination: 
The participants will be asked to complete questionnaires on demographic characteristics and health history at 
baseline. A detailed history will be obtained and physical examination will be conducted on each subject during 
the baseline period and during the last week of each study period. During these periods, they will also be 
asked to complete a 3-day food record and questionnaires to assess quality of life and drug side effects (see 
appendix). Height and body mass will be measured by standard procedures. 
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1H Magnetic Resonance Spectroscopy (MRS):  
1H MRS studies will be performed at least 4 hours post 
prandially with the patients lying prone as described previously (61). Briefly, image-guided, proton-localized, 
MRS and high resolution T1-weighted imaging will be performed on a 1.5 T Gyroscan Intera whole body 
system (Philips Medical Systems, Best, The Netherlands) with the following parameters: repetition time (TR) of 
5 s, spin echo time (TE) of 25 ms for liver, and 1024 data points over 1000 kHz spectral width. Volumes of 
interest (voxel) will be centered on the right lobe of the liver (30 mm3) taking care to avoid vascular structures. 
Spectra will be processed and resonances quantified using a standard analysis package (NUTS; ACORNNMR, 
Fremont, CA). The hepatic TG concentration will be expressed as percentage of the intensity of the water 
resonance peak (61) (Fig. 7).  
 Fig. 7 1H MR spectra of the abdomen of a human subject with steatosis. Voxel was 
sequentially placed over subcutaneous juxtahepatic fat (A), liver (B), or both (C). 
Chemical shifts were measured relative to tissue water at 4.80 ppm. Note that a 
single methylene peak originates from adipose fat and is located at 1.6 ppm, 
whereas the intracellular fat within liver appears at 1.4 ppm. From Szczepaniak et al. 
(61).  
Liver size:  Prior to performing the 1H MRS, sagittal, coronal and axial slices are obtained routinely through the 
liver to select a spectroscopic volume of interest avoiding major blood vessels, intrahepatic bile ducts and 
lateral margin of the liver. We will use the axial slices obtained on T-1 weighted images of 10 mm thickness 
with a 10 mm gap in-between. The volume of the liver at each slice will be mapped manually using a track ball 
on the computer screen and summed up for each slice and in-between gap to determine the liver volume. We 
have previously used similar program to measure subcutaneous and intra-abdominal adipose tissue volume 
(62, 63). 
Serum chemistry, lipoproteins, insulin, and FGF19:  
Blood will be obtained after overnight (12 h) fast 
daily for chemistry profile (SMA-25), lipoprotein, insulin and FGF19 levels while the patients are admitted to the 
CTRC. Plasma insulin concentrations will be determined by radioimmunoassay using kits (Millipore, Billerica, 
MA). Plasma FGF19 levels will be measured by an ELISA kit (Phoenix Pharmaceuticals Inc., Burlingame, CA). 
Serum chemistry profile including the aminotransferases, gamma-glutamyl transpeptidase, lipids and 
lipoproteins, glucose and electrolytes etc. will be measured by a commercial laboratory (Quest Diagnostics).  
Three-Day Food Record: 
Dietary intake will be assessed by 3-day food record (two weekdays and one 
weekend day), a valid and reliable method (64). The measure will be taken at baseline and each of the follow-
up visits. The participants will be instructed on how to record in detail all the food and drink consumed in the 3-
day food record booklet provided. The booklet will be available in both English and Spanish (see Appendix). 
The participants will also be provided a two-dimensional visual chart of food portions to aid them in estimating 
portion sizes. Any questionable input or incomplete food entries recorded will be promptly addressed when the 
subjects return their food records. The food records will be analyzed for nutrient content using the University of 
Minnesota Nutrient Data System (NDS) for research. The NDS database contains more than 18,000 foods, 
8,000 brand name products, and many ethnic foods. The database is continuously updated to reflect newly 
published or provisional data provided by the United States Department of Agriculture, new analytic data from 
the scientific literature, and current food composition data for new and reformulated commercial products. The 
database is also put through rigorous quality control (65). The NDS has the capability of calculating daily 
totals 
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and amounts by food groups for 120 nutrients and nutrient ratios. It can also calculate gram weight for 
individual foods. 
Oral Glucose Tolerance Test (OGTT):  A 3 hour OGTT will be performed after 10-12 h overnight fast. An 
intravenous line will be placed for blood drawing. On the day of fasting, patient will have a fasting venous 
blood sample collected and then will be Instructed to drink the glucose solution (75 g of glucose in 200 ml of 
water)  over a maximum of 15 minutes (ideally within 5 minutes).  Time will be noted. Blood tests will be done 
at half-hour intervals for three hours to check patient’s glucose and insulin response. A total of 45 ml blood or 
3 tablespoons (for adults) will be withdrawn during this test. For oral glucose tolerance tests, the volumes are 
adjusted for weight, and the sample frequency and duration are decreased.  
Mutational Analysis of LMNA gene: To confirm the diagnosis of FPLD, direct sequencing of the entire coding 
region and the surrounding intron-exon boundaries of the LMNA gene will be conducted in the probands from 
each pedigree followed by sequencing of the disease-causing variant in the rest of the family members. 
Primers that amplify each exon of LMNA from genomic DNA templates have been designed from published 
sequence information (69).  
Monitoring of potential side effects:   Biochemical testing and routine urinalysis will be done every 6 weeks, 
during the periods when patients are on study drug or placebo. Telephone contact will be initiated with subjects 
every 2 weeks to assess for symptoms such as new or worsening pruritus, abdominal pain, new or worsening 
fatigue, anorexia, nausea, rash, vomiting, diarrhea, jaundice (yellow skin or sclera, high amber colored urine 
and pale stools) and vague neuropsychiatric symptoms. For patients outside of Dallas, blood tests will be 
arranged every 6 weeks and if there are any abnormalities, they will be asked to either visit us in person (for 
those living in the Dallas area) or see their primary care physician for physical examination (for those from 
outside Dallas).  We will communicate with their physicians about the lab data and physical examination 
findings.  
Drug will be discontinued in subjects immediately who develop liver decompensation events (e.g., variceal 
bleed, hepatic encephalopathy, ascites, etc.) and will not restart the drug even if the events are resolved. 
Patients will be asked to report following symptoms as it will trigger immediate evaluation of the patient for 
hepatic toxicity: new or worsening pruritus, abdominal pain, new or worsening fatigue, anorexia, nausea, rash, 
vomiting or diarrhea. Even vague neuropsychiatric symptoms have been associated with acute liver failure. If 
prompt evaluation is not possible, the investigational drug will be immediately discontinued. 
Patients will be asked to withhold drug during intercurrent illness, such as gastroenteritis resulting in 
dehydration, or other reasons for dehydration, and that patients should be reevaluated with both biochemical 
testing and physical exam prior to restarting the drug. 
Physical exam and liver biochemistries including ALT, AST, total bilirubin, and ALP will be performed at each 
clinic visit and at any unscheduled visit triggered by patients reporting symptoms. If elevations in ALT, AST, 
total bilirubin (TB), and ALP levels trigger reevaluation, then platelet count, INR, albumin, direct bilirubin, 
electrolytes and creatinine will be included in repeat testing. 
We will use the same Liver Laboratory Criteria for Monitoring of Suspected Hepatic Injury or Decompensation 
as submitted recently by Intercept Pharmaceuticals (Table 1) (Protocol 747-303 Safety Amendment). 
Table 1: Liver Laboratory Criteria for Monitoring for Suspected Hepatic Injury or Decompensation 
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Protocol version number 1, 08042014 
Criteria Resulting in Immediate Interruption of Investigational Product Upon First 
Observation 
Baseline 
Upper Laboratory Threshold 
Frequency of Monitoring 
(Repeat Testing) 
Conj. bilirubin ≤ULN 
≥1.5x ULN 
Not applicable 
If Total Bili rise >=0.5 mg/dL, 
reassess conjugated if >ULN 
Creatinine 
>ULN AND increase by 20%
Criteria Resulting in Repeat Testing 
Baseline 
Upper Laboratory Threshold 
Frequency of Monitoring 
(Repeat Testing) 
Key Liver Parameters for Hepatic Injury 
ALT ≤ULN 
≥3x ULN 
2-3 days
ALT >ULN and 
<2x ULN 
≥3x baseline or incremental 
increase from baseline >250 
U/L 
2-3 days
ALT ≥ 2x ULN 
≥2x baseline or incremental 
increase from baseline >250 
U/L 
AST ≤ULN 
≥3x ULN 
2-3 days
AST >ULN and 
<2x ULN 
≥3x baseline or incremental 
increase from baseline >250 
U/L 
2-3 days
AST ≥ 2x ULN 
≥2x baseline or incremental 
increase from baseline >250 
U/L 
ALP ≤ULN 
≥1.5x ULN 
7 days 
ALP >ULN 
≥1.5x baseline 
7 days 
Total bilirubin 
≤ULNa 
≥1.5x baseline AND >ULN 
2-3 days
Total bilirubin 
>ULNa
≥1.5x baseline 
2-3 days
INR≤ULNb 
≥30% increase from baseline 
2-3 days
INR>ULNb 
>1.5 AND ≥10% increase from
baseline 
2-3 days
GGT ≤ULN 
≥3x ULN 
2-3 days
GGT >ULN 
≥3x baseline 
2-3 days
Other Parameters Reflective of Overall Hepatic Health 
Albumin 
<3.2 g/dL 
2-3 days
Platelets 
<100x103/mm3 AND ≥10% 
decrease from baseline 
2-3 days
Electrolytesc 
Sodium <130 
2-3 days


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a Diagnosis of Gilbert’s Syndrome should be established during baseline. Conjugated bilirubin to be sole 
determinant in such subjects. 
b Does not apply in subjects on anti-coagulants 
c Sodium will be measured as an assessment of liver failure (hyponatremia). 
Study Medication – Obeticholic Acid 
The chemical name of OCA is 3α,7α-dihydroxy-6α-ethyl-5βcholan-24-oic acid. It is also referred to as 6α-
ethylchenodeoxycholic acid, or 6-ECDCA. The international nonproprietary name (INN) is obeticholic acid. The 
structure of this molecule is provided in Figure 9.  
  Fig. 9 Chemical structure of obeticholic acid 
The drug and placebo will be made available by Intercept Pharmaceuticals, San 
Diego, CA (see letter of support).  An IND (number 63,307) has been filed by 
Intercept Pharmaceuticals and our IND will cross reference to this IND.   
Non Clinical Studies:  OCA has been evaluated in a variety of animal models of acute and chronic liver injury. 
The preclinical results demonstrate that OCA has broad hepatoprotective effects including: 
• Regulation of bile synthesis and flow to improve cholestasis
• Inhibition of hepatic and systemic inflammatory responses
• Action as a potent antifibrotic agent to prevent and reverse fibrosis
• Ability to reverse cirrhosis and portal hypertension
Such hepatoprotective effects are largely attributable to FXR activation, which is not seen with UDCA. In 
addition, other preclinical metabolic data demonstrate that OCA has the capacity to normalize fasting glycemia 
and insulin sensitivity in a rabbit model of metabolic syndrome. Studies in FXR knockout mice show that FXR 
is involved in the regulation of insulin signaling pathways and appears to have a beneficial role in decreasing 
insulin resistance (IR) and gluconeogenesis, as well as in regulating triglyceride, free fatty acid, and lipid levels 
(40, 70). This adds to the rationale for clinical testing of OCA in subjects with chronic liver disease where IR is 
a major risk factor for progression to cirrhosis; e.g., nonalcoholic fatty liver disease (NAFLD) and its more 
clinically significant subtype nonalcoholic steatohepatitis (NASH) (37).  
Studies in cell-free assays, primary cultures of human and mouse hepatocytes, and human hepatocyte cell 
lines have established that OCA is a potent FXR agonist with an EC50 of 85 to 100 nM, approximately 100-fold 
more potent than the endogenous FXR agonist CDCA it is derived from (42, 43). Importantly, glyco- and tauro-
conjugated OCA are as potent and selective FXR agonists as free OCA. OCA is highly selective for FXR. The 
compound does not bind other nuclear receptors and, with the exception of weakly activating the dedicated bile 
acid receptor TGR5 (EC50 = 20 μM), it does not activate any G-protein coupled receptors (GPCRs) screened 
(Investigator Brochure 2012). In addition, OCA does not block the human ether-à-go-go-related gene (hERG) 
potassium channel (Investigator Brochure 2012).  
Nonclinical safety: Pharmacology studies have evaluated the neuropharmacologic, pulmonary, and 
gastrointestinal (GI) effects of OCA in rats. These studies showed no adverse effects due to OCA. OCA has 
also been evaluated for cardiovascular in vitro and in vivo effects. There were no clinically relevant effects 
reported on human ether-à-go-go related gene (hERG) channels. There were no cardiovascular effects 
observed in a dog in vivo study. Clinical trials have, to date, not shown any effects on cardiac conduction and, 
in particular, QTc prolongation effects.  
Nonclinical toxicology studies: Administration of OCA to mice, rats, and dogs in toxicology studies as single 
doses and with daily dosing for up to 6 and 9 months, respectively, resulted primarily in adverse effects on the 
liver and GI tract. Bile acids are detergents which explain their well-recognized emulsificant properties in 
the 
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gut. In general, the toxicology findings with CDCA-derived OCA are consistent with tissue (primarily hepatic) 
exposure to detergents at high concentrations.  
OCA was not genotoxic in a battery of 3 genotoxicity studies. The drug demonstrated no embryo-fetal 
toxicity in rats and rabbits, nor adverse effects on either fertility in male or female rats, or early embryonic 
development to implantation in female rats.  
Currently, rodent carcinogenicity studies are ongoing; the in-life portion of these studies will be completed 
soon. Genotoxicity studies are also ongoing with the OCA taurine and glycine conjugates. In addition, a pre- 
and post-natal developmental toxicity study in rats is planned to complete the nonclinical safety testing with 
OCA.  
Pharmacology: PK profiles for OCA and its metabolites (glyco-6-ECDCA and tauro 6-ECDCA) have been 
evaluated in 2 phase 1 healthy volunteer clinical trials following single doses of 50 to 500 mg and repeated 
dosing of 25 to 250 mg for up to 12 consecutive days. The glyco-6-ECDCA and tauro-6-ECDCA metabolites of 
OCA are known to be pharmacologically active, and due to the likelihood of enterohepatic recycling and 
reconversion to OCA, their plasma PK profiles were of interest.  
Overall, the PK of OCA shows the profile expected of a bile acid. There is rapid absorption, followed by 
extensive metabolism to the glyco- and tauro-conjugates. These occur at significantly higher concentrations 
than the parent drug. There are numerous peak and trough plasma levels seen consistent with the expected 
extensive enterohepatic circulation of a bile acid. Plasma concentrations dramatically increase shortly after 
food intake, consistent with gall bladder emptying into the duodenum, as expected.  
Pharmacokinetics: Following oral administration, OCA appeared to be rapidly absorbed with the first 
measurable plasma OCA concentration occurring at 0.25 to 0.5 hour post dose at the 2 higher dose levels. The 
initial peak plasma OCA concentrations occurred, on average, around 2 hours post dose. OCA was rapidly 
eliminated from plasma, and was generally not measurable by about 6 hours after administration of the 2 
higher doses. Plasma t1/2 of OCA ranged from approximately 1 to 2 hours at the higher dose levels where it 
could be measured. 
OCA has been administered to healthy volunteers in 2 phase 1 trials: a single dose trial (747-101) and a 
trial involving daily dosing for 12 days (747-102). Both trials demonstrated that OCA is rapidly absorbed, 
extensively metabolized via conjugation to 6-glyco-ECDCA and 6-tauro-ECDCA, and eliminated presumably in 
feces. The plasma profiles of both OCA and its conjugated metabolites (glyco-6-ECDCA and tauro-6-ECDCA) 
demonstrated multiple peaking in the elimination phase (consistent with extensive enterohepatic recirculation). 
Plasma concentrations of glyco-6-ECDCA and tauro-6-ECDCA were considerably higher than the parent drug 
(OCA) following administration of repeat doses.  
The overall low urinary recovery for OCA in its parent and conjugated forms, as well as the plasma profiles 
of OCA and its conjugates, suggests that there is biliary excretion coupled with extensive enterohepatic 
recirculation that eventually leads to fecal elimination.  
OCA and its glyco- and tauro-conjugates achieve an apparent steady-state concentration after 
approximately 1 week of once daily dosing. There is only mild accumulation of OCA in plasma following repeat 
doses and plasma concentrations of the parent drug increase in a dose proportionate manner over the dose 
range of 25 to 250 mg. There is significant accumulation of glyco-6-ECDCA and tauro-6-ECDCA 
concentrations in plasma following repeat dosing for 12 days.  
Pharmacokinetics: Following oral administration, OCA appeared to be rapidly absorbed with the first 
measurable plasma OCA concentration occurring at 0.25 to 0.5 hour post dose at the 2 higher dose levels. The 
initial peak plasma OCA concentrations occurred, on average, around 2 hours post dose. OCA was rapidly 
eliminated from plasma, and was generally not measurable by about 6 hours after administration of the 2 
higher doses. Plasma t1/2 of OCA ranged from approximately 1 to 2 hours at the higher dose levels where it 
could be measured. 
OCA has been administered to healthy volunteers in 2 phase 1 trials: a single dose trial (747-101) and a 
trial involving daily dosing for 12 days (747-102). Both trials demonstrated that OCA is rapidly absorbed, 
extensively metabolized via conjugation to 6-glyco-ECDCA and 6-tauro-ECDCA, and eliminated presumably in 
feces. The plasma profiles of both OCA and its conjugated metabolites (glyco-6-ECDCA and tauro-6-ECDCA) 
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demonstrated multiple peaking in the elimination phase (consistent with extensive enterohepatic recirculation). 
Plasma concentrations of glyco-6-ECDCA and tauro-6-ECDCA were considerably higher than the parent drug 
(OCA) following administration of repeat doses.  
The overall low urinary recovery for OCA in its parent and conjugated forms, as well as the plasma profiles 
of OCA and its conjugates, suggests that there is biliary excretion coupled with extensive enterohepatic 
recirculation that eventually leads to fecal elimination.  
OCA and its glyco- and tauro-conjugates achieve an apparent steady-state concentration after 
approximately 1 week of once daily dosing. There is only mild accumulation of OCA in plasma following repeat 
doses and plasma concentrations of the parent drug increase in a dose proportionate manner over the dose 
range of 25 to 250 mg. There is significant accumulation of glyco-6-ECDCA and tauro-6-ECDCA 
concentrations in plasma following repeat dosing for 12 days. 
Trial 747-203 – Type 2 Diabetes Mellitus and NAFLD: This double blind, placebo controlled, trial evaluated 
the effects of OCA on insulin sensitivity by means of a 2-stage euglycemic insulin clamp (49). Subjects with 
Type 2 diabetes mellitus and NAFLD, diagnosed by elevated aminotransferases (20%), imaging (84%) and/or 
histology (3%), were randomized to receive placebo, OCA 25 mg, or 50 mg once daily for 6 weeks. Sixty-four 
(64) subjects were enrolled (placebo: n = 23; OCA 25 mg: n = 20, 50 mg: n = 21). Forty-four (44) subjects had
successful pre and post treatment insulin clamps and were analyzed for efficacy. Glucose disposal rate (GDR)
was determined (pre and post treatment) after steady state was achieved with low and high dose insulin
infusions rates (60 and 120 mU/m2 body surface area/min).
Fig. 10 Glucose disposal rates at low dose insulin 
infusion. Combined doses versus placebo p =0.048. 
Glucose infusion rates showed a significant improvement at the 25 mg dose, compared with placebo. While 
the improvement at the 50 mg dose did not attain statistical significance on its own, when both OCA doses   
Fig. 11 Glucose disposal rates at high dose insulin 
infusion. Combined doses versus placebo p =0.022. 


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Protocol version number 1, 08042014 
In conclusion, the improvements in glucose infusion rates after both insulin infusion levels implies that OCA 
has a beneficial effect on glucose disposal in both the liver (low dose) and peripherally (high dose, when 
hepatic glucose uptake is “switched off”). These data are consistent with an improvement in glucose disposal. 
Increases in mean LDL and mean total cholesterol (TC) and decreases in mean HDL and mean triglycerides 
(TG) were observed at end of treatment/early termination compared to baseline in both dose groups (25 and 
50 mg) which appeared to be greater than that observed in the placebo group. Serum ALT (25 mg) and GGT 
(25 and 50 mg) decreased by approximately 25% and 50% (p < 0.001), respectively. 
Toxicology: In the ascending single dose trial (747-101) testing a dose range of 50 to 500 mg, only 2 mild 
AEs, upper abdominal pain and nasopharyngitis, were observed in 2 different subjects from a total of 24 
subjects. No SAEs, deaths, or trial withdrawals were reported.  
In the multiple dose escalation trial (747-102), daily doses of OCA for 12 days were safe and well tolerated 
in these healthy volunteers at doses up to 100 mg/day. The most commonly occurring AE was pruritus, which 
was only reported in subjects receiving the highest dose (250 mg) of OCA. One (1) subject in the OCA 250 mg 
group was withdrawn from the trial due to rash that was possibly related to study medication; the subject had 
also complained of pruritus. No SAEs were reported, and no deaths occurred during the trial. Overall, no 
clinically significant mean changes from baseline in vital sign measurements, electrocardiogram (ECG) results, 
physical examination findings, and laboratory values were noted with the exception of the liver transaminases, 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST).  Only at the  dose of 250 mg,  OCA 
daily was associated with transient increases in aminotransferase liver enzymes in 6 of 8 subjects; and  4 
subjects (50%) developed mild pruritus. No changes of clinical note were observed at daily doses of 50 and 
100 mg. Most importantly, all SAEs have occurred in trials of patients with primary biliary cirrhosis (PBC).  
Trial 747-203 was a US multi-center clinical trial of OCA in subjects with Type 2 diabetes mellitus and 
NAFLD (49). In this trial, 64 subjects were randomized to receive placebo or OCA at 25 mg or 50 mg once 
daily for 6 weeks. The drug was well tolerated and the AEs were not clearly different to placebo although 24% 
of the subjects in the 50 mg group reported constipation (versus 0% in the placebo group).  
5. Criteria for Inclusion of Subjects:
1. 1. Patients with familial partial lipodystrophy with heterozygous disease-causing missense mutation
in lamin A/C (LMNA),  PPARG, or other known FPL genes.
2. Hepatic steatosis (>5.6% hepatic triglyceride content) as demonstrated by 1H magnetic resonance
spectroscopy.
3. Age 18-70 years.
4. Alcohol intake of less than 20 g per day in females and 30 g per day in males.
5. Participants and their partners with whom they are having sex, must use medically-acceptable birth
control (contraceptives) during the study.  Medically-acceptable methods of contraception include: (1)
surgical sterilization, such as hysterectomy, tubal ligation or vasectomy. (2) approved hormonal
contraceptives, such as birth control pills, patch or ring; Depo-Provera, Implanon. (3) barrier methods,
such as condom, cervical cap or diaphragm used with a spermicide. (4) an intrauterine device (IUD).
6. Patients with well-controlled diabetes on diet and /or metformin therapy with HbA1c <7.0%.
6. Criteria for Exclusion of Subjects:
1.Laboratory or other histologic findings highly suggestive of liver disease due to causes other than
non-alcoholic steatohepatitis, such as chronic viral hepatitis, autoimmune hepatitis, primary biliary
cirrhosis, biliary obstruction or genetic liver diseases such as Wilson’s disease, hemochromatosis or
alpha-1-antitrypsin deficiency. Patients who have any evidence of cirrhosis will be excluded and


Page 14 of 24 
patients who progress to cirrhosis during the trial will also be discontinued. The definition of “no 
evidence of cirrhosis” will be: normal total and direct bilirubin (0.2-1.2 mg/dL & ≤0.2 mg/dL, 
respectively), normal platelet count (140- 400 thousand/µL), and normal prothrombin time (9-11.5 sec) 
/INR (0.9-1.1) (unless patient is on anticoagulants). In addition, patients with known or prior clinical 
evidence of cirrhosis on physical examination (such as ascites, splenomegaly) or noninvasive testing 
(esophageal varices), will be excluded.  
2. Treatment with drugs associated with steatohepatitis, e.g., corticosteroids, high dose estrogens,
methotrexate, amiodarone, tamoxifen, valproic acid, sulfasalazine, or oxacillin for more than 2 weeks in
the 6 months prior to the study.
3. Decompensated liver disease as evidenced by clinical features of hepatic failure (variceal bleeding,
ascites, hepatic encephalopathy etc.) and laboratory investigations (prolonged prothrombin time with
INR > 1.3, hypoalbuminemia with serum albumin less than 3.0 g/dL, or presence of esophageal varices
etc.)
4. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver
mass on imaging study suggestive of liver cancer.
5. Use of drugs which can potentially decrease hepatic steatosis during previous 3 months;
ursodeoxycholic acid, thiazolidinediones, high-dose vitamin E, betaine, acetylcysteine and choline.
6.Significant systemic or major illnesses other than liver disease, such as congestive heart failure,
cerebrovascular disease, respiratory failure, renal failure (serum creatinine >2 mg/dL), acute
pancreatitis, organ transplantation, serious psychiatric disease, and malignancy, that could interfere
with the trial and adequate follow up.
7. Acute medical illnesses precluding participation in the studies.
8. Known HIV-infected patient.
9. Current substance abuse.
10. Pregnant or lactating woman.
11. Hematocrit of less than 30%.
12. History of weight loss during past 3 months.
13. Patients on bile acid binding resins, cholestyramine, colestipol or colesevelam.
14. Hypersensitivity or intolerance to OCA or any components of its formulation.
15. Failure to give informed consent
16 .Previous clinical diagnosis of diabetes mellitus in patients taking insulin , GLP-1 analogues, SGLT2 
inhibitors, DDP-4 inhibitors or sulfonylureas or hemoglobin A1c ≥ 7.0 %.________ 
7. Sources of Research Material:
Research material will consist of questionnaires, blood and urine specimens, physical examination, and 3-day
food records obtained from the subjects according to the protocol.
8. Recruitment Methods and Consenting Process:
Subjects will be recruited from referring physicians, clinics and medical schools across the U.S. and 
Canada. Specifically, we will recruit from other researchers in lipodystrophy and gastrointestinal/liver 
specialists. Previously, patients with lipodystrophies have participated in our clinical trials from Canada, 
Portugal, Germany and Kazakhstan. All subjects will be informed of the nature and purpose of the research by 
the Investigators or Research Coordinator and will give informed consent as required by the UT Southwestern 
Institutional Review Board. Investigators will obtain informed consent after explaining the study and the 
subjects having read..Consent will be obtained prior to any study procedures being performed. A copy of the 
consent form will be given to the subjects and the original consent will be maintained in the subject’s research 
records, which will be maintained in the General Clinical Research Center. 
9. Potential Risks:
All subjects will undergo a history, physical examination, liver MRS, quality of life questionnaire, a
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Page 15 of 24 
questionnaire on gastrointestinal symptoms, subjects will be asked to undergo a glucose clamp study for which 
there is a minimal risk of psychological or physical discomfort from fasting and an intravenous saline locks, the 
risk of hypoglycemia, the inconvenience of time spent and the unlikely risk for bruising, fainting, or infection. 
Subjects will also have phlebotomy for DNA and genotyping for LMNA, and repeated phlebotomy for which 
there are the minimal risks of physical and psychological discomfort, the requirement of fasting, and the 
unlikely risk for bruising, fainting or infection. 
The potential risks and discomforts of the evaluation methods being used are: Magnetic Resonance 
Spectroscopy (MRS) scans: requires holding still in a noisy scanner, no radiation risk. 3-day food recalls: no 
risk, the inconvenience of the brief time spent. Quality of life and gastrointestinal symptoms questionnaires: no 
risk, the inconvenience of the brief time spent Phlebotomy and line placement for OGTT carries the rare to 
occasional minimal risk of discomfort, hematoma, infection, fainting and/or vasovagal response. Oral glucose 
tolerance test carries minimal, occasional risk for nausea and/or vomiting.  
Subjects will be asked to undergo phlebotomy for DNA and genotyping for LMNA, for which there is the risk of 
phlebotomy, ,fasting, and the minimal risk of bruising, fainting, infection or hypoglycemia. Subjects will also 
undergo repeated 
routine fasting phlebotomy for which there is a minimal risk of psychological or physical discomfort, the 
discomfort of fasting, the inconvenience of time spent and the unlikely risk for bruising, fainting or infection. 
The potential risks of Obeticholic acid therapy: Obeticholic acid at the proposed dose of 25 mg per day 
appears safe and well tolerated. Approximately 385 subjects have been exposed to Obeticholic acid in various 
trials. Serious adverse events, possibly or probably related to Obeticholic Acid such as, chest pain, jaundice, 
GI Bleed, flare of primary biliary cirrhosis (PBC) were noted only in PBC trials. The most common non-serious 
adverse event with OCA therapy in PBC patients and across other trials is pruritus. In a multiple dose 
escalation trial in healthy volunteers OCA was safe and well tolerated at doses up to 100 mg/day without 
pruritus. Only at 250 mg/day dose, pruritus and transient LFT elevations were noted. Of note, the incidence 
and severity of pruritus in the type 2 diabetes NAFLD trial at OCA doses of 25 or 50 mg/day was similar in the 
treated and placebo groups. Additional adverse events associated with OCA include: diarrhea, constipation, 
abdominal pain, stomach discomfort, nausea, abdominal distension, excoriation, arthralgia, peripheral edema, 
sinusitis, pain in extremity, back pain, myalgia, hemorrhoids, muscle spasms, cough, gastroesophageal reflux 
disease, pharyngolaryngeal pain, fatigue, headache, upper respiratory infection, insomnia, pallor, chest pain, 
decreased hemoglobin, anxiety, headache, dizziness, excoriation, depressed mood, dysmenorrhea, rash, 
nasopharyngitis, dry eye, vomiting, pyrexia, epistaxis, oropharyngeal pain, maculopapular rash, palpitations, 
urinary tract infection and sinusitis. Elevations in the liver enzymes (ALT, AST) were reported only at the 
dose of 250 mg/d in healthy volunteers. 
10. Subject Safety and Data Monitoring:
We propose the creation of an internal Data and Safety Monitoring Committee composed of experts in 
statistics, lipid and liver metabolism.  Identified for the necessary expertise are individuals who are not 
associated with this trial and not collaborators of the principal investigator.  1. William Lee, M.D., Professor of 
Internal Medicine, Director of the Center for Liver Diseases.  2. Alan Elliott, Ph.D., Faculty Associate, 
Department of Clinical Sciences.  3.  Scott Grundy, M.D., Ph.D. Professor of Internal Medicine 4.  Fredrick 
Dunn, M.D., Professor of Internal Medicine.
The Committee will be asked to:  a) Review the research protocol, informed consent documents and 
the plans for data and safety monitoring. b) Evaluate the progress of the study including periodic assessments 
of data quality and timeliness, recruitment, retention, and risk versus benefit.  c) Report on the safety and 
scientific progress of the trial.  d) Make recommendations to the PI, and if needed to the IRB, NIH, CTRC and 
FDA concerning continuation, termination or modifications of the trial based on the observed beneficial or 
adverse effects of the interventions under study.  e) Conduct or review the interim analysis with regards to 
safety in accordance with stopping rules, which should be defined in advance of the data analysis. f) Ensure 
data integrity. g) Ensure the confidentiality of the data and results of monitoring.  h) Maintain study integrity by 
commenting on any problems with study conduct, enrollment, and statistics or data collection. 
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The PI will hold the primary oversight responsibility for this trial and as such he will be responsible for 
surveying the medical literature for scientific or therapeutic developments that may impact the safety of 
participants or the ethics of the study.  He will insure that: subjects are fully informed of the study requirements 
throughout the trial, insure that study subjects receive a study calendar upon enrollment, are updated on any 
new information relevant to their continued participation or change in the risk versus benefit ratio of the 
interventions.  The PI will be responsible for reporting adverse events to the IRB, NIH, CTRC and FDA in 
accordance with IRB policies and time frames.  The PI is responsible for submitting continuing review reports 
to the IRB, NIH and FDA.   
11. Procedures to Maintain Confidentiality:
Confidentiality will be maintained by utilizing study codes to identify subjects, all files will be kept locked and all
information on computers will be password protected.  Access to research data is restricted to key personnel
directly involved with the study who have been trained in the protection of human subjects and signed
statements assuring their compliance with University policies protecting the privacy of research subjects.
12. Potential Benefits:
The potential benefit of obeticholic acid therapy is an improvement in hepatic steatosis as demonstrated by ¹H 
MRS of the liver, as well as possible improvement in raised levels of hepatic enzymes such as transaminases 
and improved insulin sensitivity.  Reduction in hypertriglyceridemia will be shown through improved fasting 
serum triglyceride levels.  The results of this study may help define a safe and effective treatment for non-
alcoholic hepatic steatosis in people with lipodystrophy. 
13. Biostatistics:
Power and sample size: The primary endpoint variable is the difference in hepatic triglyceride 
concentration between OCA and Placebo after four months of each treatment. Sample size estimates are 
based on our preliminary data with a geometric mean hepatic triglyceride concentration of 16% in 29 patients 
with FPLD who have hepatic triglyceride concentration >5.6% and a corresponding coefficient of variation of 
25% based on log transformed data. We expect a reduction in hepatic fat of at least 25% (i.e., reduction from 
16% to 12% liver fat with OCA) and calculate, for an alpha of 0.05 and power of >0.90, we will need 16 
patients for the study. Allowing for a 20% drop-out rate, a total of 20 patients will be required. The drop-out 
rate is estimated from our recent studies in patients with FPL (18, 71). 
Randomization: The sequence of OCA and placebo treatment will be determined by blocked 
randomization.  
Statistical analysis: Descriptive statistics and 95% confidence intervals will be used to summarize 
responses to OCA and Placebo treatment and treatment differences of this crossover study.  For hepatic 
triglyceride concentration, mixed linear repeated measures models will be constructed to compare OCA 
versus Placebo after four treatment months and to evaluate treatment sequence effects. Secondary endpoint 
variables will be FGF19 levels, hepatic insulin sensitivity measurements from the euglycemic, 
hyperinsulinemic glucose clamp, serum triglycerides, insulin, and aminotransferase levels and will be 
analyzed with similar mixed linear repeated measures models. Two month treatment response comparisons, 
gender subgroup interactions, per-protocol hepatic triglyceride concentration responses will be assessed as 
secondary analyses.  The primary and secondary endpoints, which are likely to be skewed, will be log 
transformed prior to analysis, as appropriate. Nonparametric tests will be implemented, if necessary, to satisfy 
analysis assumptions.  Exploratory analyses: Delta responses (OCA-Placebo) will be computed for primary 
and secondary variables and the association among the delta variables will be evaluated with Spearman 
correlation coefficients. A two-sided p value of <0.05 will be considered statistically significant. No interim 
analysis is planned because of the relatively short study duration and limited sample size. SAS (SAS Institute, 
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Protocol version number 1, 08042014 
Cary, NC) statistical software will be used; particularly SAS PROC MIXED will be used for repeated measures 
models. The data will be analyzed according to intention-to-treat principles; our mixed model analysis 
approach can accommodate certain types of missing data. If a subject is unable to complete or tolerate the 
intervention in either blinded treatment period, we will continue follow-up if possible or the post-treatment and 
other final measurements may be made prior to 4 months to minimize missing outcome data.  


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Protocol version 01, 0804201 
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 Criteria for Discontinuing Drug/Placebo: Patients will be carefully recruited and screened to 
maximize retention.  A proactive retention plan will be in place for study personnel to stay in close 
contact with study subjects. We will continue to follow patients and encourage patients to return for 
follow up evaluation regardless of adherence to protocol.  The study drug/placebo will be 
discontinued as necessary, for safety reasons particularly if the patients report serious adverse 
reactions. Patients developing serious acute medical conditions, which in the opinion of the 
investigators will interfere with subjects continued participation, will be withdrawn from the 
drug/placebo as well as women who become pregnant.    
Study Stopping Criteria: 
•
For individual subject: In the event of a single subject CTCAE Grade 3 (severe AE) or higher
adverse event, regardless of whether it is attributed to OCA unless it is caused by an accident that 
could not reasonably be attributable to the drug.  
•
For all subjects: In the event of two or more subjects experiencing a CTCAE Grade 3 or higher
adverse event, regardless of whether it is attributed to OCA unless it is caused by an accident that 
could not reasonably be attributable to the drug.  
Potential Problems and Alternate Strategies:  
The accrual of adequate number of subjects and 
retention of study patients is considered to be a potential problem.  We intend to address this problem 
by taking the following steps. a. Direct Referrals to the P.I.:  In the past, several patients have been 
referred to the P.I. for diagnosis, clinical evaluation and management.  Many colleagues and patients 
have contacted the P.I. after reading our publications. We continue to ascertain new pedigrees with 
FPLD. We have ascertained and molecularly confirmed 5 new pedigrees with FPLD in the last year. 
Currently, approximately 20 new pedigrees with FPL are awaiting to undergo LMNA genotyping. Many 
of these pedigrees have multiple (>5 affected subjects). We will also extend the current 79 FPLD 
pedigrees to find more eligible subjects. b. Contact authors of published papers: In the past, we have 
successfully recruited several new patients and their pedigrees by directly corresponding with the 
senior authors of papers or abstracts.  We will continue these efforts in the future. c. Referrals through 
organizations for rare diseases: We have received referrals from the National Organization of Rare 
Disorders (NORD), U.S., and from the Children Living with Inherited Metabolic Diseases (CLIMB), 
U.K., in the past and expect to ascertain more patients in the future. d. WebSite: In addition, a website
(www.lipodystrophy.info) is maintained by the PI for recruitment of patients for research studies. e.
Advertisement on NIH Clinical Trials Website: Our studies will be posted at the website. f.
Advertisement on Lipodystrophy United and Lipodystrophy Connect: Lipodystrophy United is a
lipodystrophy patient support group based in the US and Lipodystrophy Connect is a new registry of
patients with lipodystrophy (see letters of support).
We get free travel vouchers (>20/year) from Southwest airlines to provide medical 
transportation for our patients with lipodystrophies and plan to use those for patients living in the US. 
We will also utilize Angel Flight for free patient transportation to Dallas. For international patients, we 
will ask them to pay for their travel.  We have previously used this model to successfully complete the 
trials in lipodystrophy patients (11, 18, 71). 
Another problem is related to patient compliance. Top priority will be placed on follow-up visits. 
Participants will be reminded by phone and in writing of their upcoming follow-up appointments. 
Missed visits will be rescheduled. We do not expect drop-outs due to side effects of obeticholic acid, 
as in previous studies it was reported to be well-tolerated. 
We are fully aware of the editorial by Clark and Brancati (72) entitled “Negative trials in 
nonalcoholic steatohepatitis: why they happen and what they teach us”. We have taken care to avoid 
the pitfalls that they indicated which may result in negative trials. For example, we are avoiding to 
use low dose of obeticholic acid and have selected to administer 25 mg/day which was also used in 
the FLINT trial. Our study design which is a cross-over design and also includes a baseline period 


Page 19 of 24 
Protocol version 01, 0804201 
Page 19 of 24 
approximately one month after the initial screening to determine eligibility will avoid regression to the 
mean. We have selected four month duration of treatment which is long enough to detect effects of 
obeticholic acid therapy on hepatic steatosis.  
 Benchmarks for success: In this pilot trial, reduction of hepatic fat by 25% will be considered a 
successful outcome for the study. In addition, among the secondary end point variables, we will 
consider 25% reduction in any of the aminotransferases and gamma glutamyl transpeptidase as 
successful outcome. Lastly, a 25% reduction in serum triglycerides will also be considered a 
successful outcome. 
 Timeline: 
The timeline is shown in Fig 12. The 
budget is requested accordingly for 3 
years. 
Fig. 12 Timeline for accomplishment  
of the goals of the project. After  
an initial planning period of 6 months, 
we will initiate the study protocol.  
  Data Collection 
The quality of the data will be ensured by extensive training of the staff and periodic 
reviews for all procedures.  Database design and management will be overseen by the PI and study 
team and facilitated using REDCap (Research Electronic Data Capture), an easy to use web-based 
solution that is designed exclusively to support data capture for research studies. REDCap is a secure 
system backed up offsite nightly and hosted in a secure environment maintained by UT Southwestern 
Information Resources. The REDCap system includes an automatic audit trail of all activity and any 
study personnel who are granted log-in access to our REDCap database project will be approved by 
the principal investigator. REDCap has a longitudinal module for capturing the repeated 
measurements that are central to this crossover study design, provides a built-in project calendar, a 
scheduling module, a randomization module, and reporting tools.  In RedCAP, customized forms for 
the treatment periods will be built by constructing a codebook which reinforces good data practices by 
requiring the codebook BEFORE data entry. We anticipate entering study data directly into REDCap 
but data from existing sources outside of REDCap can be imported easily once the data is checked 
for problems before final import. Data management activities will also have standard operating 
procedures (SOPs) for data entry that will be reviewed by the PI. Our database manager will 
supervise timely data entry, tracking, and cleaning of research data and oversee development of site 
specific data collection instruments for building and maintaining the local REDCap database and 
oversee quality assurance.  Study specific case report forms (CRFs) will be developed that can be 
used by specific personnel to enter data; REDCap provides data validation at time of entry. Study 
form development consultation is available through the Division of Biostatistics for optimizing the data 
collection instruments.  
Year 1
Year 2
Year 3
Year 1
Year 2
Year 3
Planning
Recruitment
Study Initiation
Study Completion
Data Analysis/
Publications


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Ahmad Z, Subramanyam L, Szczepaniak L, Simha V, Adams-Huet B, Garg A. Cholic Acid for 
Hepatic Steatosis in Patients with Lipodystrophy: A Randomized, Controlled Trial. European Journal 
of Endocrinology. 2013. Epub 2013/03/01. doi: EJE-12-0969 [pii] 
10.1530/EJE-12-0969. PubMed PMID: 23447519. 
72. 
Clark JM, Brancati FL. Negative trials in nonalcoholic steatohepatitis: why they happen and 
what they teach us. Hepatology. 2004;39(3):602-3. PubMed PMID: 14999677. 
 
 
 

ICF_001.pdf: 
INFORMED CONSENT FORM 
Official title: Phase 2 Study of Obeticholic Acid 
for Lipodystrophy patients. 
NCT number: NCT02430077 
IRB Approved date:04-16-2018 


Page 1 of 14                                      DO NOT DISCLOSE 
The University of Texas Southwestern Medical Center at Dallas
Parkland Health & Hospital System
Children’s Medical Center
Retina Foundation of the Southwest
Texas Scottish Rite Hospital for Children
Texas Health Presbyterian Hospital of Dallas
CONSENT TO PARTICIPATE IN RESEARCH
Title of Research:
Phase 2 Study of Obeticholic Acid for Lipodystrophy patients.
Funding Agency/ Sponsor:  National Institutes of Health
Study Doctors:
Abhimanyu Garg, M.D.
Zahid Ahmad, M.D.
Jeffrey Browning, M.D.
Research Personnel:
Claudia Quittner, RN, BSN, MS
Chandna Vasandani, Ph.D.
You may call these study doctors or research personnel during regular office hours at 214-648-
9296.  At other times, you may call them through the operator by calling   214-645-5555 and 
pressing 0.  You will need to ask the operator to have the study doctor paged. Please ask the 
operator to page Dr. Abhimanyu Garg, or Dr. Zahid Ahmad.
Instructions:
Please read this consent form carefully and take your time making a decision about whether to 
participate.  As the researchers discuss this consent form with you, please ask him/her to 
explain any words or information that you do not clearly understand.  The purpose of the study, 
risks, inconveniences, discomforts, and other important information about the study are listed 
below.  If you decide to participate, you will be given a copy of this form to keep.
Why is this study being done?
This study is being done to evaluate the efficacy (ability to produce desired effect of the 
intervention) and safety of Obeticholic acid (OCA) therapy in treating hepatic steatosis (fatty 
Liver) in patients with familial partial lipodystrophy (FPL), Dunnigan variety. Familial partial 
lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of 
body fat (adipose tissue) from various areas of the body. 
  
Because this is a research study, Obeticholic acid will be given to you only during this study 
and not after the study is over.
Why is this considered research? 
Study ID: STU 062014-033   Date Approved: 4/16/2018


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This is a research study because Obeticholic acid, a modified bile acid (bile acids are produced 
by the liver to help with digestion of fats) is an investigational drug and has not been approved 
by the U.S. Food and Drug Administration (FDA) for the treatment of hepatic steatosis (fatty 
liver) in patients with lipodystrophy. Lipodystrophy is a body fat disorder and is characterized by 
selective loss of fat tissue. 
 
The following definitions may help you understand this study: 

Double-blind means neither you nor the researchers will know when you are receiving 
study drug, Obeticholic acid or placebo.

Placebo-controlled means that in one of the study periods you will get a placebo. A 
placebo looks like the investigational drug but it includes no active ingredients. 

Randomization means you will be placed by chance (like a flip of a coin) to receive either 
Obeticholic acid  or placebo in the first study period.  

Standard medical care means the regular care you would receive from your personal 
doctor if you choose not to participate in this research.

Researchers means the study doctor and research personnel at the University of Texas 
Southwestern Medical Center at Dallas and its affiliated hospitals.
Why am I being asked to take part in this research study?
You are being asked to participate in this research because you have a body fat disorder known 
as familial partial lipodystrophy, a condition which results in areas of selective or generalized fat 
loss, and in addition, you have hepatic steatosis, or a fatty liver (excess fat accumulation in the 
liver). Having fatty liver can place you at risk for other serious liver problems such as hepatitis 
(inflammation of the liver) or cirrhosis (scarring and abnormal function of the liver). Currently, 
there are no standard treatments that are proven to be safe and effective for treating fatty liver, 
a disease condition.  
    
Do I have to take part in this research study?”
No.  You have the right to choose whether you want to take part in this research study.  If you 
decide to participate and later change your mind, you are free to stop participation at any time.
If you decide not to take part in this research study it will not change your legal rights or the 
quality of health care that you receive at this center.
How many people will take part in this study?
About 20 people will take part in this study at UT Southwestern. 
What is involved in the study?
If you volunteer to take part in this research study, you will be asked to sign this consent form 
and will have the following tests and procedures.  Some of the procedures may be part of your 
standard medical care, but others are being done solely for the purpose of this study.
If you are found to be eligible, during the baseline period, you will continue your usual diet and 
other lifestyle measures without changing any medications for 1 month in order to establish a 
baseline state. Three blood samples will be obtained during this period at the Clinical and 
Translational Research Center. Following the baseline period, you will be randomized to receive 
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 3 of 14                                      DO NOT DISCLOSE 
either Obeticholic acid (OCA) or an identical placebo in the dose of 25 mg/day for a period of 4 
months and then will receive the other treatment (OCA or placebo) for 4 months. There will be a 
wash-out period of 4 months in-between the two study periods. You will be in this study for 
approximately 12 months.  
Screening Procedures
To help decide if you qualify to be in this study, the researchers may ask you questions about 
your health, including medications you take and any surgical procedures you have had.
You will be asked about any previous testing done regarding liver diseases or function, such as 
a liver biopsy or tests for hepatitis.
You will have the following evaluations:  a physical exam including weight, blood tests for liver 
function and liver diseases, a general chemistry panel with triglycerides and cholesterol (blood 
fats), insulin, a complete blood count, urine tests, and a urine pregnancy test if appropriate.
You will fill out a questionnaire about your quality of life, your diet and also your gastrointestinal 
symptoms. You will have an MRS (magnetic resonance spectroscopy) scan of your liver, an 
MRS is an imaging scan which does not involve radiation and which shows if you have a fatty 
liver. 
 
Randomization
If the study doctor believes that you qualify to participate in this research, you will take tablets by 
mouth. The study is a randomized, placebo controlled, crossover design. "Randomized" means 
that you will be assigned to one of two groups. The study assignment is made in advance by a 
process similar to flipping a coin. Depending on which group you are assigned to, you will take 
either active Obeticholic acid tablets or placebo (an inactive substance) tablets for 4 months and 
then either Obeticholic acid tablets or placebo for another 4 months. There will be a wash-out 
period of 4 months in-between the two study periods. Whichever treatment group you begin on, 
after 4 months of that treatment, there will be a wash-out period of 4 months in-between and 
you will "crossover" to the other treatment group. That is why it is called a "crossover" design.
Neither you, or your study doctor, or other research personnel will know what your study 
assignment is.  
Treatment
Obeticholic acid (25 mg) or placebo will be given in a tablet form. 
Procedures and Evaluations during the Research
You will be admitted to the Clinical and Translational Research Center for the baseline 
evaluations (at the beginning of the two study periods), and at the end of four months during 
each study period. Biochemical testing and routine urinalysis will be done every 6 weeks during 
the periods when you are on study drug or placebo. We will provide kits to you for mailing the 
blood and  urine samples using courier service.
During your 3 day stay in CTRC you will have the following tests and procedures or 
assessments in this study: 
 
Demographic Characteristics, Health History, and Physical Examination: You will be asked 
to complete questionnaires on demographic characteristics and health history during baseline 
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 4 of 14                                      DO NOT DISCLOSE 
period and during the last week of each study period. Height and body mass will be measured 
by standard procedures.
Serum chemistry, lipoproteins, insulin, and FGF19: Blood will be obtained after overnight 
(12 h) fast daily.  Blood sample will be used for chemistry profile ,(, lipids (blood fats), 
hemoglobin A1c ( a measure of what your average  blood glucose levels have been over the 
past three months) and hormones ( e.g. Insulin, and fibroblast growth factor-19)., The test 
involves drawing about 15 mL (1 tablespoon) on adults of blood in the morning before you eat.
  
Proton Magnetic Resonance Spectroscopy (MRS):  Proton MRS Studies will be performed 
on you to measure liver fat content. These studies will be performed at 0, 2, and 4 months 
during each study period. This technique is closely related to magnetic resonance imaging and 
can accurately measure tissue concentrations of glucose fat. The test involves lying down on a 
table that slides into the magnet tube.
Magnetic Resonance Imaging (MRI):  Your liver size will be measured using MRI. Magnetic 
resonance imaging is a type of scan that uses magnetic fields and radio waves to make a 
picture of the liver.
Three-Day Food Record: Dietary intake will be assessed by 3-day food record (two weekdays 
and one weekend day), a valid and reliable method. The measure will be taken at baseline and 
each of the follow-up visits. You will be instructed on how to record in detail all the food and 
drink consumed in the 3-day food record booklet provided. You will also be provided a two-
dimensional visual chart of food portions to aid in estimating portion sizes.
Oral Glucose Tolerance Test (OGTT):  A 3 hour OGTT will be performed after 10-12 h 
overnight fast. An intravenous line will be placed for blood drawing. On the day of fasting, you 
will have a fasting blood sample collected and then you will be Instructed to drink the glucose 
solution (75 g of glucose in 200 mL of water)  over a maximum of 15 minutes (ideally within 5 
minutes).  Time will be noted. Blood tests will be done at half-hour intervals for three hours to 
check your glucose and insulin response. A total of 45 mL blood or 3 tablespoons (for adults) 
will be withdrawn during this test.  
The quantity of blood drawn at any one time for adults will be a maximum of 2 1/2 tablespoons. 
The blood and urine testing, questionnaires and liver MRS scans are evaluation methods for the 
research team to follow you for the safety, tolerability and effectiveness of the Obeticholic acid 
therapy for your fatty liver.
How long can I expect to be in this study?
You will be expected to be in the study for a period of 12 months. 
What are the risks associated with the study? 
Study Procedure/Intervention
Because of your participation in this study, you are at risk for the following side effects. You 
should discuss these with the researchers and your regular health care provider. 
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 5 of 14                                      DO NOT DISCLOSE 
Obeticholic acid 
Obeticholic acid is an investigational drug. 
Obeticholic acid at the proposed dose of 25 mg per day appears generally safe and well 
tolerated. 
The most common non-serious adverse event with OCA therapy in primary biliary cirrhosis (a 
liver disease affecting bile ducts; PBC) patients and across other trials is pruritus (Itching of the 
skin). In a multiple dose escalation trial in healthy volunteers OCA was safe and well tolerated at 
doses up to 100 mg/day without pruritus (Itching of the skin).
Approximately 1023 subjects have been exposed to Obeticholic acid in various trials.
Serious adverse events either possibly or probably related to Obeticholic Acid are rare and 
include: stroke, ataxia (poor coordination), vertigo (dizziness), chest pain, gastrointestinal bleed, 
liver toxicity and  myocardial infarction (heart attack). A single subject who was taking 
Obeticholic acid died of myocardial infarction. Although the investigator considered this death to 
be possibly related to the drug, however, she also had high blood pressure, high cholesterol, 
obesity and was taking hormone replacement therapy, all of which could have contributed to 
myocardial infarction.   In rare PBC patients flare up of the disease was also noticed. 
Additional adverse events associated with OCA include: 
Common events: itching, constipation, mouth/throat pain.
Other uncommon events:  

diarrhea, , abdominal pain, stomach discomfort, nausea, vomiting, abdominal distension, 
jaundice ( yellow tone to skin)

excoriation (skin-picking)

arthralgia (joint pain), 

peripheral edema (fluid accumulation), 

sinusitis ( swelling of the sinus lining)

pain in extremity, back pain 

myalgia (muscle soreness) 

hemorrhoids

muscle spasms

cough

gastroesophageal reflux disease ( heart burn or  indigestion)

fatigue, headache 

upper respiratory infection

insomnia (sleep disturbance) 

pallor (paleness of skin)

chest pain

decreased hemoglobin ( decreased blood count)

anxiety 

headache, dizziness, , depressed mood

dysmenorrhea ( painful periods)

rash

nasopharyngitis (viral infection of the upper respiratory system)

dry eye
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 6 of 14                                      DO NOT DISCLOSE 

vomiting

pyrexia (fever)

epistaxis (nose bleed) 

maculopapular rash (rash characterized by a flat, red area on the skin that is covered 
with small raised bumps

Palpitations and urinary tract infection.
Elevations in the liver enzymes (ALT, AST), increased bilirubin and hepatic (liver) adverse 
events were reported only at the OCA dose of 25 mg mg and above and were reversible with 
stopping the drug..
Lipid profile changes;  including  decrease in total and high density lipoprotein (HDL or good) 
cholesterol have been noted but reversed once OCA drug dosing was stopped.
 3-day food recalls: no risk, the inconvenience of the brief time spent.
Quality of life and gastrointestinal symptoms questionnaires: no risk, the inconvenience of 
the brief time spent.
MRS Risks
There are no known risks from exposure to magnetic fields.  You may experience nervousness 
and/or anxiety due to the loud banging made by the machine while it is taking pictures and from 
confinement in a tight space (claustrophobia). If you become anxious, you can stop the 
procedure at any time. If you have any metal clips or plates in your body, you should tell the 
investigator. You may also experience some discomfort and fatigue from lying still during 
imaging.
MRI risks
There are no known risks from exposure to magnetic fields. You may experience nervousness 
and/or anxiety due to the loud banging made by the machine while it is taking pictures and from 
confinement in a tight space (claustrophobia). If you become anxious, you can stop the 
procedure at any time.
You may also experience some discomfort and fatigue from lying still during imaging.
If you have any metal clips or plates in your body, you should tell the investigator.
MRI may not be appropriate if you are pregnant or are trying to become pregnant. MRI may not 
be appropriate if you have permanent eyeliner or eyebrows or any pieces of metal in your body, 
such as the following:
• heart pacemaker, heart valve replacement, or aortic clips
• metal fragments in your eyes, skin, or elsewhere in your body
• brain clips or pieces of metal used in aneurysm surgery or intercranial bypass
• venous umbrella
• pieces of metal in the body resulting from work as a sheet-metal worker or welder
• clips placed in an internal organ
• prosthetic devices, such as middle ear, eye, joint, or penile implants
• joint replacement.
• hearing aid that cannot be removed
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 7 of 14                                      DO NOT DISCLOSE 
• neurostimulator
• insulin pump
• intrauterine device (IUD)
• shunts or stents
• metal mesh or coil implants
• metal plate, pin, screws, or wires, or any other metal implants
If you have a history of an implanted device or clips in your pelvis (involving your uterus or 
fallopian tubes) or under your skin, acting as a contraceptive to prevent pregnancy, the MRI 
technologist will obtain specific information about the make and model of your implanted device 
to determine if it is safe for you to receive the MRI examination.
OGTT risks: Phlebotomy and line placement for OGTT carries the rare to occasional minimal 
risk of discomfort, hematoma, infection, fainting and/or vasovagal response. Oral glucose 
tolerance test carries minimal, occasional risk for nausea and/or vomiting.
Placebo Risk:  
 During one of the study periods, you will receive a placebo.  Taking a placebo may be similar to 
not taking any medication. During this period your disease/condition may spontaneously get 
better or worse, just as it may have done without additional treatment.  
Blood draws: A blood draw may cause faintness, inflammation of the vein, pain, bruising, or 
bleeding at the site of puncture.  There is also a slight chance of infection. 
Fasting: Fasting could cause dizziness, headache, stomach discomfort, or fainting Subjects will 
also undergo repeated routine fasting phlebotomy for which there is a minimal risk of 
psychological or physical discomfort.
Urine Sampling: This may cause some inconvenience but there are no risks involved
Other Risks
Since the study drug is investigational when taken alone or in combination with other 
medications, there may be other risks that are unknown.  All drugs have a potential risk of an 
allergic reaction, which if not treated promptly, could become life threatening.  You should get 
medical help and contact the study doctor right away if you think you have any of the following 
symptoms of a serious allergic reaction:  trouble breathing, or swelling of the face, mouth, lips, 
gums, tongue or neck.  Other allergic reactions may include rash, hives, or blisters.
It is important that you report all symptoms and side effects that you experience as soon 
as they occur, whether or not you think they are caused by the study drug.  The phone 
numbers for the study team are on the first page of this document.
Loss of Confidentiality
Any time information is collected; there is a potential risk for loss of confidentiality.  Every effort 
will be made to keep your information confidential; however, this cannot be guaranteed. 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant
Study ID: STU 062014-033   Date Approved: 4/16/2018


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The effects of Obeticholic acid on sperm, a pregnancy, or a nursing child are not known.  If you 
are currently pregnant, planning to become pregnant or father a child, or breastfeeding a child, 
you should not join this study.  
Males: being in this research may damage your sperm, which could cause harm to a child that 
you may father while on this study. If you take part in this study and are sexually active, you 
must agree to use a medically-acceptable form of birth control. Medically-acceptable forms of 
birth control include:
(1) surgical sterilization (vasectomy), or
(2) a condom used with a spermicide (a substance that kills sperm).
Females: If you are part of this study while pregnant or breast-feeding an infant, it is possible 
that you may expose the unborn child or infant to risks. For that reason, pregnant and breast-
feeding females cannot participate in the study. If you can become pregnant, a blood pregnancy 
test will be done (using 1 teaspoon of blood drawn from a vein by needle-stick), and it must be 
negative before you participate in this study. If you take part in this study and you are sexually 
active, you and any person that you have sex with must use medically-acceptable birth control 
(contraceptives) during the study. Medically-acceptable birth control (contraceptives) includes:
(1) surgical sterilization (such as hysterectomy or “tubes tied”),
(2) barrier methods (such as condom or diaphragm) used with a spermicide (a substance that 
kills sperm), or
(3) an intrauterine device (IUD).
If you do become pregnant during this study, you must tell the researchers immediately.
How will risks be minimized or prevented?  
Potential risks and discomforts must be minimized to the greatest extent possible by using 
procedures such as appropriate training of personnel, monitoring, withdrawal of the subject 
upon evidence of difficulty or adverse event; referral for treatment, counseling or other 
necessary follow-up. 
Biochemical testing and routine urinalysis will be done every 6 weeks during the periods when 
you are on study drug or placebo. Telephone contact will be initiated with you every 2 weeks to 
assess for symptoms such as new or worsening pruritus (itching), abdominal pain, new or 
worsening fatigue, anorexia, nausea, rash, vomiting, diarrhea, jaundice (yellow skin or sclera, 
high amber colored urine and pale stools) and vague neuropsychiatric symptoms.
If you live outside of Dallas, blood tests will be arranged every 6 weeks and if there are any 
abnormalities, you will be asked to either visit us in person (for those living in the Dallas area) or 
see your primary care physician for physical examination (for those from outside Dallas).  We 
will communicate with your physicians about the lab data and physical examination findings. 
Drug will be discontinued immediately if you develop liver decompensation events (e.g., variceal 
bleed, hepatic encephalopathy, ascites, etc.) and we will not restart the drug even if the events 
are resolved.
You will be asked to report following symptoms as it will trigger immediate evaluation of for liver 
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 9 of 14                                      DO NOT DISCLOSE 
toxicity: new or worsening pruritus (itching), abdominal pain, new or worsening fatigue, 
anorexia, nausea, rash, vomiting or diarrhea. Even vague neuropsychiatric symptoms have 
been associated with acute liver failure. If prompt evaluation is not possible, the investigational 
drug will be immediately discontinued.
You will be asked to withhold drug during intercurrent illness, such as gastroenteritis resulting in 
dehydration, or other reasons for dehydration, and you will  be reevaluated with both 
biochemical testing and physical exam prior to restarting the drug.
Physical exam and liver biochemistries will be performed at each clinic visit and at any 
unscheduled visit triggered by your  reporting symptoms. If elevations in blood tests trigger 
reevaluation, then platelet count, INR, albumin, direct bilirubin, electrolytes and creatinine will be 
included in repeat testing.
What will my responsibilities be during the study?  
While you are part of this study, the researchers will follow you closely to determine whether 
there are problems that need medical care.  It is your responsibility to do the following:

Take the study drug as instructed.

Ask questions about anything you do not understand.

Keep your appointments.

Follow the researchers’ instructions.

Let the researchers know if your telephone number or address changes.

Store study materials in a secure place at home away from anyone who is unable to 
read and understand labels, especially children.

Agree to use a highly effective contraceptive method throughout the study and your 
doctor can discuss the method(s) of birth control or contraception that is appropriate for 
you.

Tell the researchers before you take any new medication, even if it is prescribed by 
another doctor for a different medical problem or something purchased over the 
counter, such as vitamins, minerals and purified food substances as well as any herbal 
remedies as these may affect the study drugs.

Tell your regular doctor about your participation in this study.  

Report to the researchers any injury or an illness while you are on study even if you do 
not think it is related. 
If I agree to take part in this research study, will I be told of any new risks that may be 
found during the course of the study?
Yes.  You will be told if any new information becomes available during the study that could 
cause you to change your mind about continuing to participate or that is important to your health 
or safety.
What should I do if I think I am having problems?
If you have unusual symptoms, pain, or any other problems while you are in the study, you 
should report them to the researchers right away.  Telephone numbers where they can be 
reached are listed on the first page of this consent form.
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 10 of 14                                      DO NOT DISCLOSE 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the nearest 
hospital emergency room, or call 911 (or the correct emergency telephone number in your 
area).  Tell emergency personnel about any medications you are taking, including any 
medications you are taking for this study.  
What are the possible benefits of this study?
It is possible that your condition or health may or may not improve because of your taking part in 
this study.  However, there is no guarantee that you will benefit in any way.  Information learned 
from this study may benefit others with fatty liver in the future.
What options are available other than being in this study?
You do not have to be in this study to receive treatment for your fatty liver. Instead of taking part 
in this study, you may choose to receive treatment with other drugs that have been approved for 
use in this country. There are no established therapies for fatty liver in patients with FPLD. You 
may try losing weight by controlling your diet and increasing physical activity. 
Will I be paid if I take part in this research study?
No. You will not be paid to take part in this research study. There are no funds available to pay 
for transportation expenses, or lost time away from work and other activities, lost wages, or child 
care expenses.
For non-local subjects a ClinCard will be given to cover travel incidentals.
You will be issued a UT Southwestern Greenphire ClinCard, which can be used as a 
credit or debit card. You will also receive instructions on how to use the card.  In order 
to receive study payments, your name, address, date of birth and Social Security 
Number (SSN) will be collected from you by the research staff.  All information will be 
stored in a secure fashion and will be deleted from the UT Southwestern Greenphire 
ClinCard system once the study has been completed.  
Important Information about Study Payments
1.Your SSN is needed in order to process your payments. Should you decide not to 
provide your SSN, your study participation payment will be decreased at the 
current IRS tax rate. Study payments are considered taxable income and are 
reportable to the IRS.
2.An IRS Form 1099 will be sent to you if your total payments are $600 or more in    a 
calendar year. 
3.Your payment nformation will not be shared with any third parties and will be kept 
completely confidential
This payment information will remain confidential unless you give your permission to 
share it with others, or if we are required by law to release it.
UT Southwestern, as a State agency, will not be able to make any payments to you for 
your participation in this research if the State Comptroller has issued a “hold” on all 
State payments to you.  Such a “hold” could result from your failure to make child 
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 11 of 14                                      DO NOT DISCLOSE 
support payments or pay student loans, etc.  If this happens, UT Southwestern will be 
able to pay you for your taking part in this research 1) after you have made the 
outstanding payments and 2) the State Comptroller has issued a release of the “hold.”
Will my insurance provider or I be charged for the costs of any part of this research 
study?
No. Neither you, nor your insurance provider, will be charged for anything done only for this 
research study (i.e., study drug, the Screening Procedures, Experimental Procedures, or 
Monitoring/Follow-up Procedures described above).  
However, the standard medical care for your condition (care you would have received whether 
or not you were in this study) is your responsibility (or the responsibility of your insurance 
provider or governmental program).  You will be charged, in the standard manner, for any 
procedures performed for your standard medical care.  Please note that the cost of any lipid 
lowering medicines will be your responsibility.
What will happen if I am harmed as a result of taking part in this study?
It is important that you report any illness or injury to the research team listed at the top of this 
form immediately.
If you experience a research injury, Dr. Garg will provide or arrange for medical treatment. A 
research injury is any physical injury or illness caused by your participation in the study.  If you 
are injured by a medical treatment or procedure that you would have received even if you 
weren’t in the study, that is not a research injury.  There are no plans to offer you payment for 
such things as lost wages, expenses other than medical care, or pain and suffering.  To help 
avoid injury, it is very important to follow all study directions.  You are not giving up any of your 
legal rights by signing this form. 
Compensation for an injury resulting from your participation in this research is not available from 
the University of Texas Southwestern Medical Center at Dallas.
You retain your legal rights during your participation in this research
Can I stop taking part in this research study?
Yes.  If you decide to participate and later change your mind, you are free to stop taking part in 
the research study at any time.
Your doctor is a research investigator in this study. He is interested in both your medical care 
and the conduct of this research study. At any time, you may discuss your care with another 
doctor who is not part of this research study. You do not have to take part in any research study 
offered by your doctor.
If you decide to stop taking part in this research study, it will not affect your relationship with the 
UT Southwestern staff or doctors.  Whether you participate or not will have no effect on your 
legal rights or the quality of your health care.
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status will not be 
affected in any way.
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 12 of 14                                      DO NOT DISCLOSE 
You may ask Dr. Garg to destroy any record of your participation in this research and to destroy 
any sample with your name on it.  You will not be asked for further information or samples.  
Your identity will be removed from all research records.   However, any data already generated 
from your samples will be kept to preserve the value of the study.  
If I agree to take part in this research study, can I be removed from the study without my 
consent?
Yes.  The researchers or the study sponsor may decide to take you off this study if:

Your medical problem becomes worse.

The researchers believe that participation in the research is no longer safe for you.

The researchers believe that other treatment may be more helpful.

The sponsor or the FDA stops the research for the safety of the participants.

The sponsor, IRB, or IEC, or regulatory agency cancels the research.

You are unable to keep appointments or to follow the researcher’s instructions.

You become pregnant, intend to become pregnant or are nursing a child during this 
study.
Will my information be kept confidential?
Medical information collected during this study and the results of any test or procedure that may 
affect your medical care may be included in your medical record. The information included in 
your medical record will be available to health care providers and authorized persons including 
your insurance company.
 You should know that certain organizations that may look at and/or copy your medical records 
for research, quality assurance, and data analysis include:
o
NIH
o
Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA) in the U.S. or other countries, involved in keeping research 
safe for people; and
o
The UT Southwestern Institutional Review Board.
o
Researchers who are conducting this study at other research sites 
The sponsor will use and disclose your information only for research or regulatory purposes or 
to prepare research publications.  In addition to using it for this study, the sponsor may 
reanalyze the study data at a later date or combine your information with information from other 
studies for research purposes not directly related to this study.  
The goal of any such research would be to learn more about drugs or diseases or to help design 
better studies in the future.  Your name will never appear in any sponsor reports or publications, 
or in any future disclosures by the sponsor.
The ways your study doctor will use your study-related health information and the people who 
may receive it are identified in a separate form entitled Authorization for Use and Disclosure of 
Health Information for Research Purposes.  You will be asked to sign that form to show that you 
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 13 of 14                                      DO NOT DISCLOSE 
give permission for these uses and sharing of your information.  You do not have to sign the 
authorization form.  However, if you do not, you will not be able to participate in the study
Where can I find additional information about this research study or the research 
results?
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time.  It may be 
many years; however, before research results are posted.
Are there procedures I should follow after stopping participation in this research?
Yes.  If you, the researchers, or the sponsor stops your participation in the research, you may 
be asked to do the following:

Let the researchers know immediately that you wish to withdraw from the research.

Return to the research center for tests that may be needed for your safety.

Return any unused study materials, including empty containers.

Discuss your future medical care, if any, with the researchers and/or your personal 
doctor.
  
Whom do I call if I have questions or problems?
For questions about the study, contact Dr. Garg or Dr. Ahmad at 214-648-2377 during regular 
business hours.   After hours, on weekends or holidays, please call   214-645-5555 press 0 and 
ask the operator to page Dr. Garg or Dr. Ahmad for you.  
For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060.
SIGNATURES:
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP.
Your signature below certifies the following:
Study ID: STU 062014-033   Date Approved: 4/16/2018


Page 14 of 14                                      DO NOT DISCLOSE 
•
You have read (or been read) the information provided above.
•
You have received answers to all of your questions and have been told who to call if you 
have any more questions.
•
You have freely decided to participate in this research.
•
You understand that you are not giving up any of your legal rights.
__________________________________________________
Participant’s Name (printed)
__________________________________________________
Participant’s Signature
_______________
Date  Time  AM/PM
__________________________________________________
Name of person obtaining consent (printed)
__________________________________________________
Signature of person obtaining consent
________________
Date TIME  AM/PM
Study ID: STU 062014-033   Date Approved: 4/16/2018