A Single-center, Open Label, Cross-over Study on the Effects of Ursodeoxycholic Acid (UDCA) in Patients With Hepatic Sarcoidosis
Phase: PHASE2
Conditions: Hepatic Sarcoidosis, Elevated Alkaline Phosphatase
Sponsor: Ethan Weinberg

  
 
              CONFIDENTIAL: This material is the property of the University of Pennsylvania.   
 
 
 
 
A SINGLE-CENTER, OPEN LABEL, CROSS-OVER STUDY ON 
THE EFFECTS OF URSODEOXYCHOLIC ACID (UDCA) IN 
PATIENTS WITH HEPATIC SARCOIDOSIS 
 
 
 
Principal Investigator (1) 
Ethan Weinberg, MD, MS 
3400 Spruce Street, 2 Dulles 
Philadelphia, PA 19104 
ethan.weinberg@uphs.upenn.edu 
 
 
Principal Investigator (2) 
 
K. Rajender Reddy, MD 
3400 Spruce Street, 2 Dulles 
Philadelphia, PA 19104 
rajender.reddy@uphs.upenn.edu 
Grant Number                             pending 
Investigational Product: 
 
URSODEOXYCHOLIC ACID (UDCA/ursodiol) tablets, for oral use  
 
 
IRB Number: 
 
 828780 
 
 
 
ClinicalTrials.gov Number       
 
 
 
NCT03602976 
 
 
 
Initial version 
14-NOV-2017 
Amendment 1  
30-JAN-2018 
Amendment 2     20-JUN-2018 
Amendment 3    26-JUL-2018 
Amendment 4    14-NOV-2018 
Amendment 5     15-JAN-2019 
Amendment 6     05-JUN-2019 
Amendment 7     01-JUL-2019 
Amendment 8 
30-JAN-2020 
Amendment 9    05-NOV-2020 
Amendment 10  02-JUN-2021 
 

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Table of Contents 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 3 
1        INTRODUCTION ................................................................................................................................... 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 3 
1.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT .......................................................... 4 
1.2.1 
Clinical Data to Date ................................................................................................................ 4 
1.2.2 
Clinical Studies in Children ...................................................................................................... 7 
1.3 
DOSE RATIONALE ........................................................................................................................... 7 
2 
STUDY OBJECTIVES ......................................................................................................................... 8 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 8 
2.2 
SECONDARY OBJECTIVES ............................................................................................................... 8 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 8 
3.1 
GENERAL DESIGN .......................................................................................................................... 8 
3.1.1 
Screening Visit......................................................................................................................... 8 
3.1.2 
Study Observational Phase ..................................................................................................... 9 
3.1.3 
Study Intervention Phase ........................................................................................................ 9 
3.1.4 
Follow Up Phase (Optional) .................................................................................................... 9 
3.2 
STUDY ENDPOINTS......................................................................................................................... 9 
3.2.1 
Primary Study Endpoints ......................................................................................................... 9 
3.2.2 
Secondary Study Endpoints .................................................................................................... 9 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ...................................................... 10 
4.1 
ELIGIBILITY CRITERIA ................................................................................................................... 10 
4.2 
SUBJECT RECRUITMENT ............................................................................................................... 10 
4.3 
DURATION OF STUDY PARTICIPATION ............................................................................................ 10 
4.4 
TOTAL NUMBER OF SUBJECTS AND SITES...................................................................................... 10 
4.5 
VULNERABLE POPULATIONS: ........................................................................................................ 10 
5 
STUDY INTERVENTION (UDCA) ...................................................................................................... 10 
5.1 
DESCRIPTION ............................................................................................................................... 11 
5.2 
INTERVENTION REGIMEN .............................................................................................................. 11 
5.3 
RECEIPT ...................................................................................................................................... 11 
5.4 
STORAGE .................................................................................................................................... 11 
5.5 
PREPARATION AND PACKAGING .................................................................................................... 11 
5.6 
ADMINISTRATION, ACCOUNTABILITY, AND SUBJECT DOSING COMPLIANCE MONITORING .................. 11 
6 
STUDY PROCEDURES ..................................................................................................................... 11 
6.1 
SCREENING ................................................................................................................................. 12 
6.2 
STUDY OBSERVATIONAL PHASE .................................................................................................... 13 
6.3 
STUDY INTERVENTION PHASE ....................................................................................................... 13 
6.4 
END OF STUDY/EARLY TERMINATION VISIT .................................................................................... 13 
6.5 
FOLLOW UP PHASE (OPTIONAL) ................................................................................................... 14 
6.6 
UNSCHEDULED VISITS .................................................................................................................. 14 
6.7 
SUBJECT WITHDRAWAL ................................................................................................................ 14 
6.7.1 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 15 
6.8 
CLINICAL LABORATORY TESTS ...................................................................................................... 15 
6.9 
OPTIONAL RESEARCH BLOOD SAMPLE COLLECTION ...................................................................... 15 
SUBJECTS WHO PROVIDE INFORMED CONSENT FOR THE COLLECTION AND USE OF THEIR BLOOD SAMPLES FOR 
FUTURE RESEARCH WILL HAVE SAMPLES COLLECTED EVERY 6 MONTHS DURING THE COURSE OF THEIR STUDY 

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PARTICIPATION. ALL SAMPLES WILL BE DE-IDENTIFIED PRIOR TO BEING STORED. SUBJECTS WHO DO NOT 
CONSENT TO THIS OPTIONAL COLLECTION WILL STILL BE ABLE TO PARTICIPATE IN THE REST OF THE STUDY. ... 15 
6.10 
EFFICACY EVALUATIONS ............................................................................................................... 15 
6.11 
SAFETY EVALUATIONS .................................................................................................................. 16 
7 
STATISTICAL PLAN ......................................................................................................................... 16 
7.1 
PRIMARY ENDPOINT ..................................................................................................................... 16 
7.2 
SECONDARY ENDPOINTS .............................................................................................................. 16 
7.3 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................... 16 
7.4 
STATISTICAL METHODS ................................................................................................................ 16 
7.4.1 
Baseline Data ........................................................................................................................ 16 
7.4.2 
Efficacy Analysis.................................................................................................................... 16 
7.4.3 
Safety Analysis ...................................................................................................................... 16 
7.5 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 17 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 17 
8.1 
DEFINITIONS ................................................................................................................................ 17 
8.1.1 
Adverse Event ....................................................................................................................... 17 
8.1.2 
Serious Adverse Event .......................................................................................................... 17 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 17 
8.3 
RELATIONSHIP OF AE TO STUDY ................................................................................................... 18 
8.4 
REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ..... 18 
8.4.1 
Follow-up report..................................................................................................................... 18 
8.4.2 
INVESTIGATOR REPORTING: NOTIFYING THE PENN IRB .................................................................. 18 
8.4.3 
Investigator reporting: Notifying the FDA .............................................................................. 18 
8.5 
MEDICAL MONITORING ................................................................................................................. 18 
8.5.1 
Data and Safety Monitoring Plan........................................................................................... 18 
9 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 19 
9.1 
CONFIDENTIALITY ......................................................................................................................... 19 
9.2 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 19 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 19 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 19 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 19 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 20 
11.1 
RISKS .......................................................................................................................................... 20 
11.2 
BENEFITS .................................................................................................................................... 20 
11.3 
RISK BENEFIT ASSESSMENT ......................................................................................................... 21 
11.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .............................................................. 21 
12 
STUDY FINANCES ............................................................................................................................ 21 
12.1 
FUNDING SOURCE ........................................................................................................................ 21 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 21 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 21 
13 
PUBLICATION PLAN ........................................................................................................................ 21 
14 
REFERENCES ................................................................................................................................... 21 
15 
ATTACHMENTS ................................................................................................................................ 22 
16 
APPENDIX ......................................................................................................................................... 22 
16.1 
REFERENCE FOR SAFETY REPORTING SECTION- COMMON DEFINITIONS FOR DEVELOPING AND 
ADVERSE EVENT TRACKING AND SERIOUS ADVERSE EVENT REPORTING PROTOCOL ................................... 22 
16.2 
EXPEDITED FDA REPORTING REQUIREMENTS ............................................................................... 22 
16.3 
SOURCE DOCUMENTS .................................................................................................................. 23 
16.4 
CASE REPORT FORMS (CRFS) ..................................................................................................... 23 
     16.5     Measurement of Liver Metabolic Function with the MBT                                                           21      

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Study Summary 
Title 
A single-center, open label, cross-over study on the effects of 
ursodeoxycholic acid (UDCA) in patients with hepatic sarcoidosis 
Short Title 
UDCA for Hepatic Sarcoid 
IRB Number 
828780 
Methodology 
Open label, cross-over design, pilot study 
Study Duration 
24 months inclusive of 12 month observational and interventional phases 
Study Center 
University of Pennsylvania (single-center)  
Objectives 
This study aims to:  
1. evaluate efficacy of UDCA in: (a) improving liver function laboratory and 
clinical parameters, (b) improving quality of life parameters  
2. monitor safety and tolerability of UDCA, as well as progression of hepatic 
sarcoidosis and liver disease, in patients diagnosed with hepatic sarcoidosis.  
Number of Subjects 
A minimum of 10 subjects are expected to be enrolled at this center. Target 
enrollment has been increased to 40 patients. 
Main Inclusion and 
Exclusion Criteria 
 
KEY INCLUSION 
KEY EXCLUSION 
-Hepatic granulomas or systemic 
sarcoidosis with evidence of liver 
involvement as denoted by any of 
the following: 
    - Elevated liver-specific ALP 
    - Granulomas on liver biopsy 
    - Hepatomegaly on imaging 
    - Portal Hypertension  
-hepatitis B, hepatitis C, alcohol-
related liver disease, autoimmune 
hepatitis, primary biliary cholangitis, 
primary sclerosing cholangitis) 
-Currently on UDCA 
-Prior intolerance to UDCA 
   
Investigational 
Product  
 
URSODEOXYCHOLIC ACID (UDCA), (ursodiol) tablets, for oral use 
Duration of 
administration  
For all subjects, initial 6 months will be observational; in subsequent 6 
months, UDCA will be administered twice daily. 

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Statistical 
Methodology 
 The primary end-point is a reduction in ALP and/or GGT from baseline. We 
plan to use the effect size obtained from this pilot study to launch a multi-
centered study that can be adequately powered to predict a specified 
percentage reduction in clinical and laboratory parameters with statistical 
significance.   
Safety Evaluations  
Laboratory parameters, including liver function and hematology panels, will 
be routinely assessed to monitor safety and tolerability of UDCA during study 
interventional phase.  
Data and Safety 
Monitoring Plan  
The PI will be responsible for monitoring the data quality and the ongoing 
safety of subjects.  
 
 
 

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BACKGROUND AND STUDY RATIONALE 
This study will be conducted in full accordance all applicable University of Pennsylvania Research Policies 
and Procedures and all applicable Federal and state laws and regulations including Good Clinical Practice 
standards: Consolidated Guidelines approved by the International Conference on Harmonisation (ICH).  
1        Introduction 
Guidelines for the treatment of hepatic sarcoid suggest waiting until a patient is symptomatic or 
experiencing evidence of liver dysfunction to treat. The approach to the treatment of hepatic sarcoid should 
be similar to two other autoimmune liver diseases: autoimmune hepatitis (AIH) and primary biliary 
cholangitis (PBC).  Liver decompensation can be prevented in both AIH and PBC if the disease is diagnosed 
and treated in the early stages.  The first-line treatment for AIH is immunosuppression with corticosteroids 
and azathioprine; for PBC, it is UDCA.  In a similar vein, patients with hepatic sarcoid may benefit from 
earlier initiation of therapy.  Given its excellent safety profile and minimal side effects, UDCA may be the 
consensus first-line treatment for hepatic sarcoid, a disease that, like PBC, usually causes a cholestatic 
liver injury.  
1.1 
Background and Relevant Literature  
Sarcoidosis is a relatively rare, poorly defined autoimmune disease characterized by the formation of sterile 
granulomas in affected organs.1  Studies over the years have implicated various genetic and environmental 
risk factors for development of sarcoidosis, but no single factor has been discovered to be the key initiator 
of the disease.2  It is known that granuloma formation in sarcoidosis is driven by host T-cell interactions 
with antigen-presenting cells, but the intricacies of the immunologic events and the particular antigens 
responsible for perpetuating the disease remain to be determined.1  Sarcoidosis is more prevalent in the 
West compared to the East, with a greater than 10-fold annual incidence of sarcoidosis seen in Northern 
Europe and the United States compared to Japan.1  Within the United States, black women are at the 
highest risk for development of sarcoidosis, with rates three times that of Caucasian women.  
Overwhelmingly, the most common organs affected by sarcoidosis are the lungs, which are affected in 
more than 95% of patients with sarcoidosis.3  This is followed by the skin, eyes, and liver.3,4  In the two 
largest prospective cohort studies of sarcoidosis, the liver was affected in 11.5% and 17.7% of patients, 
respectively.3,4 The diagnosis of hepatic sarcoid is often presumed based upon an elevated liver-specific 
isoenzyme of alkaline phosphatase or imaging findings suggestive of portal hypertension, hepatomegaly, 
or liver lesions in a patient with known pulmonary sarcoidosis; a minority of hepatic sarcoid cases are 
diagnosed through liver biopsy.4   
 
The mainstay of treatment of systemic sarcoidosis in those with symptoms is immunosuppression with 
corticosteroids, which are gradually tapered over months.5  The disease course for sarcoidosis can vary; 
patients who are asymptomatic can be monitored without therapy, while some require intermittent 
corticosteroids for flares.  For those patients with persistent symptoms on corticosteroids, additional 
immunosuppressive or cytotoxic agents (e.g. azathioprine, methotrexate, infliximab, rituximab) are used.5  
The expert guidelines for treatment of hepatic sarcoid suggest waiting until a patient is symptomatic or 
experiencing evidence of liver dysfunction to treat. This approach is in opposition to the treatment of primary 
liver diseases in which treatment is often initiated based upon abnormal lab values even without symptoms, 
as symptoms of liver disease (ascites, variceal bleeding, pruritus, jaundice, and encephalopathy) often 
occur late in the disease.   
 
The approach to the treatment of hepatic sarcoid should be similar to two other autoimmune liver diseases: 
AIH and PBC.  Liver decompensation can be prevented in both conditions if the disease is diagnosed and 
treated in the early stages.  The first-line treatment for AIH is immunosuppression with corticosteroids and 
azathioprine; for PBC, it is UDCA.  In a similar vein, patients with hepatic sarcoid may benefit from earlier 
initiation of therapy.  Given its excellent safety profile and minimal side effects, UDCA may be the consensus 
first-line treatment for hepatic sarcoid, a disease that, like PBC, usually causes a cholestatic liver injury.  
There have been case reports and retrospective studies documenting the beneficial effects of UDCA on 
hepatic sarcoid.6–8  However, thus far, there have been no clinical trials to evaluate the efficacy of UDCA in 
hepatic sarcoid. 

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1.2 
Name and Description of the Investigational Product  
Ursodeoxycholic acid (abbreviated UDCA), also known as ursodiol, is available as a film-coated tablet for 
oral administration as 250 mg (URSO 250®), 500 mg (URSO Forte®) film-coated tablets, and Actigall 
300mg capsules for oral administration. UDCA is a naturally occurring bile acid found in small quantities in 
normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white 
powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in 
chloroform, sparingly soluble in ether, and practically insoluble in water. The chemical name of UDCA is 
3α,7ß-dihydroxy-5ß-cholan-24-oic (C24 H40 O4). UDCA has a molecular weight of 392.56. Its structure is 
shown below:  
 
 
1.2.1 
Clinical Data to Date 
A multicenter, randomized, double-blind, placebo-controlled study was conducted in the US to evaluate the 
efficacy of ursodeoxycholic acid at a dose of 13 to 15 mg/kg/day, administered in 3 or 4 divided doses in 
180 patients with PBC (78% received QID dosage). Upon completion of the double-blind portion, all patients 
entered an open-label active treatment extension phase.  
 
Treatment failure, the main efficacy end point measured during this study, was defined as death, need for 
liver transplantation, histologic progression by two stages or to cirrhosis, development of varices, ascites 
or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum 
bilirubin and voluntary withdrawal. After two years of double-blind treatment, the incidence of treatment 
failure was significantly reduced in the URSO 250® group (n=89) as compared to the placebo group (n=91). 
Time to treatment failure was also significantly delayed in the URSO 250® treated group regardless of 
either histologic stage or baseline bilirubin levels (>1.8 or <1.8 mg/dl).  
 
Using a definition of treatment failure which excluded doubling of serum bilirubin and voluntary withdrawal, 
time to treatment failure was significantly delayed in the URSO 250® group. In comparison with placebo, 
treatment with URSO 250® resulted in a significant improvement in the following serum hepatic 
biochemistries when compared to baseline: total bilirubin, SGOT, alkaline phosphatase and IgM.  
 
A second study conducted in Canada randomized 222 PBC patients to UDCA, 14 mg/kg/day or placebo, 
administered as a once daily dose in a double-blind manner during a two-year period. At two years, a 
statistically significant difference between the two treatments, in favor of UDCA, was demonstrated in the 
following: reduction in the proportion of patients exhibiting a more than 50% increase in serum bilirubin; 
median percent decrease in bilirubin, transaminases and alkaline phosphatase; incidence of treatment 
failure; and time to treatment failure. The definition of treatment failure included: discontinuing the study for 
any reason; a total serum bilirubin level greater than or equal to 1.5 mg/dl or increasing to a level equal to 
or greater than two times the baseline level; and the development of ascites or encephalopathy. Evaluation 
of patients at 4 years or longer was inadequate due to the high drop-out rate and small number of patients. 
Therefore, death, need for liver transplantation, histological progression by two stages or to cirrhosis, 
development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritis, inability to 
tolerate the drug, doubling of serum bilirubin and voluntary withdrawal were not assessed.  
 
A randomized, two-period crossover study in fifty PBC patients compared efficacy of URSO 250®  
(UDCA) in BID (two) versus QID (four) divided dosing schedules in 50 patients for 6 months in each 
crossover period.  Mean percent changes from baseline in liver test results and Mayo risk score (n=46) and 
serum enrichment with UDCA (n=34) were not statistically significant with any dosage at any time interval. 

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This study demonstrated that UDCA (13 to 15 mg/kg/day) given BID is equally effective to UDCA given 
QID. In addition, URSO 250® was given as a single (once daily) versus TID (three) dosing schedules in 10 
patients. Due to the small number of patients in this arm of the study, it was not possible to conduct 
statistical comparisons between these regimens. 
 
In a randomized, cross-over study in sixty PBC patients, four patients (6.7%) experienced one serious 
adverse event each (diabetes mellitus, cyst and breast neoplasm (experienced by two patients)). No deaths 
occurred in the study. Forty-three patients (43, 71.7%) experienced at least one treatment-emergent 
adverse event (TEAEs) during the study.  The most common (>5%) TEAEs were asthenia (11.7%), 
dyspepsia (10%), peripheral edema (8.3%), hypertension (8.3%), nausea (8.3%), GI disorders (5%), chest 
pain (5%), and puritius (5%). Seven patients (11.6%) reported nine events that were judged as possibly or 
probably related to study medication. These nine TEAEs included abdominal pain and asthenia (1 patient), 
nausea (3 patients), dyspepsia (2 patients) and anorexia and esophagitis (1 patient each). One patient on 
the BID regimen (total dose 1000 mg) withdrew due to nausea.  All of these nine TEAEs except esophagitis 
were observed with the BID regimen at a total daily dose of 1000 mg or greater.   
 
On the basis of clinical trial results in a total of 868 patients with radiolucent gallstones treated in 8 studies 
(three in the U.S. involving 282 patients, one in the U.K. involving 130 patients, and four in Italy involving 
456 patients) for periods ranging from 6 to 78 months with Actigall doses ranging from about 5-20 
mg/kg/day, an Actigall dose of about 8-10 mg/kg/day appeared to be the best dose. With an Actigall dose 
of about 10 mg/kg/day, complete stone dissolution can be anticipated in about 30% of unselected patients 
with uncalcified gallstones < 20 mm in maximal diameter treated for up to 2 years. Patients with calcified 
gallstones prior to treatment, or patients who develop stone calcification or gallbladder nonvisualization on 
treatment, and patients with stones > 20 mm in maximal diameter rarely dissolve their stones. The chance 
of gallstone dissolution is increased up to 50% in patients with floating or floatable stones (i.e., those with 
high cholesterol content), and is inversely related to stone size for those < 20 mm in maximal diameter. 
Complete dissolution was observed in 81% of patients with stones up to 5 mm in diameter. Age, sex, weight, 
degree of obesity, and serum cholesterol level are not related to the chance of stone dissolution with 
Actigall. A nonvisualizing gallbladder by oral cholecystogram prior to the initiation of therapy is not a 
contraindication to Actigall therapy (the group of patients with nonvisualizing gallbladders in the Actigall 
studies had complete stone dissolution rates similar to the group of patients with visualizing gallbladders). 
However, gallbladder nonvisualization developing during ursodiol treatment predicts failure of complete 
stone dissolution and in such cases therapy should be discontinued. Partial stone dissolution occurring 
within 6 months of beginning therapy with Actigall appears to be associated with a > 70% chance of eventual 
complete stone dissolution with further treatment; partial dissolution observed within 1 year of starting 
therapy indicates a 40% probability of complete dissolution. Stone recurrence after dissolution with Actigall 
therapy was seen within 2 years in 8/27 (30%) of patients in the U.K. studies. Of 16 patients in the U.K. 
study whose stones had previously dissolved on chenodiol but later recurred, 11 had complete dissolution 
on Actigall. Stone recurrence has been observed in up to 50% of patients within 5 years of complete stone 
dissolution on ursodiol therapy. Serial ultrasonographic examinations should be obtained to monitor for 
recurrence of stones, bearing in mind that radiolucency of the stones should be established before another 
course of Actigall is instituted. A prophylactic dose of Actigall has not been established.  
 
Two placebo-controlled, multicenter, double-blind, randomized, parallel group trials in a total of 1,316 obese 
patients were undertaken to evaluate Actigall in the prevention of gallstone formation in obese patients 
undergoing rapid weight loss. The first trial consisted of 1,004 obese patients with a body mass index (BMI) 
≥ 38 who underwent weight loss induced by means of a very low calorie diet for a period of 16 weeks. An 
intent-to-treat analysis of this trial showed that gallstone formation occurred in 23% of the placebo group, 
while those patients on 300, 600, or 1200 mg/day of Actigall experienced a 6%, 3%, and 2% incidence of 
gallstone formation, respectively. The mean weight loss for this 16-week trial was 47 lb for the placebo 
group, and 47, 48, and 50 lb for the 300, 600, and 1200 mg/day Actigall groups, respectively. The second 
trial consisted of 312 obese patients (BMI ≥ 40) who underwent rapid weight loss through gastric bypass 
surgery. The trial drug treatment period was for 6 months following this surgery. Results of this trial showed 
that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 600, or 1200 
mg/day of Actigall experienced a 9%, 1%, and 5% incidence of gallstone formation, respectively. The mean 

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weight loss for this 6-month trial was 64 lb for the placebo group, and 67, 74, and 72 lb for the 300, 600, 
and 1200 mg/day Actigall groups, respectively. 
1.2.1.1 
Human Pharmacokinetics 
UDCA is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral 
administration, the majority of UDCA is absorbed by passive diffusion and its absorption is incomplete. 
Once absorbed, UDCA undergoes hepatic extraction to the extent of about 50% in the absence of liver 
disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, UDCA 
is conjugated with glycine or taurine, then secreted into bile. These conjugates of UDCA are absorbed in 
the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the 
ileum by intestinal enzymes, leading to the formation of free UDCA that can be reabsorbed and 
reconjugated in the liver. Nonabsorbed UDCA passes into the colon where it is mostly 7-dehydroxylated to 
lithocholic acid. Some UDCA is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also 
undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in 
the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine 
and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and 
then lost in feces.  
 
Lithocholic acid, when administered chronically to animals, causes cholestatic liver injury that may lead to 
death from liver failure in certain species unable to form sulfate conjugates. UDCA is 7-dehydroxylated 
more slowly than chenodiol. For equimolar doses of UDCA and chenodiol, steady state levels of lithocholic 
acid in biliary bile acids are lower during UDCA administration than with chenodiol administration. Humans 
and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with UDCA 
therapy, a reduced capacity to sulfate may exist in some individuals. Nonetheless, such a deficiency has 
not yet been clearly demonstrated and must be extremely rare, given the several thousand patient-years 
of clinical experience with UDCA.  
 
In healthy subjects, at least 70% of UDCA (unconjugated) is bound to plasma protein. No information is 
available on the binding of conjugated UDCA to plasma protein in healthy subjects or primary biliary 
cirrhosis (PBC) patients. Its volume of distribution has not been determined, but is expected to be small 
since the drug is mostly distributed in the bile and small intestine. UDCA is excreted primarily in the feces. 
With treatment, urinary excretion increases, but remains less than 1% except in severe cholestatic liver 
disease.  
 
During chronic administration of UDCA, it becomes a major biliary and plasma bile acid. At a chronic dose 
of 13 to 15 mg/kg/day, UDCA constitutes 30-50% of biliary and plasma bile acids. 
 
Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption 
of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous 
bile acids, and does not appear to affect secretion of phospholipids into bile. With repeated dosing, bile 
ursodeoxycholic acid concentrations reach a steady-state in about 3 weeks. Although insoluble in aqueous 
media, cholesterol can be solubilized in at least two different ways in the presence of dihydroxy bile acids. 
In addition to solubilizing cholesterol in micelles, ursodiol acts by an apparently unique mechanism to cause 
dispersion of cholesterol as liquid crystals in aqueous media. Thus, even though administration of high 
doses (e.g., 15 -18 mg/kg/day) does not result in a concentration of ursodiol higher than 60% of the total 
bile acid pool, ursodiol-rich bile effectively solubilizes cholesterol. The overall effect of ursodiol is to increase 
the concentration level at which saturation of cholesterol occurs. The various actions of ursodiol combine 
to change the bile of patients with gallstones from cholesterol-precipitating to cholesterol-solubilizing, thus 
resulting in bile conducive to cholesterol stone dissolution. After ursodiol dosing is stopped, the 
concentration of the bile acid in bile falls exponentially, declining to about 5% to 10% of its steady-state 
level in about 1 week. 
1.2.1.2 
Clinical Studies in Adults: Pregnancy Category B 
Teratology studies have been performed in pregnant rats at oral doses up to 2,000 mg/kg/day (12,000  

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mg/m2/day, 22 times the recommended maximum human dose based on body surface area) and in 
pregnant rabbits at oral doses up to 300 mg/kg/day (3,600 mg/m2/day, 7 times the recommended maximum 
human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to 
the fetus due to UDCA.  
 
There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies 
are not always predictive of human response, this drug should be used during pregnancy only if clearly 
needed. It is also not known whether UDCA is excreted in human milk. Because many drugs are excreted 
in human milk, caution should be exercised when URSO 250® and URSO Forte® are administered to a 
nursing mother. 
 
There are no contraceptive requirements for males. Ursodiol was not genotoxic in the Ames test, the mouse 
lymphoma cell (L5178Y, TK+/-) forward mutation test, the human lymphocyte sister chromatid exchange 
test, the mouse spermatogonia chromosome aberration test, the Chinese hamster micronucleus test and 
the Chinese hamster bone marrow cell chromosome aberration test. Ursodiol at oral doses of up to 2,700 
mg/kg/day (16,200 mg/m2/day, 29 times the recommended maximum human dose based on body surface 
area) was found to have no effect on fertility and reproductive performance of male and female rats. 
1.2.2 
Clinical Studies in Children  
The safety and effectiveness of URSO 250® and URSO Forte® in pediatric patients have not been 
established. 
1.3 
Dose Rationale   
The recommended adult dosage for URSO 250® and URSO Forte® in the treatment of PBC is 13-15  
mg/kg/day administered in two to four divided doses with food. The URSO Forte® scored tablet can be 
broken in halves to provide recommended dosage. Due to the bitter taste, segments should be stored 
separately. Half-tablets (scored URSO Forte® 500 mg tablets broken in half) maintain acceptable quality 
for up to 28 days when stored in the current packaging (bottles) at 25ºC (77ºF), The recommended adult 
dosage for Actigall 300mg (for treatment of radiolucent gallbladder stones) is 8-10 mg/kg/day given in 2-3 
divided doses. Dosing regimen should be adjusted according to each patient’s need at the discretion of the 
physician.   We will be using 250mg or 500mg tablets, or 300mg capsules for this protocol. This decision 
will be determined based on price, pill burden, and adherence complexity. Subjects will receive a targeted 
dose of 13-15 mg/kg/day in divided doses to be taken with meals. As the approach to the treatment of 
hepatic sarcoid in this protocol is designed to resemble that of the treatment of PBC, the targeted dose for 
subjects taking the Actigall 300mg capsules will also be 13-15 mg/kg/day, which remains within safe means 
of dosing for this formulation. For subjects in which the dosing increment does not fall into the 13-15mg/kg 
range, we will initiate intervention using the lower dose. For example, if a subject is 80kg, the dose range 
is from 1040-1200mg/kg/day.  We will initiate 1000mg/day (12.5mg/kg/day in our 80kg example) rather than 
1250mg/day (15.6 mg/kg/day).  If the subject tolerates this lower dose well and the ALP and GGT have not 
reached a 20% decreased by month 9 (after 3 months of treatment), the subject will receive an additional 
250mg tablet for daily administration. A dose calculation assessment will be performed at each in-person 
visit following UDCA administration.  UDCA doses in the range of 17-23mg/kg have been used in long-term 
trials for PSC (PMID: 11606503, PMID:16285948). The UDCA studies in PSC demonstrated an 
improvement in ALP and GGT in subjects taking UDCA without an increase in adverse events from the 
medication. 
 
Accidental or intentional overdosage with UDCA has not been reported. The most severe manifestation of 
overdosage would likely consist of diarrhea which should be treated symptomatically.  
Single oral doses of UDCA at 10, 5 and 10 g/kg in mice, rats and dogs, respectively, were not lethal. A 
single oral dose of UDCA at 1.5 g/kg was lethal in hamsters. Symptoms of acute toxicity were salivation 
and vomiting in dogs, and ataxia, dyspnea, ptosis, agonal convulsions and coma in hamsters. Doses of 
Actigall in the range of 16-20 mg/kg/day have been tolerated for 6 to 37 months without symptoms by 7 
patients. The LD50 for ursodiol in rats is over 5000 mg/kg given over 7 to 10 days and over 7500 mg/kg for 
mice. 

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2 
Study Objectives 
The objectives of this study are to evaluate the efficacy of UDCA in improving liver function and quality of 
life, and to assess the safety and tolerability of UDCA, as well as the progression of disease, in patients 
with hepatic sarcoidosis. 
2.1 
Primary Objective 
 Evaluate the efficacy of UDCA in improving liver function as measured by a reduction in alkaline 
phosphatase (ALP) and/or gamma-glutamyl transferase (GGT) from baseline 
2.2 
Secondary Objectives  
 Evaluate the efficacy of UDCA in improving other liver function laboratory and clinical parameters 
(as measured by improvements in liver function tests and Fibroscan measurements) 
 Assess quality of life parameters prior to and following intervention with UDCA (as measured by 
improvements in patient-reported outcomes (PRO) questionnaire scores) 
 Assess the safety and tolerability of UDCA, as well as disease progression (as measured by 
laboratory tests including liver function and hematology panels) 
 Assess the effect of UDCA on the metabolic capacity of the liver as determined by the 13C 
methacetin breath test (exploratory objective) 
 Assess the effect of UDCA on other laboratory measures associated with sarcoidosis, including 
angiotensin converting enzyme (ACE) and soluble interleukin 2 receptor (sIL2R) 
 Collect serum and plasma samples for biobanking 
3 
Investigational Plan  
3.1 
General Design 
This will be a pragmatic, single-center, cross-over pilot study to evaluate the safety and efficacy of UDCA 
in patients subjects with hepatic sarcoidosis.  For this project, potential subjects (i.e. patients with a prior 
diagnosis of sarcoidosis and lab/imaging findings suggestive of hepatic sarcoid) seen at Penn Medicine 
clinics will be identified by the study team and screened in the Hepatology clinic at the Perelman Center for 
Advanced Medicine.  .  At least ten patients will be enrolled for an expected twelve month duration. 
Frequency of clinical evaluations will align with standard of care monitoring of this patient population; the 
study-specific intervention will be the administration of UDCA (unblinded). Study-specific procedures 
include research labs, patient-reported outcomes questionnaires; optional biomarker retains, methacetin 
breath test (MBT) measurements; further details on the schedule of events for this study can be found in 
section 6. 
NOTE: All subjects enrolled under Amendment 10 (JUN 2021) or later will NOT be included in the 
optional MBT sub-study. 
3.1.1 
Screening Visit 
At the screening visit, prior to any study-related screening procedures being performed on the subject, the 
informed consent statement will be reviewed with the subject by the PI and signed and dated by the subject 
and the PI. For all subjects, the PI and/or study coordinator will: record medical history, record prior and 
current medications, record general health (including averse events and illnesses), conduct physical 
examination (including assessment of certain physical symptoms that are associated with liver disease), 
collect vital signs, perform a Fibroscan (ultrasound of abdomen to measure liver stiffness), administer 
quality of life (QoL) questionnaires, and collect blood samples for routine laboratory tests specific to liver 
function. A urine pregnancy test will be performed at screening for women of child-bearing potential 
(WOCBP). These subjects will also be required to confirm the use of appropriate contraceptive prior to 
receiving UDCA while in the study. 

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3.1.2 
Study Observational Phase 
Once the PI confirms a subject’s eligibility, subject will be called by the study coordinator and asked to 
come back to the clinic for 4 future visits over the course of 1 year. The visits will occur approximately every 
3 months, according to standard of care monitoring of this patient population.  
 
The Day 1 and Month 3 study assessments will be observational in nature, and can be performed remotely, 
per standard of care for patients with hepatic sarcoidosis. During the Day 1 telephone encounter, the study 
coordinator will review current medications with subjects. During the Month 3 visit, for all subjects, the PI 
and/or coordinator will: review prior and current medications, record your general health (including averse 
events and illnesses), conduct physical examination, including assessment of certain physical symptoms 
that are associated with liver disease, collect vital signs (if visit is conducted in clinic), height and weight,  
and collect blood samples for routine laboratory tests specific to liver function. If visiting the clinic at Month 
3 is impractical for the subject for any reason, Month 3 assessments can be conducted remotely. 
3.1.3 
Study Intervention Phase  
Study medication will be dispensed at Month 6 to initiate the interventional phase of the study. During study 
visits, for all subjects, the research team will: review prior and current medications, record your general 
health (including adverse events and illnesses), conduct physical examination, including assessment of 
certain physical symptoms that are associated with liver disease, collect vital signs, height and weight, 
perform a Fibroscan (ultrasound of abdomen to measure liver stiffness), perform MBT (Month 6 and Month 
12), administer QoL questionnaires, collect blood samples for routine laboratory tests specific to liver 
function, initiation of study medication (Month 6), and assess medication compliance (Month 9 and Month 
12). For WOCBP, urine pregnancy testing will be performed at Month 6 and every 4 weeks while on drug. 
Home pregnancy testing kits will be provided for this. WOCBP will be contacted by the study coordinator 
every 4 weeks while on drug for reporting results of urine pregnancy tests. Subjects will be instructed to 
notify Dr. Weinberg or the study coordinator if they become pregnant at any time during the study, and to 
discontinue study drug immediately upon suspecting pregnancy. Drug will be discontinued immediately for 
any subject who becomes pregnant during the study. Pregnancy will not be considered an AE, nor will an 
elective abortion to terminate a pregnancy without medical reasons. Pregnancy outcomes will not be 
followed for this study. 
3.1.4 
Follow Up Phase (Optional) 
Subjects will have the option to remain on UDCA after study completion if it can be obtained through 
prescription outside of the trial.     PI will continue to follow all of these patients in hepatology clinic after 
completion of the trial as clinically indicated. Data will be collected for an additional 12 months. 
3.2 
Study Endpoints  
3.2.1 
Primary Study Endpoints 
To evaluate the efficacy of UDCA in improving liver function, the following laboratory parameters will be 
assessed: 
1.  Reduction in ALP and/or GGT from baseline 
3.2.2 
Secondary Study Endpoints 
1. safety and tolerability of UDCA in patients with hepatic sarcoidosis (liver function tests will be 
monitored alongside reporting of adverse events)  
2. efficacy of UDCA in the improvement of liver stiffness as a clinical parameter of liver function 
(Fibroscan stiffness readings (in kPa) will be monitored)  
3. Changes in quality of life parameters prior to and following intervention with UDCA (PRO 
questionnaire scores will be assessed for improvements)  
4. Changes in the 13C-methacetin breath tests in all subjects prior to and following intervention with 
UDCA (exploratory endpoint) 
5. Changes in ACE and sIL2R 
 

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4 
Study Population and Duration of Participation  
A minimum of ten adult patients with a prior diagnosis of sarcoidosis and lab/imaging findings suggestive 
of hepatic sarcoid will be enrolled for a twelve-month comprehensive observational and interventional 
period. Subjects will have the option to continue being followed for another year; thus the study will last 
approximately 24 months, cumulative of recruitment, enrollment, data collection, and analysis.  
4.1 
Eligibility Criteria 
Study Eligibility Criteria 
Inclusion 
Exclusion 
1. Male or female, at least 18 years of age, and able to 
provide written informed consent  
2. Systemic sarcoidosis with evidence of liver 
involvement as denoted by any of the following: 
    - Elevated liver-specific alkaline phosphatase 
    - Granulomas on liver biopsy 
    - Hepatomegaly on imaging 
    - Portal Hypertension (via imaging or endoscopy) 
OR granulomas on liver biopsy (not attributable to 
infection) AND elevated liver-specific alkaline 
phosphatase 
3. Stable dose of immunosuppressant > 6 months (with 
the exception of changes in prednisone less than or 
equal to 20 mg or prednisone equivalent) 
4. If cirrhotic, absence of hepatocellular carcinoma as 
indicated by imaging within 6 months of screening 
1. Female who is pregnant, planning to become 
pregnant during the study, or breastfeeding 
2. Clinically significant abnormalities, co-morbidities, or 
recent alcohol/drug abuse that make the subject an 
unsuitable candidate 
3. hepatitis B, hepatitis C, alcohol-related liver disease, 
autoimmune hepatitis, primary biliary cholangitis, 
primary sclerosing cholangitis) 
4. Currently on or prior intolerance to UDCA 
5. Receipt of any investigational product within a time 
period equal to 10 half-lives of the product, or 6 weeks 
(whichever is longer), to study drug administration 
6. Current evidence of hepatic decompensation 
(variceal bleeding, hepatic encephalopathy, or ascites). 
In the event potential participant is post-transplant, no 
evidence of hepatic decompensation since 
transplantation 
4.2 
Subject Recruitment  
Potential subjects will be recruited from Penn Medicine clinics as well as remote clinics. The PI and study 
team will identify study candidates; referrals from physicians or the subjects themselves will be accepted 
and further assessed for eligibility by the PI during a screening visit which will take place in the Hepatology 
clinic at the Perelman Center for Advanced Medicine.  
4.3 
Duration of Study Participation 
The expected duration of the subjects’ participation is initially 12 months. Monitoring for an additional 12 
months will be optional.   
4.4 
Total Number of Subjects and Sites  
It is approximated that 15 subjects will need to be screened in order to produce 10 evaluable subjects.  
4.5 
Vulnerable Populations:  
All subjects to be recruited in this trial will be referred to us by their physician. Children, pregnant women, 
fetuses, neonates, or prisoners are not included in this research study. No mentally disabled or 
economically disadvantaged persons will be enrolled. Only subjects able to provide informed consent 
autonomously will be eligible for enrollment. Penn students or employees will not be directly targeted or 
excluded. In the event that Penn students or employees present for screening, they will be informed that 
their decision regarding whether or not to participate will in no way impact their standing at the University. 
5 
Study Intervention (UDCA) 
During the second 6 months of the study, all subjects will receive open-label UDCA 250mg or 500mg 
tablets, or 300mg capsules. This will be obtained through prescription and initiated at the Month 6 visit. 
Subjects will take this medication twice daily as instructed for 6 months, as described above. If the subject 
is taking a sequestrant, the UDCA would need to be taken 5 hours apart from it (because bile acid 
sequestrants, such as cholestyramine, can bind UDCA).  Bile acid sequestrants and estrogen can lower 

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the therapeutic effect of UDCA, but these are not contraindications to taking UDCA. More information on 
the study medication, UDCA, can be found in section 1.2 as well as the package insert for Ursodiol. 
5.1 
Description 
See section 1.2 and 1.3, as well as the package inserts for Ursodiol for more information. 
5.2 
Intervention Regimen 
 
Dosing for study participants with mild liver disease: 
After at least 3 months of treatment and if subject weighs more than 200 lbs., PI may decide to increase 
dose of study drug based on a review of lab results and ability to tolerate the study drug.  Dose would be 
increased to two tablets (500mg) with breakfast and one tablet (250mg) with dinner. If subject is on the 
300mg option, their dosage would be calculated accordingly using these models. 
 
Dosing for study participants with moderate liver disease:   
If during the screening period of the study, it is determined that subject has moderate liver disease, subject 
may receive corticosteroids (per standard of care).  If subject is already taking corticosteroids, dose may 
be increased. 
5.3 
Receipt  
At the Month 6 visit, a 3-month supply of drug will be prescribed by study investigator and obtained through 
insurance and filled at pharmacy of choice. Subjects will be prescribed another 3-month supply at Month 9 
visit. Subjects will take this medication as instructed and return to the clinic at Month 9 and Month 12 for 
routine care visits, inclusive of dosing compliance assessment.  
5.4 
Storage 
UDCA will be stored at 20C to 25C (68F to 77F) and dispensed in a tight container.  
5.5 
Preparation and Packaging 
Each URSO 250® elliptical, biconvex, film-coated tablet, white, engraved with "URS785", contains 250 mg 
of UDCA.  Available in bottles of 100 tablets (NDC 58914-785-10) and 500 tablets (NDC 58914-785-50). 
Each URSO Forte® elliptical, biconvex, scored, film-coated tablet, white, engraved with "URS790", contains 
500 mg of ursodiol. Available in bottles of 100 tablets (NDC 58914-790-10) and 500 tablets (NDC 58914-
790-50).  
Actigall Capsules are opaque white and pink capsules imprinted “ACTIGALL” on one half and “300 mg” on 
the other half of the capsule in black. Bottles of 100 are supplied with child-resistant closures. (NDC 0023-
6145-01)  
5.6 
Administration, Accountability, and Subject Dosing Compliance Monitoring 
The investigator or his/her designated and qualified representatives will prescribe study drug only to 
subjects enrolled in the study in accordance with the protocol. The study drug must not be used for reasons 
other than that described in the protocol. At the start of the study, each subject should receive counseling 
regarding the importance of dosing compliance. At visits following the initiation of dosing, study site 
personnel will assess subject compliance by asking subjects if any doses were missed. Treatment 
compliance will be based on the subjects’ responses, as recorded in source.  
6 
Study Procedures 
Schedule of study assessments 
Activity 
Screening 
(CV) 
Month 0 
(PC) 
Month 3 
(CV/PC) 
Month 6 
(CV) 
Month 9 
(CV/PC) 
Month 12 
(CV) 
Month 18 
follow-up 
(CV) 
Month 24 
follow-up 
(CV) 
Informed consent 
X* 
 
 
 
 
X* 
 
 

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Demographics & medical 
history (including assessment 
of liver disease) 
X 
 
 
 
 
 
 
 
Urine pregnancy test for 
WOCBP 
X* 
 
 
X* 
X* 
X* 
 
 
Physical exam & vital signs 
X 
 
X 
X 
X 
X 
X 
X 
Fibroscan 
X 
 
 
X* 
 
X 
X* 
X 
13C-methacetin breath test 
(optional sub-study)*** 
 
 
 
X* 
 
X* 
 
 
QoL questionnaire 
X* 
 
 
X* 
 
X* 
X* 
X* 
Concomitant medication 
assessment 
X 
X* 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
Drug initiation 
 
 
 
X* 
 
 
 
 
Weight-based daily dosage 
calculation (if in-person visit) 
 
 
 
 
X 
X 
 
       X 
 
       X 
Drug accountability & 
adherence assessment 
 
 
 
 
X* 
X* 
X* 
X* 
Blood draw: clinical laboratory 
assessments:**  
-LFP 
-CBC 
-GGT 
X 
 
X 
X 
X 
X 
X 
X 
Blood draw: research lab 
assessments: 
-ACE 
-sIL2R 
-optional research samples 
X* 
 
 
X* 
 
X* 
X* 
X* 
*Research specific activity       
 **Subjects can have labs drawn at the laboratory of their choice       
CV = clinic visit; PC = phone call; QoL = Quality of Life 
LFP = liver function panel; CBC = complete blood count; GGT = gamma-glutamyl transferase 
*** NOTE: All subjects enrolled under Amendment 10 (JUN 2021) or later will NOT be included in the 
optional MBT sub-study. 
 
6.1 
Screening  
The following procedures are completed during the screening visit: 
 
Informed Consent  
 
Record medical history, which includes questions about social history, smoking, alcohol use, and 
disease history 
 
Record prior and current medications  
 
Record general health (including averse events and illnesses) 
 
A physical examination, including assessment of certain physical symptoms that are associated 
with liver disease 
 
Quality of Life questionnaire  
 
Vital signs, which include blood pressure, heart rate, breathing rate, body temperature, will be 
measured. height and weight may also be recorded 
 
A Fibroscan (ultrasound scan of abdomen to measure the stiffness of liver). Fibroscan results 
available within a month of screening may be used in place of a repeat at screening 

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 
Blood samples will be collected for routine & research laboratory tests (about 3 tablespoons, 30 
mL) and to test for liver function  
 
Urine pregnancy test for women of child-bearing potential 
6.2 
Study Observational Phase 
Assessmentsduring the observational phase will include the following procedures: 
 
Review prior and current medications  
 
Record general health (including adverse events and illnesses) 
 
A physical examination, including assessment of certain physical symptoms that are associated 
with liver disease* 
 
Vital signs, which include blood pressure, heart rate, breathing rate, body temperature, will be 
measured. height and weight may also be recorded* 
 
Blood samples will be collected for routine laboratory tests (about 2 tablespoons, 20 mL) and to 
test for liver function  
*if in-person clinic visit is conducted 
6.3 
Study Intervention Phase 
Clinic visits during the interventional phase will include the following procedures: 
 
Review prior and current medications  
 
Record general health (including adverse events and illnesses) 
 
A physical examination, including assessment of certain physical symptoms that are associated 
with liver disease 
 
Quality of Life questionnaire  
 
Vital signs, which include blood pressure, heart rate, breathing rate, body temperature, will be 
measured. height and weight may also be recorded 
 
A Fibroscan (ultrasound scan of abdomen to measure the stiffness of liver)  
 
Blood samples will be collected for routine & research laboratory tests (about 3 tablespoons, 30 
mL) and to test for liver function  
 
MBT performed (month 6 and month 12) if subject has consented to optional sub-study 
 
Study drug instruction (month 6) 
 
Study drug compliance assessment  
 
Weight-based daily dosage calculation 
 
Urine pregnancy test for women of child-bearing potential 
6.4 
End of Study/Early Termination Visit 
If subjects complete the interventional phase of the study, or decide to end participation, an End of Study 
visit will include the following:.  
 
Review prior and current medications  
 
Record general health (including adverse events and illnesses) 
 
A physical examination, including assessment of certain physical symptoms that are associated 
with liver disease 
 
Quality of Life questionnaire  
 
Vital signs, which include blood pressure, heart rate, breathing rate, body temperature, will be 
measured. height and weight may also be recorded 
 
A Fibroscan (ultrasound scan of abdomen to measure the stiffness of liver)  
 
MBT performed if subject has consented to optional sub-study 
 
Blood samples will be collected for routine laboratory tests (about 2 tablespoons, 20 mL) and to 
test for liver function  

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 
Study drug compliance assessment  
 
6.5 
Follow Up Phase (Optional) 
Subjects will have the option to remain on UDCA after study completion if it can be obtained through 
prescription outside of the trial. Subjects will be seen at 2 additional clinic visits which will consist of the 
following:  
 
Review prior and current medications  
 
Record general health (including adverse events and illnesses) 
 
A physical examination, including assessment of certain physical symptoms that are associated 
with liver disease 
 
Quality of Life questionnaire  
 
Vital signs, which include blood pressure, heart rate, breathing rate, body temperature, will be 
measured. height and weight may also be recorded 
 
A Fibroscan (ultrasound scan of abdomen to measure the stiffness of liver)  
 
Blood samples will be collected for routine laboratory tests (about 2 tablespoons, 20 mL) and to 
test for liver function  
 
Study drug compliance assessment (when applicable) 
 
Weight-based daily dosage calculation 
6.6 
Unscheduled Visits 
Unscheduled/safety visits may be conducted at any time and may repeat assessments.  This is not common 
but may be necessary to ensure subjects overall health and safety.  Similarly, in case of any important 
findings from study laboratory tests, physical exams or any side effects that may be related to the study 
drug, PI may follow up for as long as necessary/until the condition or side effect stabilizes, resolves, or is 
no longer of concern.   Follow-up may include any additional assessments needed to understand the nature 
or cause of the event and may include collection of additional blood samples, other assessments, or 
consultation with other healthcare professionals.  
6.7 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care.  They may also be 
discontinued from the study at the discretion of the PI for lack of adherence to intervention or study 
procedures or visit schedules, AEs, or upon the development of varices, ascites or encephalopathy, 
doubling of serum bilirubin, marked worsening of fatigue or pruritus, inability to tolerate the drug, or 
voluntary withdrawal. .  The PI may also withdraw subjects who violate the study plan, or to protect the 
subject for reasons of safety or for administrative reasons.  It will be documented whether or not each 
subject completes the clinical study. Subjects who withdraw early will be asked to have one final visit to 
collect investigational product and to follow up regarding adverse events.  
 
Requirements for stopping the study: 
The study will be stopped if there is a pattern seen of adverse events related to the MBT test among the 
subjects. Since this is a small pilot study if serious adverse events related to the MBT test are seen in one 
subject the study will be stopped. 
 
Stopping Criteria for Administration of MBT Test:  
 
Prior occurrence of any adverse events related to 13C-Methacetin solution and device 
 
Change in subject’s health which makes continued participation unsafe. PI will see subject prior to 
administration of test. 
 
Subject has not followed the pre-requisites for taking the MBT test (e.g., requirements for fasting, 
caffeine consumption, general anesthesia, use of excluded medications). 
 
Early Termination of the Breath Test:  

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Key personnel will be trained how to terminate the breath test early if a subject is unable to complete the 
full 75 minutes of breath collection. In the following situations, the breath test collection will be terminated:  
 
The subject vomits.  
 
The subject has to be disconnected from the nasal cannula/ collection device for more than 1 
minute due to an urgent procedure.  
 
The subject is inadvertently disconnected from the BreathID® MCS device. 
 
The BreathID® MCS device malfunctions. 
 
Should an interruption in breath collection due to removal of the cannula or its disconnection occur during 
the administration of the MBT and the device cannot compute the delta over baseline results, the test may 
be repeated at a different date (minimum time allowed before repeating is 24 hours) provided the subject 
still qualifies and is willing to repeat testing. If the interruption occurred at the beginning of the Breath Test 
(during baseline breath collection) and before ingestion of the 13C-Methacetin solution, the test can be 
repeated immediately. 
 
6.7.1 
Data Collection and Follow-up for Withdrawn Subjects 
If subjects withdraw from the study, the information that was collected before withdrawal will still be used.  
No new information will be collected without subject permission except to follow up on safety events that 
might have happened during the study.   
 
6.8 
Clinical Laboratory Tests  
Category 
Tests 
Hematology 
RBC, hemoglobin, hematocrit, platelet count, WBC with differential 
Liver associated tests  
(Hepatic function panel) 
SGOT/AST, SGPT/ALT, total Bilirubin, GGT, ALP, Albumin 
  
 
6.9 
Optional Research Blood Sample Collection  
Subjects who provide informed consent for the collection and use of their blood samples for future research 
will have samples collected every 6 months during the course of their study participation. All samples will 
be de-identified prior to being stored. Subjects who do not consent to this optional collection will still be able 
to participate in the rest of the study. 
 
6.10 Efficacy Evaluations 
Standard of care laboratory tests for liver function: See 3.2.1, 6.7 
 
FibroScan® as a standard of care measure for liver stiffness (3.2.2): 
Transient elastography is a non-invasive, reproducible method for measuring liver stiffness that 
correlates with liver fibrosis and will be measured using FibroScan® (manufacturer Echosens). An 
ultrasound transducer probe is mounted on the axis of a vibrator; vibrations of mild amplitude and low 
frequency are transmitted by the transducer, inducing a wave that propagates through 
the underlying tissue. The propagation velocity of the wave is then measured. The velocity is 
directly related to tissue stiffness; the stiffer the tissue, the faster the wave propagates 
 
Methacetin Breath Test for liver metabolic capacity (3.2.2, optional, exploratory): 
The 13C-methacetin breath test (MBT) is a noninvasive tool to assess liver microsomal capacity 
to metabolize the nonradioactive 13C-labeled Methacetin. The Breath Test System consists of 
the BreathID® Molecular Correlation Spectrometry (MCSTM) device and a test kit containing a 

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breath collection nasal cannula and a nonradioactive isotope 13C-methacetin solution. The 
BreathID MCS device measures and computes the 13CO2/12CO2 ratio in the subject’s exhaled 
breath in real time. Additional details for the procedure are provided in Appendix 5 (16.5). 
 
Subjects will be asked to sit in a chair with a nasal cannula (a small tube) attached to the 
BreathID MCS device placed inside their nostrils while breathing normally. The BreathID MCS 
device will measure the subject’s baseline carbon dioxide production for approximately 
10 minutes (up to 25 minutes), after which the subject will be administered 1 cup of a solution of 
a 75 mg Methacetin pre-dissolved in water. Methacetin is exclusively broken up in the liver and 
turns into carbon dioxide and acetaminophen. The subject will remain sitting in a chair with the 
nasal cannula in their nose breathing in a normal fashion for another 60 minutes while the 
BreathID MCS device measures carbon dioxide production. The MBT will be performed at screening, Month 
6, and Month 12 for this protocol. 
 
6.11 Safety Evaluations 
Laboratory tests for liver function and adverse event reporting: See 3.2.2.  
7 
Statistical Plan 
7.1 
Primary Endpoint 
The primary end-point is a reduction in ALP and/or GGT from baseline.   
7.2 
Secondary Endpoints  
To assess the safety and tolerability of UDCA in patients with hepatic sarcoidosis, liver function tests will 
be monitored alongside reporting of adverse events. 
To assess efficacy of UDCA in the improvement of liver stiffness as a clinical parameter of liver function, 
Fibroscan stiffness readings (in kPa) will be monitored. 
To assess quality of life parameters prior to and following intervention with UDCA, PRO questionnaire 
scores will be assessed for improvements.  
To assess changes in metabolic capacity of the liver, 13C-methacetin breath tests will be analyzed and 
resulted in all subjects prior to and following intervention with UDCA (exploratory endpoint). 
7.3 
Sample Size and Power Determination 
This is a descriptive, pilot study of UDCA in subjects with hepatic sarcoid.  We aim to enroll at least ten 
subjects over two years.  We will use the effect size obtained from this pilot study to launch a multi-centered 
study that can be adequately powered. 
7.4 
Statistical Methods 
 The primary end-point is a reduction in ALP and/or GGT from baseline. We plan to use the effect size 
obtained from this pilot study to launch a multi-centered study that can be adequately powered to predict a 
specified percentage reduction in clinical and laboratory parameters with statistical significance.   
7.4.1 
Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive statistics (including 
mean and standard deviation for continuous variables such as age and standard percentages for 
categorical variables such as gender). 
7.4.2 
Efficacy Analysis  
See 7.1. 
7.4.3 
Safety Analysis  
See 7.2. 

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7.5 
Subject Population(s) for Analysis 
All-treated population:  Any subjects enrolled into the study that received at least one dose of investigational 
product.   
 
8 
Safety and Adverse Events  
8.1 
Definitions 
8.1.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
For FDA regulated studies the FDA defines an adverse event as the following:  
Adverse event means any untoward medical occurrence associated with the use of a drug in humans 
whether or not considered drug related.  
Adverse events will be collected at each study visit. The start and stop date(s) of the event(s) (if known), 
and relationship to study drug (UDCA), to methacetin or, MBT procedure will also be collected. 
 
Anticipated AEs related to the study drug are listed in the package insert for UDCA/ursodiol. 
There are no anticipated AEs with methacetin.  
8.1.2 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 

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All adverse events occurring during the study period will be recorded.  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study intervention or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
will be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study intervention or study participation will be 
recorded and reported immediately. 
 
All subjects taking part in the optional MBT substudy will be monitored for AEs for 24 hours following MBT 
administration. This assessment will be conducted remotely; subjects will be contacted by phone one day 
following MBT administration.  
8.3 
Relationship of AE to Study  
The relationship of each adverse event to the study procedures will be characterized by the PI (as definitely 
related, probably related, possibly related, unlikely or unrelated). 
8.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
 If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study intervention was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association 
between the event and study intervention 
 
 
Additionally all other events (unanticipated problems, adverse reactions, unanticipated adverse device 
effects and subject complaints will be recorded and reported with respect to institutional and federal policies 
as described in the Penn Manual and below.  
 
In accordance with Abbreviated IDE requirements outlined in 812.150(b)(1)-(3) & (5)-(10) & 812.150(a)(1), 
(2), (5), & (7), any unanticipated adverse device effects will be reported to IRB and FDA (21 CFR 812.3s).  
 
8.4.1 
Follow-up report 
If SAE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) will be submitted to the IRB. The investigator is 
responsible for ensuring that all SAE are followed until either resolved or stable.  
8.4.2 
Investigator Reporting: Notifying the Penn IRB  
It is the responsibility of the PI to oversee the notification of adverse events to the IRB.  
8.4.3 
Investigator reporting: Notifying the FDA   
It is the responsibility of the PI to report all unanticipated, related and serious adverse events to the FDA.  
8.5 
Medical Monitoring 
It is the responsibility of the PI to oversee the safety of the study.  This safety monitoring will include careful 
assessment and appropriate reporting of adverse events as noted above.   
8.5.1 
Data and Safety Monitoring Plan 
The PI is responsible for ensuring protocol adherence, regulatory oversight and reporting, data collection, 
and protection of research subjects. The PI is also responsible for evaluating factors external to the study, 
including scientific or therapeutic developments in the disease or investigational agent/procedure that may 

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influence study subject safety; the PI will allocate adequate time for such monitoring activities. Some PI 
responsibilities may be delegated to study team members, but ultimately the PI is accountable for all study 
activities.  Yearly progress reports will be submitted to the IRB. 
 
9 
Study Administration, Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
9.2 
Data Collection and Management  
All patient and study documents will be kept confidential. The research team will be responsible for the 
confidentiality of the data associated with subjects enrolled into this study in the same manner they are 
responsible for the confidentiality of any patient information within their spheres of responsibility. All forms 
and submitted records used for abstraction of the study data will be de-identified to maintain subject 
confidentiality. All study staff will identify patients by the patient identifier number generated at the first visit. 
The investigator and institution will permit study-related monitoring, audits, IEC/IRB review and regulatory 
inspection, providing direct access to source data documents. Participants grant permission to share 
research data with these entities in the consent document. Federal regulations govern the protection of 
patients’ rights relative to data confidentiality and use of research data. Consent procedures and forms, and 
the communication, transmission and storage of patient data will comply with the University of Pennsylvania 
IRB and federal requirements for compliance with HIPAA.  
– REDCap will be used to enter source data as eCRFs 
– PI and coordinator will have access to PHI  
– Data will be stored indefinitely  
– All safeguards will be used to ensure privacy. Subjects will only be seen by the investigators and 
coordinators in a private, research designated clinic room in the GI clinic and will not be identified to 
anyone in the clinic practice as anything other than a patient. 
.   
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
See 8.5.1 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 

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11 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to the University of Pennsylvania Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  The 
decision of the EC/IRB concerning the conduct of the study will be made in writing to the investigator before 
commencement of this study.  
11.1 Risks 
Study drug: UDCA 
There are risks, discomforts, and inconveniences associated with any study.  All of the risks associated 
with taking the study drug may not currently be known. See package insert for comprehensive information 
on UDCA, inclusive of the adverse reactions observed in placebo-controlled clinical trials for PBC, as well 
as the side effects reported during postapproval use of UDCA.  Subjects may have side effects from taking 
UDCA in this study and will be checked at each study visit for side effects.  The side effects reported by 
patients receiving UDCA in clinical trials may have occurred due to other reasons; because clinical trials 
are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 
drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates 
observed in clinical practice. The side effects reported after the FDA approval of UDCA were reported 
voluntarily from a population of uncertain size; it is not always possible to reliably estimate their frequency 
or establish a causal relationship to drug exposure. Additionally, in a randomized, cross-over study in sixty 
PBC patients, seven patients (11.6%) reported nine adverse reactions: abdominal pain and asthenia (1 
patient), nausea (3 patients), dyspepsia (2 patients) and anorexia and esophagitis (1 patient each). One 
patient on the twice a day regimen (total dose 1000 mg) withdrew due to nausea. All of these nine adverse 
reactions except esophagitis were observed with the twice a day regimen at a total daily dose of 1000 mg 
or greater. However, an adverse reaction may occur at any dose. 
 
Venipuncture: 
When blood samples are taken from a vein, there may be some minor pain and risk of bruising at the needle 
site.  Sometimes a person may become dizzy or faint when blood is drawn and there is a rare possibility of 
infection. 
 
Data confidentiality: 
All safeguards will be used to ensure privacy. Subjects will only be seen by the investigators and the 
research team in a private research designated clinic room in the GI clinic and will not be identified to 
anyone in the clinic practice as anything other than a patient. All patient and study documents are kept 
confidential. The research team of Drs. Reddy and Weinberg will be responsible for the confidentiality of 
the data associated with subjects enrolled into this study in the same manner they are responsible for the 
confidentiality of any patient information within their spheres of responsibility. All forms and submitted 
records used for abstraction of the study data will be identified by coded identifiers to maintain subject 
confidentiality. All study staff will identify patients by the patient identifier number generated at the study 
site. The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB review and 
regulatory inspection(s), providing direct access to source data documents. Participants grant permission 
to share research data with these entities in the consent document. Federal regulations govern the 
protection of patients’ rights relative to data confidentiality and use of research data. Consent procedures 
and forms, and the communication, transmission and storage of patient data will comply with the University 
of Pennsylvania IRB and federal requirements for compliance with HIPAA. 
11.2 Benefits 
The information that is obtained during this study may be useful scientifically and thus be helpful to others 
with the same condition in the future. The subject may or may not benefit from being in this study but their 
participation in this research study may benefit future patients with the same disease or condition. Subjects’ 
condition may get better, it may get worse, or it may stay the same. 

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11.3 Risk Benefit Assessment 
Risks associated with UDCA, including the risks of AEs and hepatic laboratory abnormalities classify this 
study as greater than minimal risk, but appear limited and manageable based on its administration in 
patients with PBC. Given the potential for improving liver enzymes and function, the risk-benefit balance is 
favorable. Incorporation of the MBT to this protocol does not introduce significant risk, as determined by 
the sponsor-investigator and confirmed by the IRB. 
11.4 Informed Consent Process / HIPAA Authorization  
The study physician will explain the study to the subject, and answer all questions regarding the study. Prior 
to any study-related screening procedures being performed on the subject, the informed consent statement 
will be reviewed and signed and dated by the subject, the study physician, and any other signatories 
necessary. A copy of the informed consent form will be given to the subject and the original will be placed 
in the subject's study chart. An entry will also be made in the subject's chart to document the informed 
consent process. Sample informed consent form is attached to initial submission.  
 
12 Study Finances 
12.1 Funding Source 
The study is supported by the Autoimmune Liver Diseases Pilot Research grant awarded to Ethan 
Weinberg by the American Association for the Study of Liver Diseases (AASLD). 
 
Exalenz Bioscience will provide device and device-associated materials required for conducting the MBT. 
12.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
12.3 Subject Stipends or Payments 
 Subjects will be reimbursed up to $50 per completed visit for expenses incurred from study required clinic 
visits. Additionally, subjects will not be charged for optional breath test.  Subjects will be responsible for the 
cost (e.g. any deductible, co-insurance, or co-payments) of standard of care medical services including 
fibroscan and all laboratory tests being assessed, The cost of the study medication will also be billed to 
subject/insurance in the usual manner when UDCA is prescribed for cholestatic conditions and subjects will 
be responsible for paying any deductible, co-insurance, or co-payments. In the unanticipated event that 
insurance does not cover UDCA and/or laboratory evaluations, sponsor-investigator may consider allotting 
study funds for these.  
13 Publication Plan 
We will make our results available to the community of scientists interested in the treatment of hepatic 
sarcoidosis. In addition, we welcome collaboration with other scientists who could make use of the results 
and make recommendations that will advance the study aims and understanding of hepatic sarcoidosis. 
Our plan includes, but is not limited to, activities such as presentations at national scientific meetings, 
lectureships, development of web-based tools and resources, and educational presentations for health care 
providers interested in the treatment of hepatic sarcoidosis.  
 
 
14 References 
1. 
Iannuzzi, M. C., Rybicki, B. A. & Teirstein, A. S. Sarcoidosis. N. Engl. J. Med. 357, 2153–2165 
(2007). 
2. 
Hu, Y., Yibrehu, B., Zabini, D. & Kuebler, W. M. Animal models of sarcoidosis. Cell Tissue Res. 
367, 651–661 (2017). 

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3. 
Baughman, R. P. et al. Clinical Characteristics of Patients in a Case Control Study of Sarcoidosis. 
Am. J. Respir. Crit. Care Med. 164, 1885–1889 (2001). 
4. 
Mañá, J. et al. Multidisciplinary approach and long-term follow-up in a series of 640 consecutive 
patients with sarcoidosis. Medicine (Baltimore). 96, e7595 (2017). 
5. 
Baughman, R. P. et al. Sarcoidosis Treatment Guidelines. Found. Sarcoidosis Res. 
6. 
Alenezi, B., Lamoureux, E., Alpert, L. & Szilagyi, A. Effect of ursodeoxycholic acid on 
granulomatous liver disease due to sarcoidosis. Dig. Dis. Sci. 50, 196–200 (2005). 
7. 
Bécheur, H. et al. Effect of ursodeoxycholic acid on chronic intrahepatic cholestasis due to 
sarcoidosis. Dig. Dis. Sci. 42, 789–91 (1997). 
8. 
Bakker, G. J., Haan, Y. C. L., Maillette de Buy Wenniger, L. J. & Beuers, U. Sarcoidosis of the 
liver: to treat or not to treat? Neth. J. Med. 70, 349–56 (2012). 
 
15 Attachments 
 Informed Consent Form and HIPAA Authorization – v. 20-JUN-2018 
 Package Insert – UDCA (URSO 250/500) 
 Package Insert – Allergan Actigall (URSODIOL, USP capsules) 
 Quality of Life questionnaires: 
 - PROMIS Fatigue 7b 
 - PROMIS Fatigue 13a 
 - PROMIS Physical Function 10b 
 - PROMIS Pool v1.0 Dyspnea 
 Prospective Reimbursement Analysis – UDCA 
 IND Exemption/IDE determination letter – 6-FEB-2018 
 Appendix 16.5: Measurement of Liver Metabolic Function with the Methacetin Breath Test 
 BreathID® MCS Device Investigator’s Brochure – 17-OCT-2017  
16 Appendix 
16.1 Reference for Safety Reporting Section- Common Definitions for Developing and Adverse 
Event Tracking and Serious Adverse Event Reporting Protocol  
16.2 Expedited FDA Reporting Requirements  
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND/ IDE safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and associated type 
of event: 
 
 Within 7 calendar days 
Any study event that is all: 
– associated with the use of the study drug, and 
– unexpected, and  
– fatal or life-threatening, 
 Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, and 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
 

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Additional reporting requirements 
Sponsors are also required to identify in IND/IDE safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Applicable events can be reported to the FDA using Form FDA3500A or in narrative format. The report 
must be sent to the correct division. Specific information that must be included in the reports can be found 
in 21 CFR 312.32 or in 21 CFR 812.150. 
 
16.3 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
16.4 Case Report Forms (CRFs) 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the item, then initial 
and date it.  
 
16.5.  Measurement of Liver Metabolic Function with the MBT (optional sub-study)