A Phase I Open Label Study of the Efficacy and Safety of Tudca in Ulcerative Colitis
Phase: PHASE1
Conditions: Ulcerative Colitis
Sponsor: Washington University School of Medicine

Clinical Research Protocol 
 
 
Version 1 
Washington University 
 
 
 
 
 
 
A PHASE I OPEN LABEL STUDY OF THE EFFICACY AND 
SAFETY OF TUDCA IN ULCERATIVE COLITIS TREATMENT 
 
 
Regulatory Sponsor: 
Matthew A Ciorba MD 
Division of Gastroenterology, Dept of Medicine 
Washington University in Saint Louis 
314-362-9054 
mciorba@wustl.edu  
 
Funding Sponsor: 
Washington University in Saint Louis School of 
Medicine with a supporting grant from The Litwin IBD 
Pioneers Program at the Crohn’s & Colitis Foundation 
Ref # 541962 
Crohn's & Colitis Foundation 
733 Third Ave 
Suite 510 
New York, NY 10017 
Phone: 800-932-2423 
Study Product: 
Tauroursoursodeoxycholic acid, brand name TudcabilTM 
These capsules will be supplied directly from Bruschettini 
Srl, Genoa, Italy which will be administered through our 
investigational pharmacy. 
Protocol Number: 
IND Number: 
142064 
 
 
 
 
 
Date: 
12/11/2018 
Amended: 
 
Administrative Change: 
 
 
 
CONFIDENTIAL 
This document is confidential and the property of the Washington University.  No 
part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 

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Table of Contents 
1 
INTRODUCTION ............................................................................................................................................... 5 
1.1 
BACKGROUND ............................................................................................................................................. 5 
1.2 
INVESTIGATIONAL AGENT ........................................................................................................................... 5 
1.3 
PRECLINICAL DATA ..................................................................................................................................... 6 
1.4 
CLINICAL DATA TO DATE ............................................................................................................................ 7 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ..................................................................................................... 7 
2 
STUDY OBJECTIVES ...................................................................................................................................... 7 
2.1 
GENERAL DESIGN ...................................................................................................................................... 8 
2.2 
PRIMARY STUDY ENDPOINTS ..................................................................................................................... 9 
2.3 
SECONDARY STUDY ENDPOINTS ............................................................................................................... 9 
3 
SUBJECT SELECTION AND WITHDRAWAL............................................................................................. 9 
3.1 
INCLUSION CRITERIA .................................................................................................................................. 9 
3.2 
EXCLUSION CRITERIA ................................................................................................................................. 9 
3.3 
SUBJECT RECRUITMENT AND SCREENING .............................................................................................. 10 
3.4 
EARLY WITHDRAWAL OF SUBJECTS ........................................................................................................ 10 
3.4.1 
When and How to Withdraw Subjects ............................................................................................ 10 
3.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 11 
4 
STUDY DRUG ................................................................................................................................................. 11 
4.1 
DESCRIPTION ............................................................................................................................................ 11 
4.2 
TREATMENT REGIMEN .............................................................................................................................. 11 
4.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .............................................................. 12 
4.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG .......................................................................... 12 
4.5 
SUBJECT COMPLIANCE MONITORING ...................................................................................................... 12 
4.6 
PRIOR AND CONCOMITANT THERAPY ...................................................................................................... 12 
4.7 
PACKAGING .............................................................................................................................................. 12 
4.8 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 12 
4.8.1 
Receipt of Drug Supplies ................................................................................................................. 12 
4.8.2 
Storage ............................................................................................................................................... 12 
4.8.3 
Dispensing of Study Drug ................................................................................................................ 12 
4.8.4 
Study Drug discontinuation .............................................................................................................. 12 
4.8.5 
Subject Withdrawal Criteria ............................................................................................................. 13 
4.8.6 
Return or Destruction of Study Drug .............................................................................................. 13 
5 
STUDY PROCEDURES ................................................................................................................................. 14 
6 
STATISTICAL PLAN AND OUTCOME ANALYSES ................................................................................ 15 
6.1 
SAMPLE SIZE DETERMINATION FOR PRIMARY ENDPOINT ....................................................................... 16 
6.2 
SECONDARY ENDPOINT ANALYSES ................................................................................................................ 17 
7 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 20 
7.1 
DEFINITIONS ............................................................................................................................................. 20 
7.2 
RECORDING OF ADVERSE EVENTS .......................................................................................................... 23 
7.3 
REPORTING OF SERIOUS ADVERSE EVENTS ........................................................................................... 23 
7.3.1 
IRB Notification by Investigator ....................................................................................................... 23 
7.3.2 
FDA Notification by Sponsor ........................................................................................................... 23 
7.4 
STOPPING RULES ..................................................................................................................................... 23 
7.5 
MEDICAL MONITORING ............................................................................................................................. 24 
7.5.1 
Internal Data and Safety Monitoring Board ................................................................................... 24 
8 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 26 
8.1 
CONFIDENTIALITY ..................................................................................................................................... 26 

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8.2 
SOURCE DOCUMENTS .............................................................................................................................. 26 
8.3 
CASE REPORT FORMS ............................................................................................................................. 26 
8.4 
RECORDS RETENTION .............................................................................................................................. 26 
9 
STUDY MONITORING, AUDITING, AND INSPECTING.......................................................................... 27 
9.1 
STUDY MONITORING PLAN ....................................................................................................................... 27 
9.2 
AUDITING AND INSPECTING ...................................................................................................................... 28 
10 
ETHICAL CONSIDERATIONS ..................................................................................................................... 28 
11 
PUBLICATION PLAN .................................................................................................................................... 28 
12 
REFERENCES ................................................................................................................................................ 28 
 

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Study Summary 
Title 
A PHASE I OPEN LABEL STUDY OF THE EFFICACY AND 
SAFETY STUDY OF TUDCA IN ULCERATIVE COLITIS 
TREATMENT 
Short Title 
 
Protocol Number 
 
Phase 
Phase I 
Methodology 
Open label 
Study Duration 
6 Weeks 
Study Center(s) 
Single-center 
Objectives 
Primary: Determine the effect of TUDCA treatment on ER stress 
in colon biopsy tissues from subjects with symptomatic 
ulcerative colitis. Secondary: Measure the safety, tolerance and 
efficacy of TUDCA treatment in symptomatic ulcerative colitis. 
Number of 
Subjects 
12 (Twelve) 
Diagnosis and 
Main Inclusion 
Criteria 
Confirmed ulcerative colitis disease through radiographic, 
endoscopic and/or histologic criteria; Confirmed with moderate 
to severe ulcerative colitis (defined as a complete Mayo score ≥ 
5 with endoscopic subscore of ≥ 1); On a stable dose of 
medications for IBD (i.e. no change in medication within 4 weeks 
of study enrollment). 
Study Product, 
Dose, Route, 
Regimen 
Tauroursoursodeoxycholic acid, brand name Tudcabil, Dosed in 
capsules containing 250 or 500mg of TUDCA for a total dose of 
1.75-2g/day 
Duration of 
administration 
6 Weeks 
Reference therapy 
N/A 
Statistical 
Methodology 
We will be specifically interested in the statistical contrasts that 
compare before and after TUDCA treatment. Correlation 
between the primary end point and secondary end point will also 
be examined. The appropriateness of all analysis of variance 
and covariance models will be evaluated using regression 
residuals. If normality or homoscedasticity requirements are 
violated, data transformations will be explored and, if appropriate 
transformations cannot be found, analyses may be done semi-
parametrically using the ranks of the data. 
 

5 
 
1 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures.  
1.1 Background 
IBD, which includes both Crohn’s disease and ulcerative colitis, is caused by a dysregulated 
inflammatory response to intestinal microbiota and affects approximately 1.5 million people in the 
United States. No medical cure currently exists and patients require a lifetime treatment with 
immune modulators, such as infliximab, which have significant risks and adverse effects. 
Strategies for developing IBD therapies face an extraordinary challenge due to our poor 
understanding of the disease pathophysiology. Recently, emerging evidence has demonstrated 
that endoplasmic reticulum stress (ER stress) and the unfolded protein response (UPR) play 
fundamental roles in IBD development1-5. 
 
The ER is the organelle in eukaryotic cells responsible for intracellular Ca2+ homeostasis, lipid 
biosynthesis and ER protein folding, transport and quality control. Alterations in the ER 
environment, such as altered Ca2+, redox state, nutrient status, increases in the rate of protein 
synthesis, pathogens or inflammatory stimuli, disrupt ER protein folding causing accumulation of 
unfolded or misfolded proteins, a condition termed ER stress, which activates the UPR. The UPR 
comprises three parallel signaling branches: PKR-like ER kinase (PERK)-mediated 
phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), Inositol requiring enzyme 1α 
(IRE1α)-mediated X-box binding protein 1 (XBP1) mRNA splicing and activating transcription 
factor 6α (ATF6α) processing. The outcome of UPR activation involves transient attenuation of 
protein synthesis and transcriptional activation to increase the capacity for ER protein folding, 
trafficking and secretion, and to increase protein degradative pathways, including ER-associated 
degradation (ERAD) and macroautophagy. If these adaptive mechanisms cannot resolve the 
protein-folding defect, cells enter apoptosis6. 
Recent studies link ER stress to the pathogenesis of IBD. Patients with active Crohn’s disease 
and ulcerative colitis exhibit signs of ER stress in their ileal and/or colonic epithelium7-9. In addition, 
human genetic studies of IBD have identified primary genetic abnormalities in several genes 
including XBP1, AGR2, and ORMDL3 that encode proteins associated with ER stress1, 10-13. 
Previous studies indicate that cells with a high load of protein folding and secretion are sensitive 
to altered ER homeostasis and this can induce inflammatory response gene expression1, 2, 5, 14, 15. 
Intestinal microbiota and their molecules stimulate IECs to increase secretion of mucins and 
antimicrobial peptides that can overwhelm the protein secretory capacity of IECs.  Conversely, 
exposure to inflammatory stimuli can cause ER stress15. Upon exposure to high levels of 
exogenous antigens and inflammatory cytokines in the intestinal lumen, IECs may require efficient 
UPR-mediated ER chaperone induction to survive the heavy burden of protein folding and 
secretion. 
1.2 Investigational Agent 
Substance: Tauroursoursodeoxycholic acid, brand name TudcabilTM. (Abbreviation: TUDCA) 
Chemical Name: (2-(3α,  7β-Dihydroxy-5β-cholan-24oylamino)ethanesulfonic acid) 
Synthesized by Prodotti Chimici e Alimentaria S.p.A. for Bruschettini Srl, Genoa, Italy.  

6 
 
Manufacturing Process: Ursodeoxycholic Acid ( 3α, 7β-dihydroxy-5β-cholan-24-oic acid 
) is considered the starting material together with Taurine ( 2-aminoethansulfonic acid) to 
be used in the production of Tauroursodeoxycholic Acid : the synthetic pathway is based 
on the formation of a carboamidic bond between the carboxyl group in position 24 of the 
bile acid and the amine group in position 2 of taurine. 
 
TUDCA has been licensed for the treatment of cholesterol gallstones and for therapy of chronic 
cholestatic liver disease in Europe since 1991. From 1996-2001 at least 20,000 doses had been 
dispensed and no reports related to the toxicity of Tudcabil capsules had arrived during this time 
period (please see product profile of IND 101,296). Infrequent, but predominant side-effects in 
human studies (summarized in attached table)  are diarrhea, headache and abdominal pain16.  
 
Human studies relevant to this application: A pilot study conducted by Dr. Samuel Klein, also at 
Washington University in Saint Louis, treated 10 obese, insulin-resistant adults with 1.75 g/day  
for 4 weeks with no adverse events17. TUDCA was given to 16 liver transplant recipients at 500 
mg/day for 12 months with no drop-outs or toxicities observed. A cohort of subjects with primary 
biliary cirrhosis were treated with 500-1500 mg/day of TUDCA for 6 months, with diarrhea 
reported as the only side-effect. Several human studies have shown that use of TUDCA is well 
tolerated in many populations including amyloidosis16, primary biliary cirrhosis18-20 and liver 
transplant21. 
 
Chronic toxicity has been studied in dogs for up to 26 weeks with treatment of up to 400-600 
mg/kg/day (30 x that of the proposed dose) with no observed toxicity. Rats treated with 2-20 times 
the proposed dose showed no evidence of carcinogenic effects after 24 months of treatment (see 
attached, “animal toxicity”). 
 
In summary, TUDCA has been tolerated at similar dose in humans with a variety of chronic 
medical conditions, with the major side-effect being mild diarrhea. The balance of the clinical 
information suggests that this drug is well tolerated and could have important health benefits for 
this study population. There are no known interactions between bile acids and immunomodelators 
or other IBD therapies.  
 
1.3 Preclinical Data 
We tested whether expression of ER chaperones prevent IBD development in mouse 
models. We found that protein misfolding in the ER caused by deletion of the ER co-
chaperone gene P58IPK/Dnajc3 exacerbates experimental colitis in mice. Furthermore, 
ATF6α null mice, with significant reduced expression of many ER chaperones (Bip, Grp94 
and P58IPK6, 22) and hyperactivation of pro-apoptotic UPR signaling in colonic IECs, were 
more sensitive to experimental colitis than control mice. In contrast, we found that oral 
delivery of the chemical chaperone tauroursodeoxycholate (TUDCA) dramatically 
decreased the clinical, histological and biochemical signs of inflammation in both innate 
immunity- and T cell-dependent colitis through reducing ER stress signaling in colonic 
IECs4.  TUDCA has been proven to facilitate protein folding and reduce ER stress both in 
vitro and in vivo by stabilizing protein-folding intermediates and preventing protein 
aggregation17, 23-26. These findings indicate that ER stress plays an indispensable role in 
IBD development, and TUDCA administration could be a very efficient therapy for IBD 
patients. 

7 
 
In this study, we would like to bring this significant research finding from bench to the 
bedside. We propose to test the efficacy and safety of TUDCA in a small number (12) of 
symptomatic ulcerative colitis patients. TUDCA has been demonstrated as safe and well 
tolerated in many human clinical trials for other disease conditions. Our study will extend 
these findings to evaluate TUDCA’s tolerance/safety in patients with active UC. If our 
research findings in mouse IBD models can be successfully translated to humans, it will 
benefit IBD patients in the near future. 
1.4 Clinical Data to Date 
This is the first clinical trial to date examining the role of TUDCA in ulcerative colitis 
patients. However, several clinical trials in other disorders have been completed or are 
ongoing. 
https://clinicaltrials.gov/ct2/results?cond=&term=tudca&cntry=&state=&city=&dist= 
 
1.5 Dose Rationale and Risk/Benefits 
A weight based regimen for TUDCA will be used, administering it in 3 divided doses 
which corresponds to an average dose of 20-25 mg/kg/day accordingly using 1750 mg 
daily for patients  <75 kg and 2000 mg daily for patients  ≥75 kg. 
It has been shown that TUDCA at the dose of 25mg/Kg/day can achieve maximum 
composition in the serum and bile in patients with primary biliary cirrhosis19. Previous 
clinical studies also have shown that 1 to 6 months of TUDCA treatment with 
1750mg/day is efficacious and safe in patients with different diseases, including primary 
biliary cirrhosis19, 27, 28, liver cirrhosis29, HCV-related chronic hepatitis30 and insulin 
resistance17. Animal studies also suggest that TUDCA appears to be very well tolerated 
even at high doses.  
 
Patients will not be charged for the drug. This will be supplied in original packaging by 
Bruschettini Srl, Genoa, Italy. TUDCA distribution will be carried out by our Investigational 
Pharmacy at Washington University. Patients will receive a 6 week supply at initiation 
visit.  
2 Study Objectives 
Intestine biopsy samples from inflamed and adjacent non-inflamed intestine tissues 
before and after the TUDCA treatment will be harvested to evaluate ER stress status by 
western-blotting for ER stress induced proteins, qRT-PCR and immunochemistry 
staining. The disease severity will be measured by the Geboes histology index and the 
complete Mayo score before and after the TUDCA treatment will be monitored. The 
overall goal of this project is to determine if the research findings in mouse IBD models 
can be successfully translated to humans and thereby provide an adjunctive to optimize 
therapeutic options in IBD patients focused on the epithelium and with a desirable 
safety profile. To address this, we propose the following Specific Aims: 
SA 1. Determine the effect of TUDCA treatment on ER stress in colon biopsy 
tissues from subjects with symptomatic ulcerative colitis as a primary endpoint. 

8 
 
We expect that TUDCA treatment will reduce ER stress in colon biopsy tissues from 
subjects with symptomatic ulcerative colitis (UC), as judged by expression levels of ER 
stress markers. As a primary study endpoint, we will assess: 
A. The primary endpoint will be the change in ER stress markers, including eIF2α 
phosphorylation, XBP1s and BIP/GRP78, in colon biopsy tissues before and after 6 
weeks of TUDCA treatment.  
 
SA 2. Measure the safety and tolerance as well as efficacy of TUDCA treatment in 
symptomatic ulcerative colitis as secondary end points.  
We expect that TUDCA treatment will alleviate the UC mucosal inflammation and 
symptoms and be well tolerated. To assess these secondary endpoints we will: 
A. 
Actively monitor UC study patients for TUDCA safety and tolerability.  
B. 
Examine efficacy endpoints endoscopic mucosal healing, clinical response 
(Mayo Score) as well as histologic severity. 
2.1 General Design 
Type of Study: Open-label clinical trial where all patients receive TUDCA at 1.75 or 
2g/day for 6 weeks, divided into three doses, after meals.   
 
Schematic of Trial Design: A total of 12 individuals with active ulcerative colitis and 
endoscopic evidence of inflammation will be eligible to participate in this open-label 
clinical trial using TUDCA (adjunct or primary therapy) at 1.75 or 2g/day for 6 weeks, 
divided into three doses, after meals as summarized in Figure 1. A full schedule of visit 
assessments and procedures is defined in Table 1 in Section 5.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of Subject Participation: 6 weeks on Trial + 2 weeks Follow up = 8 weeks. 
Screening: Confirmed with active ulcerative colitis with evidence of inflammation on endoscopy (≥ Mayo 
Grade 1); On a stable dose of medications for ulcerative colitis; Endoscopy with colon epithelial biopsy 
samples; Plasma concentration of bile acid species; and stool samples for microbiota study.  
Figure 1. Trial schema 
12 Subjects with moderate to severe ulcerative colitis 
1.75 or 2g TUDCA x 6 weeks 
Endoscopy with colon epithelial biopsy samples; plasma concentration of bile acid species; and stool 
samples for microbiota study.  
Dose reduction to 1g if dose 
related TUDCA side effects 

9 
 
2.2 Primary Study Endpoints 
As the primary study endpoint, we will assess the change in ER stress markers, including 
eIF2α phosphorylation, XBP1s and BIP/GRP78, in colon biopsy tissues before and after 
6 weeks of TUDCA treatment.  
BIP, XBP1 splicing, phosphorylated eIF2α will be assessed by Western blot and RT-PCR 
and immunohistochemistry (IHC). Other ER stress markers, such as PERK, ATF4, 
CHOP, IRE1α and ATF6α will also be examined. In addition, we expect that cell death 
markers in colon biopsy tissues will also be downregulated, including cJUN, JNK, cleaved 
caspase 2 and cleaved caspase 3. We will also monitor expression of inflammatory 
cytokines, IL-1B, TNFα, IL-6 and IFNγ. Additional samples aliquots will be saved (flash 
frozen and RNAlater) for future studies evaluating adaptive and innate immune readouts. 
2.3 Secondary Study Endpoints 
1. Safety and Tolerance of TUDCA in Ulcerative Colitis patients  
2. Efficacy of TUDCA treatment in symptomatic ulcerative colitis based on 
endoscopic mucosal healing, clinical response (Mayo Score) as well as 
histologic severity (Geboes histology index). 
3 Subject Selection and Withdrawal 
3.1 Inclusion Criteria 
1)  Ages Eligible for Study: 18 Years to 65 Years;  
2) Confirmed ulcerative colitis disease through radiographic, endoscopic and/or histologic criteria;  
3) Confirmed with active ulcerative colitis (defined as a complete Mayo score ≥ 5 with endoscopic 
subscore of ≥ 1) See Appendix for Mayo Score using recent adaptation to include any friability on 
endoscopy to be scored as “2”.  
4) On a stable dose of medications for IBD (i.e. no change in medication within 4 weeks of study 
enrollment) and not planning to initiate new medication other than TUDCA. 
 
3.2 Exclusion Criteria 
1) Those that received other chemical chaperone therapies in the 3 months prior to screening;   
2) Individuals accompanied by gallstones, other intestinal disorders or cancers, or any possible 
cholestatic pathologies that could alter the enterohepatic circulation of the bile acids, including 
previous cholecystectomy or short bowel syndrome;  
3) Subjects with alcohol or drug abuse within the recent year;  
4) Serious heart, lung, kidney, digestive, nervous, mental, or autoimmune diseases  
5) Those with plans for abdominal surgery; 
  

10 
 
6) Those unable or unwilling to provide informed consent or failure to comply with the test 
requirements;  
7) Pregnant, lactating women;  
8) Those receiving or planning to receive medicines that inhibit the absorption of the bile acids in 
the intestine;  
9) All female subjects must have birth control and not plan to become pregnant during the study. 
As TUDCA may interfere in the absorption of oral contraceptives, the acceptable methods of birth 
control should include abstinence or 2 of the following intrauterine device (IUD-with or without 
local hormone release), diaphragm, spermicides, cervical cap, contraceptive sponge, and /or 
condoms. 
10) Subjects with baseline liver transamines (AST or ALT) > 1.5X the upper limit of normal.  
11) Patients with complete biliary obstruction and known hypersensitivity or intolerance to TUDCA 
or any of the components of TudcabilTM (or to other bile acids). 
12) Patients with moderate-to-severe hepatic impairment. 
 
13) Evidence of worsening liver function based on the 2 initial laboratory values used to 
establish the baseline.  See Section 6.2. 
 
3.3 Subject Recruitment and Screening 
Recruitment: Division of Gastroenterology at Washington University: More than 2500 
patients with IBD annually are cared for by the Division’s IBD specializing 
gastroenterologists (n=10). The division actively participates in IBD clinical trials (8 in 
2016 alone) and has an established infrastructure for recruitment and execution of new 
studies examining IBD specific medications. As a leading center for IBD patients sample 
Biobanking, the Washington University IBD Division also has a robust infrastructure for 
acquiring and rapidly processing research quality IBD specimens including serum 
samples, stool and biopsy material.  Two of the Washington University site PIs (Drs. 
Gutierrez and Ciorba) have worked in the field of IBD for more than 10 years.  We 
anticipate enrolling 2-3 patients per month.  
  
Screening: 
Medical examination. All subjects will be screened with a detailed history and physical 
examination, pregnancy test (if female) and laboratories including CBC, complete 
metabolic panel with a liver panel, C-reactive protein and fecal calprotectin.31 
 
3.4 Early Withdrawal of Subjects 
3.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn  from the study prior to the expected completion if that 
subject is deemed by the treating physician and study PI to have an adverse reaction to 
TUCDA (safety reasons and/or disease worsening), failure of the subject to adhere to 

11 
 
protocol requirements or if consent is withdrawn by the subject.   The subjects will be 
informed orally and in writing that they are free to withdraw from the study at any time 
with no bias or prejudice.   
3.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Even though subjects may be withdrawn prematurely from the study, we will collect all 
data available up until the point of withdrawal and at least confirm all survival data for 
two weeks after the final visit and attempts should be made to obtain permission to 
record at least survival data up to the protocol-described end of subject follow-up 
period.  This will include at least 4 phone calls to subject, phone calls to next-of-kin if 
possible and sending of a certified letter.  Of note, given the recognized safety of 
TUDCA, we do not in any way anticipate any risk of mortality, this is only for 
completeness of protocol. 
4 Study Drug  
4.1 Description 
Tauroursoursodeoxycholic acid, brand name TudcabilTM  is a naturally occurring bile salt 
proven to reduce ER stress both in vitro and in vivo, dramatically decreases the clinical, 
histological and biochemical signs of inflammation in four different IBD mouse models 
through reducing ER stress in colonic IECs4. TUDCA has been tested in many clinical 
trials for other disease conditions and its safety in humans has been proven.  Subjects 
will receive capsules containing 250 mg of TUDCA provided by Bruschettini Srl, Genoa, 
Italy which will be administered through our investigational pharmacy.  The consituents 
other than TUDCA are microcystalline cellulose, lactose, corn starch and magnesium 
stearate 
 
4.2 Treatment Regimen 
A weight based regimen for TUDCA will be used, administering it in 3 divided doses 
which corresponds to an average dose of 20-25 mg/kg/day accordingly using 1750 mg 
daily for patients  <75 kg and 2000 mg daily for patients  ≥75 kg. 
 It has been shown that TUDCA at the dose of 25mg/Kg/day can achieve maximum 
composition in the serum and bile in patients with primary biliary cirrhosis19. Previous 
clinical studies also have shown that 1 to 6 months of TUDCA treatment with 
1750mg/day is efficacious and safe in patients with different diseases, including primary 
biliary cirrhosis19, 27, 28, liver cirrhosis29, HCV-related chronic hepatitis30 and insulin 
resistance17. Animal studies also suggest that TUDCA appears to be very well tolerated 
even at high doses.  
Patients will not be charged for the drug. This will be supplied in original packaging by 
Bruschettini Srl, Genoa, Italy. TUDCA distribution will be carried out by our Investigational 
Pharmacy at Washington University. Patients will receive a 6 week supply at initiation 
visit.  

12 
 
4.3 Method for Assigning Subjects to Treatment Groups 
Open label study.  All patients will receive TUDCA.  
4.4 Preparation and Administration of Study Drug 
Please see TUDCA related manufacturing information from Bruschettini Srl. 
 
No additional preparation of the study drug will be necessary.  Bruschettini Srl, Genoa, 
Italy will supply our investigational pharmacy with 250 mg capsules in bottles of 120 
capsules (15 day supply).  The study drug will be distributed by our investigational 
pharmacy. 
4.5 Subject Compliance Monitoring 
Subjects will be addressed at the time points described for the study visits for 
compliance. A final outcome will be determined by study staff at the in-person visits. 
Subjects not achieving 90% compliance will be subject to withdrawal from the study. 
4.6 Prior and Concomitant Therapy 
Patients may be on any concomitant therapies as needed for their ulcerative colitis or 
other conditions. However, patients should not start any new medication that modifies 
ER stress. It is also not allowed to start any other new therapies for ulcerative colitis.   
4.7 Packaging 
Bruschettini Srl, Genoa, Italy will supply our investigational pharmacy with standard 
packaging bottles containing 120# of the 250 mg capsules (15 day supply). 
4.8 Receiving, Storage, Dispensing and Return 
4.8.1 Receipt of Drug Supplies 
Bruschettini Srl, Genoa, Italy will be supply the drug in original packaging to our 
Investigational Pharmacy at Washington University who will distribute it. 
4.8.2 Storage 
Capsules are stored in a controlled environment at room temperature in the study 
pharmacy. Adherence will be made to the manufactures expiration date. No other 
special handling requirements during storage 
4.8.3 Dispensing of Study Drug 
Patients will receive a 6 week supply of the drug at initiation visit. 
4.8.4 Study Drug discontinuation 
All subjects who discontinue study drug should be considered withdrawn from the 
study and should complete the study completion visit assessments.  If subjects fail 
to return for these visits, or are unable to do so, every effort will be made by the 
investigator to contact them or a knowledgeable informant by telephone or by 

13 
 
sending appropriate correspondence (i.e. certified letter) that will become part of the 
investigator’s file to record that efforts were made to reach the subjects. 
4.8.5 Subject Withdrawal Criteria 
Subjects may voluntarily withdraw from or be withdrawn from the study at the 
discretion of the investigator (or sponsor) at any time.  Patients may be withdrawn 
from the study if any of the following occur: 
1. subject withdrew consent 
2. Clinically significant new abnormal laboratory value that requires new therapy 
which may impact the study or suggests the patient is having an adverse 
response to TUDCA. 
3. adverse event 
4. clinically significant abnormal test procedure result 
5. protocol violation 
6. administration of prohibited concomitant medication 
 
If such withdrawal occurs, subjects should complete the Study Completion visit 
assessments at the investigators’ discretion. If subjects fail to return for these 
visits, or are unable to do so, every effort should be made by the investigator to 
contact them or a knowledgeable informant by telephone or by sending appropriate 
correspondence (i.e. certified letter) that will become part of the investigator’s file to 
record that efforts were made to reach the subjects. If the subjects fail to return for 
visits, the investigator must determine the primary reason for a subject’s premature 
withdrawal from the study, and record this information on the Study Completion 
CRF page. 
4.8.6 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, 
drug consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be investigated, 
resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files. 

14 
 
5 Study Procedures 
Table 1 summarize study procedures, complementing Fig 1 above. Also see Appendix 1 
 
Endoscopic disease activity. The complete Mayo score will be completed at baseline 
and after 6 weeks of treatment, based on stool frequency, rectal bleeding, endoscopic 
findings and physician’s global assessment32. In this trial, we are adapting the Mayo 
Scoring used in the OCTAVE clinical trial program.33 Whereas standard Mayo scoring 
designates mild friability as an endoscopic subscore of 1, in the OCTAVE clinical trial 
program, any sign of friability led to an endoscopic subscore of 2. See Appendix 1. 
 
Colonoscopic biopsies will be obtained under our current approved protocol 
(#201111078, DDRCC Biobank).  Patients will be enrolled and consented by the 
Washington University site coordinators.  Consent will be obtained in the outpatient clinic, 
the outpatient endoscopy suite or in the hospital with the permission of the treating 
physician.  Up to 12 additional endoscopic biopsies will be obtained and used as a source 
for RNA, DNA or protein extraction, immunohistochemical analysis as described below. 
Tissue Biopsy. Tissues will be obtained from inflamed and adjacent non-inflamed colon 
as available. The PI and Co-I’s as well as clinical collaborators are highly skilled at 
colonoscopy with biopsy having performed thousands of these procedures. Moreover, 
investigators have routinely used colonoscopy for grading of endoscopic severity and 
tissue sampling for histology and study purposes. These procedures are generally 
tolerated well by patients. 

15 
 
Stool sample collection will be performed by protocol of the Washington University 
DDRCC Biobank Core https://ddrcc.wustl.edu/ with patient directed collection and 
courier- based delivery.  
Geboes Histology Score: All biopsy specimens will be evaluated by the simplified 
Geboes Histology Score34 based on the original Geboes Index.35 This is provided in 
Appendix 1, Table 2.  
Quality of Life Questionnaire: Health Related Quality of Life will be assessed by the 
Short Inflammatory Bowel Disease Questionnaire (SIBDQ) which has been validated in 
ulcerative colitis.36, 37 Measures quality of life as measured in four domains, bowel 
symptoms, emotional health, systemic systems and social function. 
Additional Analysis on Samples and collection of samples for future studies. 
Measurement of serum bile acid concentration. Blood will be collected before and 
after TUDCA treatment, along with safety labs. Plasma bile acids will be measured 
using high-performance liquid chromatography tandem mass spectrometry.38  These 
studies will be carried out in the metabolomics core at Washington University School of 
Medicine and overseen by Dr. Davidson.  We will measure total AND individual serum 
bile acids (including TUDCA).  These measurements will be conducted on fasting serum 
obtained at the start of TUDCA and at timed intervals (at endoscopic evaluation and 
week 2). 
Microbiota composition analysis. As indicated above, stool samples before and after 
TUDCA treatment will be collected for potential future analysis of microbiota.  In the event 
that we proceed with metagenomic profiling (which would be based on the objective 
responses noted) microbial community composition will be determined by 16s 
metagenomic sequencing using the Illumina MiSeq platform. Libraries will be prepared 
in-house according to Illumina protocols and pooled libraries will be sent to the SBPMDI 
for deep sequencing. The resulting sequence data will be analyzed with the current 
version of Qiime 39.  
We recognize that TUDCA treatment may not have a significant impact on gut microbiota 
composition, as our preliminary data from IBD mouse models showed and for this reason 
will collect stool samples but not undertake metagenomic profiling at this time. 
Future analyses. We will biobank tissues, stool and serum for deeper immunologic 
analyses that may be pursued with additional funding from alternative sources.  This study 
will provide a rich resource for expanded immunological studies and will bank 
biospecimens (snap frozen, RNA later tissue, serum, stool) for future studies including 
full cytokine profiles and innate/adaptive immune readouts. These will be processed and 
stored in our NIDDK sponsored Digestive Diseases Research Center Biobank Core. Stool 
will also be stored for future microbial/metabolome analyses. 
 
6 Statistical Plan and Outcome Analyses 
 

16 
 
ER stress and cell death markers. We expect that TUDCA treatment will reduce ER 
stress in colon biopsy tissues from subjects with symptomatic ulcerative colitis (UC), as 
judged by expression levels of ER stress markers as we have observed in IBD mouse 
models. Colon biopsy samples from inflamed and (if available) adjacent non-inflamed 
colon before and after 6 weeks of TUDCA treatment will be harvested for analysis listed 
below.  
As the primary study endpoint, we will assess the change in ER stress markers, including 
eIF2α phosphorylation, XBP1s and BIP/GRP78, in colon biopsy tissues before and after 
6 weeks of TUDCA treatment.  
BIP, XBP1 splicing, phosphorylated eIF2α will be assessed by Western blot and RT-PCR 
and immunohistochemistry (IHC). Other ER stress markers, such as PERK, ATF4, 
CHOP, IRE1α and ATF6α will also be examined. In addition, we expect that cell death 
markers in colon biopsy tissues will also be downregulated, including cJUN, JNK, cleaved 
caspase 2 and cleaved caspase 3. We will also monitor expression of inflammatory 
cytokines, IL-1B, TNFα, IL-6 and IFNγ. Additional samples aliquots will be saved (flash 
frozen and RNAlater) for future studies evaluating adaptive and innate immune readouts.  
 
Dr. Randal J. Kaufman, the co-PI of this study, has a broad background in ER stress and 
cell death, and discovered the therapeutic role of TUDCA in IBD mouse models with 
support from CCFA. His laboratory has extensive experience in evaluation of ER stress, 
inflammation and cell death markers by western-blotting, PCR and IHC in both mouse 
models and human samples. All the colon biopsy samples will be sent under dry ice for 
analysis by Dr. Kaufman’s laboratory. Dr. Ruishu Deng, a Research Associate in Dr. 
Kaufman’s laboratory will be responsible for analyzing and processing data from the 
clinical samples.  
 
Significance of primary outcomes: Changes in ER stress markers will clarify the 
mechanisms through which TUDCA may act to alleviate inflammation in colon tissue of 
subjects with UC.  
6.1 Sample Size Determination for Primary Endpoint 
 
Estimates of change in the primary outcomes: We expect that TUDCA treatment will 
lead to similar changes on ER stress markers in UC patients as that in IBD mouse models. 
As judged by quantification results of western blot, the expression levels of ER stress 
markers in IBD mouse models were significantly reduced by 25% to 45% after TUDCA 
treatment.4 A previous publication, as well as our own data, has shown that standard 
deviations of the ER stress markers are less than ¼ of the means in intestinal biopsy 
samples of IBD patients40. Considering there might be greater variation after the TUDCA 
treatment, we set the standard deviations at half of the means of all the ER stress markers 
(Table 2).     
 
Table 2 Sample size calculation 

17 
 
ER stress 
markers 
Difference 
between means 
Estimated 
standard 
deviation 
Sample size at 
power=0.8  
Sample size at 
power=0.9  
p-eIF2α 
1.16-0.64=0.52 
0.26 
5.09 
6.39 
XBP1s 
1.21-0.73=0.48 
0.24 
5.09 
6.39 
BIP 
1.13-0.84=0.30 
0.15 
5.09 
6.39 
  
Power Estimates for each primary endpoint: We used the quantification results of 
western blot on ER stress markers to calculate the sample size needed. Since the impact 
of TUDCA on intestine tissues in humans has not been examined, we used the difference 
between the mean values of ER stress markers in groups treated with or without TUDCA 
that we obtained in murine studies.4 Power analysis using the R software shows that 7 
patients are sufficient to detect the difference before and after the treatment, when P<0.05 
is considered significant. Due to the relatively variability in IBD patient disease activity 
and high dropout rate in IBD clinical trials, we will enroll a total of 12 patients will be 
recruited for the study with an expected  
 
Statistical analysis:  We will be specifically interested in the statistical contrasts that 
compare before and after TUDCA treatment. Correlation between the primary end point 
and secondary end point will also be examined. The appropriateness of all analysis of 
variance and covariance models will be evaluated using regression residuals. If normality 
or homoscedasticity requirements are violated, data transformations will be explored and, 
if appropriate transformations cannot be found, analyses may be done semi-
parametrically using the ranks of the data.  
 
6.2 Secondary Endpoint Analyses 
 
As this is an open label, Phase I study, secondary endpoints of safety and tolerability 
will be reported qualitatively. Efficacy will be measured and reported qualitatively by 
change in Mayo Score, Goebes Histology Index and SIBDQ.  As appropriate Student’s t 
test, Mann Whitney U or ANOVA will be used to compare between time points. 
 
1. Active monitoring of UC study patients for TUDCA safety and tolerability  
 
TUDCA has a strong record of safety in several patient populations19, 20, 30 (See Detailed 
Safety Data Review below). However, TUDCA has not been examined specifically in a 
UC population. Therefore, we aim to define its safety/tolerability in this population through 
frequent monitoring and symptom assessment as detailed in the study procedures. 
Adverse events will be categorized according to CTCAE v5.0 criteria and grading. 
 
Infrequent side effects of TUDCA therapy include diarrhea and headache. Our study 
nurse coordinator will contact all study patients biweekly to assess for any experienced 

18 
 
adverse events. Additionally, in line with WUSM Center for Clinical Trials protocols, 
patients will have 24 hour access to report suspected Adverse Events.  All adverse events 
or serious adverse events will be recorded and reviewed with treating physician as well 
as PI. In the event that patients experience an adverse event potentially related to 
TUDCA, the patient will be offered the option of dose de-escalation or study withdrawal.  
 
TUDCA dose de-escalation strategy: In the setting of a toxicity that the treating physician 
determines most likely related to TUDCA, we will reduce the dose to 1000 mg (42-50% 
of initial dose). Common side effects are diarrhea and headache.  Since diarrhea is 
already a symptom implicit to inclusion, we will consider an increase of ≥3 bowel 
movements/day to be a likely drug toxicity. 
 
Early stopping rules and Dosage Reduction: In the event that ≥50% of patients experience 
a TUDCA associated side effect or intolerance, we will initiate early study termination or 
enroll all future patients at the 1000 mg dose. This decision will be made with the guidance 
of the appointed Data Safety and Monitoring Committee.  Full Stopping rules are 
described in Section 7.4. Note, individual and study stoppage criteria should be applied 
to these patients as well. 
 
  
 
 
2. Active Monitoring and Management of new elevations in liver transaminases:  
The following is our plan to a plan to evaluate subjects for other causes of liver injury 
and for the potential of drug-induced liver injury (DILI) and include protocol responses to 
persistent or new deterioration of hepatic function. 
 
For new elevations in transaminases greater than 2x ULN in subjects with normal 
baseline values or 2x baseline in subjects with abnormal baseline values, repeat 
measurement should be performed within 48 hours. If elevations persist, subjects should 
be evaluated for other causes of transaminase elevations and with tests of hepatic 
function. This may include imaging and/or labs at the treating physicians discretion and, 
if appropriate, in consultation with the study PI. If no other cause is found then the subjects 
need to be “Monitored Closely” and the drug should be discontinued as per the 
recommendations in the Guidance for subjects with normal baseline liver function. For 
patients with abnormal baseline indices, we will follow the recommendation below. 
  
Recommendation: For patients with normal baseline liver biochemistries, the drug should 
be discontinued as per: The Guidance for Industry - Drug Induced Liver Injury (Guidance 
for Industry-Drug Induced Liver Injury: Premarketing Clinical Evaluation at: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf) 
 
The guidance provides recommendations for monitoring and decision-making for drug 
discontinuation in trials that enroll subjects who have normal liver transaminases and 
bilirubin at baseline. Drug should be discontinued, and the subject followed until resolution 
of symptoms or signs in the following situations: 
• 
ALT or AST >8x ULN 

19 
 
• 
ALT or AST >5x ULN for more than 2 weeks 
• 
ALT or AST >3x ULN and (TB >2x ULN or INR >1.5) 
• 
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
  
For patients with abnormal baseline indices, see the recommendations below. 
• 
Baseline values should be established (by at least two samples obtained at least 
4 weeks and no more than 8-12 weeks apart or up to 16 weeks apart if the potential 
subject has ≥3 LFT labs in the clinical chart) to account for disease related changes 
in liver enzymes and bilirubin while on study that may otherwise be inappropriately 
attributed to study drug. The differences in repeat measurements of baseline 
serum AST, ALT, ALP and total bilirubin (TBL) should be small (<20%) to be 
eligible for study entry. You should not enroll subjects with evidence of worsening 
liver function based on the 2 initial laboratory values used to establish the baseline.  
• 
If subjects with abnormal baseline liver indices develop elevations of AST or ALT 
>2x baseline or total bilirubin >1.5x baseline values during the study, repeat testing 
should be performed within 48 -72 hours. If there are persistent elevations (ALT or 
AST >2x baseline or TBL >1.5x baseline values) upon repeat testing, then close 
observation (testing and physical examination 2-3 times per week) should be 
implemented and discontinuation of drug should be considered (see c below). 
  
A decision to discontinue or temporarily interrupt the study drug should be 
considered based on factors that include how much higher than baseline ALT and 
AST were relative to the upper limit of normal (ULN) and how much the on study 
ALT and AST levels have increased relative to baseline, in addition to whether 
there is concomitant elevation of bilirubin or INR. You need to discontinue or 
temporarily interrupt the study drug:  
• 
If baseline measurements (BLM) were <2x ULN, discontinue if ALT or AST 
increases to >5x BLM.  
• 
If BLM ≥2x ULN but <5x ULN, discontinue if ALT or AST increases to >3x BLM 
• 
If BLM ≥ 5x ULN, discontinue if ALT or AST increases to >2x BLM  
• 
Discontinue if ALT or AST increase > 2x BLM AND the increase is accompanied 
by a concomitant increase in TBL to >2x BLM OR the INR concomitantly increases 
by >0.2. 
In any subjects with signs and symptoms of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
 
3. Examine efficacy endpoints endoscopic mucosal healing, clinical response 
(Mayo Score) as well as histologic severity (Geboes histology index). 
 
We anticipate that TUDCA therapy will reduce ER stress and promote mucosal healing. 
As TUDCA has the potential to increase stool frequency, it is important to measure 
efficacy through objective measures (endoscopy and histology) as well as clinical 
symptoms. Thus, we will obtain a complete Mayo UC score at weeks 0 and 6 and a partial 
(no endoscopic subscore) at weeks 2 and 4.32  Biopsies will be obtained at both 

20 
 
endoscopic procedures and objectively scored by the Goebes index. Thus, secondary 
endpoints will include the following using FDA recommended UC Clinical trial 
guidelines41:  
 
1) Mucosal Healing: A decrease of at least 1 point on the Mayo endoscopic subscore  with a 
final score of 0 or 1 will be used as a marker of mucosal healing.  
2) Clinical Response: A decrease in Mayo Score of ≥ 3 points and a decrease in Mayo Score 
of ≥ 30% from baseline and a decrease in the rectal bleeding score of ≥ 1 or an absolute rectal 
bleeding score of 0-1.  
a. Clinical Remission will also be recorded if achieved as defined by a total Mayo Score 
of ≤2 with no subscore >1 and improvement of endoscopic appearance of the mucosa 
(Mayo 0 or 1). 
3) Histologic activity: Histologic disease activity. Colon biopsy samples will be harvested and 
fixed as described. H&E stained sections will be evaluated for tissue damage and 
inflammation by a gastrointestinal pathologist in a double-blinded manner, using the simplified 
Geboes histology index34, 35  
 
We expect that TUDCA treatment will significantly alleviate inflammation in colon tissues, 
which will be correlated with increased plasma concentration of TUDCA or the 
deconjugated form UDCA. We will collect stool samples both before and after TUDCA 
treatment for potential (longer range) studies of gut microbiota composition. 
Data analysis, interpretation and alternative plans: We expect that there will be 
minimal adverse effects due to TUDCA treatment, as its safety in humans has been 
proven in clinical trials for other disease conditions.  We expect that TUDCA treatment 
will improve endoscopic and histologic parameters of inflammation. We also anticipate 
that it will improve overall Mayo scores and lead to clinical response, if not remission. It 
is possible though that TUDCA will exacerbate diarrhea in UC patients and clinical 
symptoms may worsen even if mucosal healing occurs. It is possible that we will not 
achieve significant improvement in the severity of inflammation, as mucosal healing can 
take as long as several months (Lialda induction trial) and our TUDCA treatment duration 
is only 6 weeks. In this case, we will analyze whether expression of ER stress, 
inflammation and cell death markers in colon biopsy tissues is correlated with the plasma 
concentration of TUDCA and its metabolites, which will provide a reliable indication for 
long-term mucosal healing.  
 
 
7 Safety and Adverse Events 
 
As Safety and tolerability are secondary endpoints, they are further described above in 
section 6. 
7.1 Definitions 
Adverse Event 

21 
 
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 
will 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 
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 
 
 
What are serious adverse events or unanticipated problems? 
 
Any incident, experience, or outcome that meets all of the following criteria: 
 
(1) unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
(2) related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research);  
 
(3) and suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
All adverse events that do not meet any of the criteria for serious should be regarded 
as non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of the 
study treatment follow-up.  For this study, the study treatment follow-up is defined 
as 14 days following the last administration of study treatment.   
Preexisting Condition 

22 
 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this 
study.  The investigator should notify the study sponsor of any death or adverse 
event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should 
also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a 
subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any 
one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should 
be documented as an adverse event if the condition meets the criteria for and 
adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 

23 
 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
7.2 Recording of Adverse Events 
At each contact with the subject, the investigative team must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events should 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. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period must 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 treatment or study participation 
should be recorded and reported immediately. 
7.3 Reporting of Serious Adverse Events 
7.3.1 IRB Notification by Investigator 
Reports of all serious adverse events or unanticipated problems (including follow-
up information) must be submitted to the IRB within 10 working days.  Copies of 
each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s binder. 
7.3.2 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission 
of any unexpected fatal or life-threatening experience associated with the use of 
the drug as soon as possible but no later than 7 calendar days from the sponsor’s 
original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the study sponsor will submit the adverse event in a 
written report to the FDA as soon as possible, but no later than 15 calendar days 
from the time the determination is made. 
7.4 Stopping Rules  
 
Individual stoppage criteria- 

24 
 
Based on extensive clinical trial data, we anticipate that TUDCA will be well tolerated.  
However, patients will be monitored via study visits and phone calls and will 
permanently discontinue study drug for any adverse event possibly or probably related 
to study drug that is considered of moderate or severe intensity. To define intensity, we 
will utilize a standard severity rating scale to ensure this safety monitoring plan is 
enforced in a standardized fashion.  Individual subjects should be discontinued for any 
adverse event rated a Grade 3 or greater in severity on the Common Terminology 
Criteria for Adverse Events (CTCAE_v5.0 November 2017) scale v, unless it is clearly 
related to the underlying disease. 
For disease specific symptoms (e.g. diarrhea, rectal bleeding) we will consider disease 
worsening as an increase in >3 points on the Mayo Score to be potentially related to 
TUDCA and will lower the dose to 1000 mg as described.  If symptoms persist or 
worsen over the subsequent 5 days, the patient will be permanently discontinued from 
the study.  
  
Study stoppage criteria- 
Enrollment of new subjects should be interrupted should 2 or more patients experience 
CTCAE Grade 3 event, or 1 or more patients experience CTCAE Grade 4 events not 
clearly related to the underlying disease. Study enrollment may be resumed following 
review of all available safety data by the investigator and study team and a concurrent 
opinion that the totality of the data suggests this event is unlikely to be related to 
TUDCA. The study should be terminated if, following the review of the safety data, it has 
not been possible to demonstrate that the adverse event has a clear relationship to the 
underlying disease or associated co-morbidity. 
 
We will initiate early study termination or enroll all future patients at the 1000 mg dose. 
This decision will be made with the guidance of the appointed Data Safety and 
Monitoring Committee. Individual and study stoppage criteria should be applied to these 
patients as well. 
 
7.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan (see section 10 Auditing, 
Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
7.5.1 Internal Data and Safety Monitoring Board 
Adverse Events and Serious Adverse Events will be assessed and recorded with 
oversight by an institutional DSMC (Data Safety and Monitoring committee) that will meet 
after the 7th patient has completed the study. At that point, the Data and Safety Monitoring 
Committee (DSMC) will meet to determine whether enrollment may continue to the 
randomized portion of the study.  
 

25 
 
In compliance with the Washington University Institutional Data and Safety Monitoring 
Plan, the DSMC will meet to review toxicity data at least every 6 months.  The report will 
be prepared by the statistician with assistance from the study team and will be submitted 
to the Quality Assurance and Safety Monitoring Committee (QASMC).  This report will 
include: 
 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
• 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual  
• 
Protocol activation date 
• 
Average rate of accrual observed in year 1, year 2, and subsequent years 
• 
Expected accrual end date and accrual by arm 
• 
Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• 
Measures of efficacy 
• 
Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• 
Summary of toxicities separated by arm 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study 
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or the Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
Additionally, if two or more serious adverse events of a similar nature occur and a causal 
relationship to the investigational product cannot be excluded, accrual to the randomized 
portion will not occur. 
 
A DSMC will consist of no fewer than 3 members including 2 clinical investigators and a 
biostatistician.  Like investigators, DSMC members are subject to the Washington 
University School of Medicine policies regarding standards of conduct. Individuals invited 
to serve on the DSMC will disclose any potential conflicts of interest to the trial principal 
investigator and/or appropriate university officials, in accordance with institution policies. 
Potential conflicts that develop during a trial or a member’s tenure on a DSMC must also 
be disclosed.  
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring 
Committee Policies and Procedures for full details on the responsibilities of the DSMC 
at https://siteman.wustl.edu/research/clinical-research-resources/   

26 
 
8 Data Handling and Record Keeping 
8.1 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. 
8.2 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. 
8.3 Case Report Forms 
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. 
8.4 Records Retention 
The investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no 
pending or contemplated marketing applications in their country or at least 2 years have 

27 
 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period if required by an 
agreement with the sponsor.  In such an instance, it is the responsibility of the sponsor 
to inform the investigator/institution as to when these documents no longer need to be 
retained.  
 
9 Study Monitoring, Auditing, and Inspecting 
9.1 Study Monitoring Plan 
 
The Principal Investigator at Washington University School of Medicine is Dr. Matthew 
Ciorba.  The Data Monitoring Plan for the Study is as follows: 
 
Study recruitment, progress and safety issues are reviewed by the investigators, 
research nurse and research coordinators at a weekly meeting.  During the meeting the 
following will be reviewed:   
o Subject enrollment 
o Preliminary finds that might affect the risk/benefit ratio or alter the 
procedures described in the protocol 
o Any out of range lab values including the resulting course of action 
o Stopping rules 
o Any  adverse events or serious adverse events that may result from the 
research procedures 
 
PI will monitor the study for any adverse and/or serious adverse events.  All serious 
adverse events will be reported to the IRB as follows: 
 
1) Death – Immediately 
2) Life-Threatening – Within seven (7) calendar days 
3) IDE – Within seven (7) working days 
4) All other SAEs - Within 7 calendar days 
 
An event that meets the three criteria above generally will warrant consideration of 
substantive changes in the research protocol or informed consent or other corrective 
actions in order to protect subjects. 
 
The same will be reported to the sponsor, and subsequently the FDA (if applicable). 
 
Should there be a serious adverse event that occurs that increases the risks to the 
participants, the study will be stopped, an investigation will be conducted, and a findings 
report will be generated before the study is resumed.  These findings will be shared with 
the IRB, the Research Subject Advocate, and the General Clinical Research Center (if 
applicable). If necessary, the research procedure will be modified and appropriate 
revisions to the consent document and consenting process will be made. 
 

28 
 
9.2  Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the 
EC/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.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
10 Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Ethics Committee (EC) or 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 and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of EC/IRB members 
and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  A copy of the Subject Informed Consent Form is included.  
This consent form will be submitted with the protocol for review and approval by the 
EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved 
consent form, must be obtained before that subject is submitted to any study procedure.  
This consent form must be signed by the subject or legally acceptable surrogate, and 
the investigator-designated research professional obtaining the consent.  
 
11 Publication Plan 
 
Results will be submitted for publication or data disseminated via meeting abstracts 
after approval by the PI and all authors/involved investigators. 
 
12 References 
 

29 
 
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