A Clinical Trial for the Off Label Use of Ursodiol for the Prevention of Recurrent C. Difficile Colitis and Diarrhea
Phase: PHASE4
Conditions: Diarrhea
Sponsor: NYU Langone Health

 
 
  
 
 
 
C. Diff 
i
 
 
 
 
 
 
 
 
 
A clinical trial for the off-label use of ursodiol for the prevention of recurrent C. difficile colitis and diarrhea 
(2). 
 
 
 
 
 
Sponsor-Investigator: 
Norman B Javitt M.D. Ph.D. 
Department of Medicine, Division of Gastroenterology 
Bellevue Hospital  
212 263 6588 
Funding Sponsor: 
Gastroenterology Division 
Bellevue Hospital 
212 263 6588 
Study Product: 
Ursodiol (Actigall, urso) 
Protocol Number: 
S15-01348 
IND Number: 
N/A Exempt from IND Requirements 
NCT Number: 
NCT02748616 
 
 
 
 
 
 
 
 
 
 
 
Initial version: February 25, 2016 
Amended: 
[July 27th, 2016] 
Amended: 
[ 02-14-2017] 
Amended: 
[May 23, 2017] 
Amended:          [January 29, 2018] 
Amended:      
[April 3, 2018] 
Amended: 
  [October 22, 2018] 
 
 
Clinical Research Protocol 

 
C. difficile and Urso. 
Version Date:  October 22nd, 2018 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg ii
Table of Contents 
 
STUDY SUMMARY ....................................................................................................................................... 1 
1 
INTRODUCTION ..................................................................................................................................... 2 
1.1 
BACKGROUND .................................................................................................................................... 2 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 3 
1.3 
PRECLINICAL DATA ............................................................................................................................. 4 
1.4 
CLINICAL DATA TO DATE ..................................................................................................................... 4 
1.5 
DOSE RATIONALE ............................................................................................................................... 5 
1.6 
RESEARCH RISKS & BENEFITS ............................................................................................................ 5 
1.6.1 
Risk of Study Drug .................................................................................................................... 5 
1.6.2 
Other Risks of Study Participation ............................................................................................ 5 
1.6.3 
Potential benefits ...................................................................................................................... 5 
2 
STUDY OBJECTIVES ............................................................................................................................. 5 
3 
STUDY DESIGN ...................................................................................................................................... 6 
3.1 
GENERAL DESIGN............................................................................................................................... 6 
3.2 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 6 
3.3 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 7 
3.4 
PRIMARY SAFETY ENDPOINTS ............................................................................................................. 3 
4 
SUBJECT SELECTION AND WITHDRAWAL ....................................................................................... 3 
4.1 
INCLUSION CRITERIA ........................................................................................................................... 7 
4.2 
EXCLUSION CRITERIA ......................................................................................................................... 7 
4.3 
SUBJECT RECRUITMENT AND SCREENING ............................................................................................ 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ..................................................................................................... 8 
4.4.1 
When and How to Withdraw Subjects ...................................................................................... 8 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................... 8 
5 
STUDY DRUG ......................................................................................................................................... 9 
5.1 
DESCRIPTION ..................................................................................................................................... 9 
5.2 
TREATMENT REGIMEN ........................................................................................................................ 4 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS.............................................................. 9 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 9 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 9 
5.6 
PRIOR AND CONCOMITANT THERAPY ................................................................................................... 9 
5.7 
PACKAGING ........................................................................................................................................ 9 
5.8 
BLINDING OF STUDY DRUG ................................................................................................................. 5 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................ 9 
5.9.1 
Receipt of Drug Supplies .......................................................................................................... 9 
5.9.2 
Storage ................................................................................................................................... 10 
5.9.3 
Dispensing of Study Drug ....................................................................................................... 10 
5.9.4 
Return or Destruction of Study Drug ...................................................................................... 10 
6 
STUDY PROCEDURES ........................................................................................................................ 11 
6.1 
VISIT 1 ............................................................................................................................................. 11 
6.2 
VISIT 2 ............................................................................................................................................... 6 
6.3 
ETC. ................................................................................................................................................... 6 
7 
STATISTICAL PLAN ............................................................................................................................ 12 
7.1 
SAMPLE SIZE DETERMINATION .......................................................................................................... 12 

 
C. difficile and Urso. 
Version Date:  October 22nd, 2018 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg iii
7.2 
STATISTICAL METHODS ..................................................................................................................... 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................................... 13 
8 
SAFETY AND ADVERSE EVENTS ...................................................................................................... 13 
8.1 
DEFINITIONS ....................................................................................................................................... 7 
8.2 
RECORDING OF ADVERSE EVENTS .................................................................................................... 13 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ..................................... 13 
8.3.1 
Investigator reporting: notifying the study sponsor ................................................................. 14 
8.3.2 
Investigator reporting: notifying the IRB ................................................................................. 14 
8.3.3 
Sponsor reporting: Notifying the FDA ..................................................................................... 11 
8.3.4 
Sponsor reporting: Notifying participating investigators ......................................................... 12 
8.4 
UNBLINDING PROCEDURES ............................................................................................................... 12 
8.5 
STOPPING RULES ............................................................................................................................. 12 
8.6 
MEDICAL MONITORING ...................................................................................................................... 13 
8.6.1 
Data Monitoring Committee .................................................................................................... 13 
9 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 15 
9.1 
CONFIDENTIALITY ............................................................................................................................. 16 
9.2 
CONFIDENTIALITY AND HIPAA .......................................................................................................... 16 
9.3 
SOURCE DOCUMENTS....................................................................................................................... 16 
9.4 
CASE REPORT FORMS ...................................................................................................................... 16 
9.5 
RECORDS RETENTION ...................................................................................................................... 17 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 17 
10.1 
STUDY MONITORING PLAN .............................................................................................................. 17 
10.2 
AUDITING AND INSPECTING ............................................................................................................. 17 
11 
ETHICAL CONSIDERATIONS ........................................................................................................... 17 
12 
STUDY FINANCES ............................................................................................................................. 18 
12.1 
FUNDING SOURCE .......................................................................................................................... 18 
12.2 
CONFLICT OF INTEREST .................................................................................................................. 18 
12.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................. 18 
13 
PUBLICATION PLAN ......................................................................................................................... 18 
14 
REFERENCES .................................................................................................................................... 18 
15 
ATTACHMENTS ................................................................................................................................. 17 
 
 
 

 
C. difficile and Urso. 
Version Date:  October 22nd, 2018 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg iv
 
List of Abbreviations 
 
Ursodeoxycholic acid    urso, ursodiol 
 
C. difficile   clostridium difficile 
 
 
 
 
 
 
 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 1 
Study Summary 
Title 
A clinical trial for the off-label use of ursodiol for the prevention of recurrent C. 
difficile colitis and diarrhea. 
 
Short Title 
C. difficile and Urso. 
Protocol Number 
S15-01348   
Phase 
Clinical trial of an off-label use of ursodeoxycholic acid 
Methodology 
Open label study with fecal bile acid monitoring 
Study Duration 
10 months 
Study Center(s) 
Multi-center Tisch (including NYU Lutheran sites),Bellevue Hospital 
Objectives 
Prevention of recurrent C. difficile colitis and diarrhea 
Number of Subjects 
32 enrolled to reach goal of 30 completed subjects 
Diagnosis and Main 
Inclusion Criteria 
Suspected C. difficile colitis and diarrhea 
Study Product, Dose, 
Route, Regimen 
Ursodiol 300 mg by mouth twice a day;  added to Metronidazole and/or 
vancomycin therapy 
Duration of 
administration 
Two months 
Reference therapy 
Metronidazole and/or Vancomycin 
Statistical 
Methodology 
Percent of patients with restoration of deoxycholic acid pool size 
 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 2 
1 Introduction 
 
This document is a clinical research protocol with each patient serving as his/her own control. Good 
Clinical Practice Standards will be followed in accordance with US government research regulations, and 
applicable international standards of Good Clinical Practice, and institutional research policies and 
procedures. 
1.1 Background 
The occurrence of inflammation of the colon and diarrhea after a patient has received a therapeutic 
course of antibiotics for an unrelated problem (i.e. pneumonia, urinary tract infection) is a well-recognized 
clinical problem.  In many instances, it has been found that when the feces of the patient undergo 
bacterial culture, they contain the bacterium clostridium difficile, which is known to produce a toxin that 
causes colonic inflammation and diarrhea. Hence the name C. difficile colitis and/or diarrhea. Data 
collected in 2011 indicates that the burden of C. difficile infection in the United States is estimated as 
15,463 cases per year  with first recurrences of 83,000 cases per year and estimated number of deaths 
as 29,300 per year.(3) 
 
The pathogenesis of this post-antibiotic C. difficile colitis has now been identified (See Figures 1a and 1b) 
and is outlined as follows: 
a. Antibiotics suppress the growth of the normal intestinal bacterial flora 
1. These bacteria have enzymes that normally metabolize the conjugated bile acids 
made by the liver, secreted into bile and emptied into the intestines, (particularly the 
glycine and taurine conjugates of cholic acid (80%)) to unconjugated cholic acid. 
2. Other normal bacterial flora have enzymes that metabolize only the unconjugated 
cholic acid to deoxycholic acid, which normally account for 80% of total fecal bile acids. 
b. Loss of these normal bacterial flora results in an increase in conjugated bile acids and 
absence of deoxycholic acid in the colon. 
c. Loss of deoxycholic acid permits the growth of C. difficile and toxin production with 
initiation of colitis and diarrhea. 
 
Figure 1A. 
 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 3 
Figure 1B
 
 
1.2 Non-Investigational and Investigational  Agent 
The non-investigational reference therapies, metronidazole, vancomycin and fidaxomicin , are FDA-
approved antibiotics currently in use today because of their effectiveness in suppressing the growth of C. 
difficile and therefore quickly eliminating the colitis and diarrhea.  HOWEVER, they do not promote the 
restoration of the normal bacterial flora. THEREFORE, when medication is stopped, the C. difficile colitis 
returns. Hence the name recurrent C. difficile colitis and diarrhea. A more recent FDA approved approach 
is fecal microbiota transplant (FMT)  where the patient is given prepared fecal material from a normal 
donor. This successful approach is based on the concept that it provides normal enteric flora which 
presumably restore normal bile acid metabolism. Refractoriness to these approaches occasionally results 
in removal of the diseased colon (4). 
       Based on the success of  FMT together with the knowledge that deoxycholic acid (1) and more 
recently ursodeoxycholic acid (2) suppress the growth of C. difficile, it is reasonable to test the hypothesis 
that augmenting the FDA approved antibiotic therapy with co-administration of ursodeoxycholic acid may 
be an alternate approach for the  restoration of  normal enteric flora.  
     Success of FMT therapy was based on the absence of recurrence of symptoms of CDI within 8 weeks 
(5).  The highest success rate was achieved by direct transplantation into the colon (5).  Administration of 
ursodeoxycholic acid for 2 months will test whether it is a surrogate for FMT with respect to recurrence  of 
symptoms. In addition, because we are analyzing fecal bile acids at 2 week intervals we will know in what 
percentage of patients there has been restoration of the endogenous deoxycholic acid pool and  
approximate rates at which restoration  occurs. This information  will provide guidance for future studies. 
   Considering the complexity of the problems that have arisen  with FMT therapy (5), it is reasonable to 
propose that the proposed study can identify individuals that restore their endogenous pool and do not 
require FMT therapy. 
     
 
Ursodeoxycholic acid (250mg and 500mg tablets) was approved by the FDA more than 15 years ago for 
the treatment of primary biliary cirrhosis.  The approved dose is 13 to 15 mg/kg/day in 2 to 4 divided 
doses.  Additionally, it is indicated for prevention of gallstones in patients undergoing rapid weight loss at 
a dose of 600mg/day (300mg capsules twice a day) and for treatment of radiolucent gallbladder stones 
(8-10mg/kg/day in 2 or 3 divided doses).  Except for occasional diarrhea, there is no acute toxicity.  

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 4 
   Ursodiol is a naturally occurring bile acid found in small quantities in normal human bile. It is a bitter-
tasting  white powder insoluble in water but soluble in ethanol and other organic solvents. The chemical 
name is 3−dihydroxy-5−cholan-24-oic acid with a molecular weight of 392.58. It is stable at room 
temperature for at least a year. 
    About 90% of a therapeutic dose of ursodiol is absorbed from the small intestines after one 
administration. It undergoes efficient extraction from portal vein blood by the liver (large “first-pass” effect) 
and is conjugated with glycine or taurine before undergoing excretion into bile. Only small amounts of 
Ursodiol enter the systemic circulation  and very little is excreted in urine.  The taurine and glycine 
conjugates of ursodiol undergo intestinal reabsorption by transporters in the ileum together with other 
conjugated bile acids. Administered ursodiol that is not absorbed enters the colon together with small 
amounts of the conjugates which are hydrolyzed and are metabolized to lithocholic acid. 
   Lithocholic acid can cause cholestatic liver disease and cirrhosis in non-human species that cannot 
sulfate lithocholic acid. Humans have the capacity to sulfate lithocholic acid and liver injury has not been 
associated with ursodiol therapy. Although diminished capacity to sulfate because of underlying liver 
disease may exist such a deficiency in humans has not been clearly demonstrated.  
                
We expect that the off-label use that we are proposing (investigational agent) will not be longer than 2 
months. The FDA has granted IND Exemption for this clinical investigation. 
1.3 Preclinical Data   
We are only aware of the one study in one patient published in the Journal of Clinical Gastroenterology 
this year identifying clinical efficacy. However the basic studies, done in vitro, that support its clinical use 
are so compelling we believe a clinical trial is fully merited.  Also a study in mice and humans (6) 
established that antibiotics suppress the growth of Clostridium scindans, a bile acid 7-dehydroxylating 
intestinal bacterium essential for generating deoxycholic acid, thus permitting the growth of C. difficile.  
Restoration of  intestinal C. scindans restored the resistance to C. difficile infection.  
 
1.4 Clinical Data to Date:   
A recent clinical study (reference 2) was published concerning the off-label use of ursodeoxycholic acid 
(ursodiol) in a single patient with recurrent C. difficile “pouchitis” who had been receiving repeated 
courses of antibiotics. On the basis of encouraging data from in-vitro studies, oral ursodiol (300mg twice 
daily) was added to the patient’s regimen for two weeks and well-tolerated.  After 2 weeks, the urosodiol 
dose was increased to 300mg 4 times daily (20 mg/kg/d) and oral vancomycin (125mg/d) was 
discontinued.  
 
The frequency of diarrhea decreased and firm bowel movements were reported. Stool cultures were 
negative for C. difficile by PCR tests for toxin B for over 12 months following the discontinuation of 
vancomycin.  Follow-up endoscopic examination of the pouch at 6 months and 1 year showed no signs of 
inflammation. The ursodiol dose was decreased to 300mg twice daily at 7 months without relapse of C. 
difficile infection. The patient refused to discontinue ol altogether in fear of relapse of C. difficile infection 
and no adverse effects have occurred, consistent with the knowledge that has accumulated with the use 
of ursodiol for FDA approved indications. 
 
In addition, in vitro findings in this study (see figure 2) establish that ursodeoxycholic acid is a surrogate 
for deoxycholic acid in preventing the growth of C. difficile, thus explaining why the recurrence was 
interrupted and the patient cured. On the basis of these encouraging in vitro results, the patient was 
prescribed oral UCDA (300 mg twice daily), which was well tolerated. After 2 weeks, the UDCA dose was 
increased to 300 mg 4 times daily (20 mg/kg/d) and oral vancomycin (125 mg/d) was discontinued. The 
frequency of diarrhea decreased and firm bowel movements were reported. Furthermore, the stool 
remained negative for C. difficile by PCR tests for toxin B over 12 months after the termination of 
vancomycin. Endoscopic examination of the pouch at 6 months and 1 year showed no signs of 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 5 
inflammation. The UDCA dose was decreased to 300mg twice daily at 7 months without relapse of CDI. 
The patient refused to discontinue UDCA altogether in fear that symptoms would come back.  
1.5 Dose Rationale  
The major hypothesis that we are testing is that after stopping antibiotics,  urso will continue to suppress 
the growth of C. difficile until the return of the normal intestinal pool of deoxycholic acid. 
Implicit in this hypothesis is the knowledge that ursodeoxycholic acid, in contrast to cholic or 
chenodeoxycholic acid does NOT downregulate primary bile acid synthesis in the liver (7) so that as normal 
enteric bacteria begin to flourish, the primary bile acids will be metabolized to intestinal bile acids and the 
deoxycholic acid pool will return to normal. 
 
There are large variations in the data concerning fecal bile acid excretion in humans, but a value of 500-
600 mg per day for deoxycholic acid fits well into the range. Therefore, we will use 300 mg of urso twice a 
day (8.57 mg/kg/day for 2 months to mimic the 8 week follow-up period in previous FMT studies (5)) during 
which the absence of recurrent symptoms was considered an indication of success. Also, considering the 
quick therapeutic response to FMT, it is reasonable to think evidence for endogenous production of 
deoxycholic acid should be obtained within this time frame. This dose does not exceed current 
recommended dosages for approved indications. 
       
1.6 Research Risks & Benefits 
1.6.1 
Risk of Study Drug: For the length of time being administered and the dose prescribed, we are not 
aware of a toxilogic risk. However, loose stool may occur and there is the risk of an allergic reaction, 
although not common. Accidental aspiration of the pill while taking it, cannot be eliminated. 
 
1.6.2 
Other Risks of Study Participation: During the course of the study the patient will be required to 
collect stool specimens at two week intervals beginning at the time of initiating antibiotic therapy. 
As a secondary aim we will be testing stool for other factors that may influence C. difficile infection, 
including microbial composition via 16S rRNA sequencing and stool pH. These analyses will not 
reveal genetic data representative of the stool donor. Therefore there are no risks associated with 
genetic testing to the study subjects. No endoscopic procedures are required for participation in 
the study. Loss of confidentiality is a small, but potential risk; however, data is coded without 
identifying information and stored on a network drive protected by the NYU Langone Medical 
Center .  
 
1.6.3 Potential benefits 
The hypothesis we are testing is that continued administration of urso will maintain suppression of C. difficile 
while allowing for return of the normal deoxy pool and thus prevent recurrence of colitis and diarrhea. Benefit 
cannot be guaranteed as it may work in some patients but not others. The knowledge gained from this 
study may ultimately benefit future patients with recurrent C. difficile colitis.   
 
Because we will be analyzing fecal bile acids every two weeks, the data can be correlated with the clinical 
response. 
2 Study Objective 
 
Primary Objective 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 6 
To eliminate recurrent C. difficile colitis and diarrhea 
 
Secondary Objectives 
To learn more about the restoration of normal fecal bile acid patterns after exposure to antibiotics   
To learn more about the relationship between fecal bile acids and gut environmental factors that may also 
predispose to C. difficile infection, including microbiome composition and stool pH. 
3 Study Design 
3.1 General Design 
This is a clinical trial where fecal bile acid and microbiome composition is monitored at two week intervals 
for a maximum of two months in each patient beginning on entry into the study. Patients will be identified 
through  referral from their clinical provider(s). Eligible patients will be those with a suspected  diagnosis of 
recurrent C. difficile colitis (more than one episode). When possible, patients will be referred and enrolled 
prior to collecting a fecal specimen for C. difficile testing. The referring physician or a study team member 
will offer the patient the opportunity of participating in the clinical trial. A study team member will administer 
the consent, and if the patient approves and signs the consent, the clinically indicated fecal specimen will 
be tested for C. difficile as well as kept for study purposes. If the laboratory test comes back positive for C. 
difficile, the ursodiol, in addition to the standard care antibiotic, is started. If the laboratory test comes back 
negative, the patient’s study participation will be stopped after the single stool collection. This stool 
specimen will serve as a negative control. For patients, who are not referred in time to collect a pre-testing 
fecal sample, the patient will only be enrolled if C. difficile infection is confirmed on clinical testing. 
 
For patients testing positive for CDI, decisions on the antibiotic treatment will be managed by the patient’s 
clinician, but the ursodiol will be continued for a total of 2 months. Serial collection of feces at 2 week 
intervals are expected to indicate an increase in ursodeoxycholic acid and the appearance of deoxycholic 
acid. Further increase in the deoxy pool size and obtaining a normal unconjugated/conjugated bile acid 
ratio (corrected for the administered urso) are anticipated to ensue within two months. Although not a 
mandatory part of the study, it will be of additional  value to establish that the return of deoxycholic acid  
extends beyond the time that the patient was taking ursodiol.  Therefore, in those patients that agree to be 
contacted  and are available after completion of the study, we will ask for two additional stool samples. 
At each study fecal collection, the study subjects will also be asked to complete a general healthy and 
dietary survey. 
 
For each follow up visit, a -4 day window will be used to account for potential scheduling difficulties and 
limit the chances of running out of medication. The patient will have at most 8 pills when returning for their 
follow-up visit. During this follow-up visit, the patient will take back their previously dispensed bottle, as well 
as a newly dispensed bottle, to take home. The patient will be instructed to continue their previously 
dispensed bottle of ursodiol until they are finished with the original bottle. Afterwards, patients can then 
start their newer bottle. The patients must bring a stool sample when obtaining the next bottle of medicine. 
 
3.2 Primary Study and Safety Endpoints 
The primary study endpoint is the restoration of the deoxycholic acid pool and conjugated/unconjugated 
fecal bile acid pattern. 
 
The primary clinical endpoint is no further occurrence of diarrhea or other symptoms of C. difficile colitis 
during the two month period. The subject will be evaluated by a study team member at 2 week intervals at 
which time a brief interim history related to the possible recurrence of symptoms of CDI is obtained. The 
subject will be instructed to report immediately to the  referring provider, as well as the study team should 
symptoms possibly related to CDI occur at any time, and a further clinical evaluation will be required to 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 7 
ascertain the cause of these symptoms. Patients with known lactose intolerance will be reminded of the 
importance of maintaining a lactose-free diet.   
3.3 Secondary Study Endpoints 
In addition, we will be testing stool for other gut environmental characteristics that may affect one’s 
predisposition for C. difficile infection. This include testing samples for stool pH , as well as for 
microbiome composition. It has been proposed that CDI are associated with alkaline stool pH and that 
FMT resolves recurrent CDI by restoration of the normal gut flora. Therefore evaluating stool pH and 
microbial composition from stool samples obtained during the study period will allow the study team to 
determine whether or not co-administration of Ursodial with antibiotics affects these secondary endpoints 
as well.For all stool testing, aliquots of feces will be analyzed and the bulk sample remain frozen at -80C 
for possible further study related to our further understanding of C. difficile infection. This is optional at 
enrollment and the subject will always have the opportunity of  specifying that stool specimens not used 
during the study be discarded at the end of the study rather than preserved. This decision will not affect 
participation. Samples will be banked in the study team’s laboratory (Bellevue Hospital C & D 600/611 or 
the Veterans Affairs Medical Center, Manhattan Campus, 6th floor).  Stored samples will be coded with 
the specimen ID so that subjects cannot be identified. The possibility that confidentiality could 
inadvertently be breached when specimens are in storage will be indicated but the design is that only the  
study team personnel will have the information linking the specimen to a specific subject. Samples will be 
stored in containers that are marked with a de-identified alphanumeric study ID, but will not contain any 
PHI.  
We will also perform microbiome analyses by processing extracted DNA samples from collected stool for 
16S rRNA. This will allow us to confirm the presence of, and evaluate the relative abundance of, C. difficile 
from study patients.  
 
3.4 Inclusion Criteria 
• 
Male and female patients with presumed recurrent C. difficile colitis 
• 
18 years of age and older 
• 
Capable of giving informed consent.  
 
There are no exclusions by race, ethnicity or sexual preference. 
3.5 Exclusion Criteria   
• 
Patients with other gastrointestinal problems prone to cause diarrhea if they cannot be controlled 
for the period of the study. Lactose intolerance or gluten enteropathy are not an exclusion provide 
that the potential subject is asymptomatic and can be expected to adhere to the appropriate 
dietary regimen. 
 
• 
Patients with contraindications to metronidazole,  vancomycin, fidaxomicin, and/or ursodiol tablets 
or components of the formulations. 
• 
Patients testing positive for C. difficile infection who are not available for long-term follow-up (2 
months) by their physician will be excluded from the study. 
• 
Patients who will not be treated with antibiotics for the C. difficile infection, but will be receiving 
fecal transplantation instead.  
 
Although ursodeoxycholic acid is used for the treatment of cholestasis of pregnancy (last trimester) its 
effects on the fetus at other times have not been studied, and the FDA does not encourage its use in 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 8 
pregnancy. Therefore, pregnant women confirmed by review of clinical records will also be excluded from 
this study.  
  
3.6 Subject Recruitment and Screening 
Providers will identify potential subjects from patients under their care for acute illness during routine clinical 
visits.  
 
If the patient has had a history of C. difficile infection, and is presumed to have the infection again, the 
provider will refer the subject to a study team member who will discuss the details of the study, risks, and 
benefits with potential subjects, answer any questions, and obtain written informed consent from subjects. 
If the subject consents, a portion of their stool sample that is clinically indicated for C. difficile infection 
testing will also be used for study testing. If the subject tests positive for C. difficile, indicating that their CDI 
is recurrent and the patient is willing to adhere to a schedule that requires additional stool collections and 
use of ursodiol for 2 months, the patient will be provided the ursodiol and a kit for the next stool sampling. 
A copy of the signed consent form will be placed in the subject’s research chart to document that informed 
consent was obtained.     
 
In order to inform physicians, the approved notecards will posted. In addition, the Clinical Microbiology 
and Immunology laboratory at NYU Langone Medical Center will generate lists of patients for whom C. 
difficile clinical laboratory testing is ordered to help identify potential patients. Furthermore, the study team 
may also use hospital generated patient censuses of  C. difficile positive patients to identify potential 
subjects. We anticipate that most patients identified by the clinical laboratory will be inpatients. We will 
use their MRNs to identify the location of the patient in the hospital and their treating provider. Patients 
will be approached in person in the hospital. For relevant outpatients, they will be approached by the 
preferred phone or email provided in their contact information.  
 
     
 
 
 
 
 
 
 
 
 
 
 
 
4.4 Early Withdrawal of Subjects 
3.41 When and How to Withdraw Subjects 
Subjects may withdraw from the study at any time without consequence to their standard treatment.  
Additionally, subjects will be withdrawn for any of the following reasons: 
• 
The subject ceases to take the ursodiol and/or provide stool samples. If the subject develops 
symptoms that could be related to CDI a complete evaluation by the principal investigator including 
fecal bile acid analysis will determine further participation in the study. 
 
 
   A “no show” to a routine visit will prompt a study team member to contact the patient to ascertain current 
status by reviewing current health and reason for missed visit. The likelihood of recurrence of the diarrhea 
will be reviewed, but there is no immediate danger to the patient. Should the patient not wish to re-join the 
study, then it will be suggested that return of diarrhea prompt immediate seeking of medical care.  
     
3.41.1 Data Collection and Follow-up for Withdrawn Subjects 
The integrity of the study is not affected by premature withdrawal since early stoppage of ursodiol vitiates 
the data set which is not included in the final results of the study. 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 9 
4 Study Drug  
4.1 Description:  
Ursodiol will be taken as a 300 mg capsule twice a day with or without food.  In the unlikely event, based 
on numbers of patients and years of use, that stools become loose the dose will be lowered to once per 
day for the reminder of the study.  Loose stools are reported in less than 10% of patients on long-term 
ursodiol therapy. 
4.2 Method for Assigning Subjects to Treatment Groups  
All C. difficile positive patients will be offered the opportunity of co-administration of urso once it is 
ascertained that they are willing to participate in a two month study with stool collection  every two weeks. 
4.3 Preparation and Administration of Study Drug 
The drug will be purchased by the principal investigator  as 300 mg capsules from Lannett Company Inc.  
that now sells to the NYU outpatient pharmacy. The bottle will be inspected for damaged capsules and a 
master log sheet containing the manufacturers information as to lot#, shelf life and storage conditions 
noted.  
As patients enter the study, bottles containing 28 capsules will be prepared and labeled ursodiol 300 mg. 
The study # corresponding to the specimen # and week of the study will be placed on the bottle. It will be 
given to the study team member who will then give the initial bottle and further bottles at 2 week intervals 
when a stool specimen is received.      
4.4 Subject Compliance Monitoring  
The proportion of urso in the fecal bile acid analysis will be the best indication of compliance. 
The patient will be informed by the study team if urso is lacking. Causes for non-compliance will be 
evaluated by the study team, and a decision made as to the likelihood of successful and sustained reentry 
into study. 
4.5 Prior and Concomitant Therapy 
Patients entering the study can continue to take all medications that they are currently taking for other 
existing medical conditions. 
 
4.6 Packaging 
Bottles containing twenty eight capsules of ursodiol 300 mg capsules will be given by study physician to 
patient every two weeks. 
4.7 Receiving, Storage, Dispensing and Return 
4.7.1 Receipt of Drug Supplies 
Medications will be dispensed by the NYU pharmacy, either to the patient directly or to a study team 
member who will then provide the medication to the patient. Patients hospitalized at Bellevue will receive 
the study medication through the Bellevue Research Pharmacy as a non-formular research drug.The 
bottle will be inspected for damage and a drug receipt log initiated 
 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 10 
4.7.2 Storage 
The drug will be stored in accordance with the manufacturers recommendation. It has a shelf life of 1 year 
at  25 C and does not require protection from light.  The principal investigator will monitor and manage the 
storage of the drug.   
4.7.3 Dispensing of Study Drug 
At the beginning of the study, once informed consent has been obtained, the subject will receive a bottle 
containing 28 capsules of 300 mg ursodiol with instruction to take a capsule in the morning and evening. If 
subjects taking bile sequestrant drugs are enrolled, they will be instructed to take ursodiol at least 5 hours 
before or after they take the bile acid sequestrant. 
 
 
When the subject returns to the study-team in 14 days, the bottle will be brought back and a new bottle 
containing 28 capsules given to the subject.  We have no precise way of knowing, other than the patient’s 
integrity, how much of the medication is actually taken (skipped doses) but analysis of the fecal specimen 
for urso will give an approximate indication of compliance. The study team will note any capsules 
remaining in the bottle at each visit. 
 
For each follow up visit, a -4 day window will be used to account for potential scheduling difficulties and 
limit the chances of the patient running out of medication. The patient will have at most 8 pills when returning 
for their follow-up visit. During this follow-up visit, the patient will take back their previously dispensed bottle, 
as well as a newly dispensed bottle, to take home. The patient will be instructed to continue their previously 
dispensed bottle of ursodiol until they are finished with the original bottle. Afterwards, patients can then 
start their newer bottle. The patients will be instructed to bring all medication bottles, whether empty or with 
remaining ursodiol.  
 
The patients must bring a stool sample when obtaining the next bottle of medicine and for the last follow-
up visit. Patients are given no more than 28 pills per dispensation to ensure patients will come back with a 
stool sample and to obtain the next bottle of pills. 
 
 
For patients at Bellevue, who are identified while hospitalized, study drug will be dispensed by the 
Bellevue Research Pharmacy. Upon discharge, patient will be provided outpatient medication as 
described above. 
4.7.4 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 by the Principal Investigator.  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. 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 11 
5 Study Procedures 
5.1 Visit 1. Presumptionof C. difficile colitis & diarrhea is established.  
• 
Study is explained to patient, informed consent obtained 
• 
Review of medical history, physical exam, height, weight, and vital signs recorded from 
clinical/standard care follow-up visit with physician  
• 
Subjects instructed to collect a stool sample for C. difficile testing and/or study testing. 
• 
Subjects are provided with a study survey.  
• 
C. difficile negative patients are finished with their study participation.  
• 
C. difficile positive patients are given ursodiol and antibiotics.  
• 
Potential adverse events are reviewed with the C. difficile positive patients. 
5.2 Visit 2. Two weeks later. (C. difficile positive patients) 
• 
Antibiotic are likely to have been discontinued 
• 
Stool specimen and study survey obtained.  
• 
28 Capsules of 300mg urso dispensed with instructions of 1 capsule twice a day.   
• 
Adverse events follow-up 
5.3 Visit 3. Two weeks later. (C. difficile positive patients) 
• 
Stool specimen and study survey obtained.  
• 
Dispense 28 capsules urso 300 mg (collect bottle from previous visit) 
• 
Adverse events follow-up 
 
5.4 Visit 4.   Two weeks later. (C. difficile positive patients) 
• 
Stool specimen and study survey obtained.  
• 
dispense 28 capsules urso 300 mg (collect bottle from previous visit) 
• 
Adverse events follow-up 
5.5 Visit 5: Two weeks later. (End of study drug administration) (C. difficile 
positive patients) 
• 
Stool specimen and study survey obtained.  
• 
Collect unused bottle from previous visit 
• 
Adverse events follow-up 
 
The table below shows each visit and the procedures done at each visit: 
Activity 
Visit Name 
#1 
Visit 
Name 
#2b 
Visit 
Name 
#3b 
Visit 
Name 
#4b 
Visit 
Name 
#5b 
Visit 
Name 
#6 
(Optional) 
Visit 
Name 
#7 
(Optional) 
Study team procedures 
  
  
  
  
  
 
 
Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Study drug dispensation 
(ursodiol) 
x 
X 
x 
x 
 
 
 
Study health and dietary 
survey 
x 
x 
x 
x 
x 
x 
x 
Adverse Event review 
x 
x 
x 
x 
x 
 
 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 12 
Laboratory Assessments 
 
 
 
 
 
 
 
 C. difficile 
Positive 
(continue 
visits 2-
5) 
 
 
 
 
 
 
 
negative 
 
 
 
 
 
 
Stool collection 
xa  
x 
x 
x 
x 
x 
x 
a. baseline stool sample can be collected on site if possible or before medication therapy is initiated 
b. Each follow-up visit will have a -4 day window to account for potential scheduling difficulties. 
Patients will have at most 8 pills when returning for follow-up visit 
 
6 Statistical Plan 
6.1 Sample Size Determination is based on (1) the likelihood of obtaining 
Up to 32 C. difficile positive patients will be enrolled so that we will reach a goal of 30 subjects who 
complete the study within a 10 month period taking screen-failures/dropouts into consideration. The 
recurrence rate of C. diffiicle in patients that were given either metronidazole or vancomycin is 
estimated at 25% and several patients a month are treated both at Bellevue and at Tisch  for recurrent 
infection. Estimating that 4 patients a month will participate in the study will yield 32 patients in 8 
months and completion of the study in 10 months. 
 Assuming the correctness of the report  that ursodeoxycholic acid (figure 2) suppresses C. difficle 
growth then the major question we wish to answer is the frequency of return to a normal fecal bile 
acid pattern during the two month period.  
We will enroll both C. difficile positive and C. difficile negative patients until the goal of 32 C. difficile 
positive patients is reached. 
 
6.2 Statistical Methods: We will be analyzing for the following fecal bile acids 
(1) Taurine conjugates (2) glycine conjugates (3) non conjugated (a) cholic acid (b) 
chenodeoxycholic acid (c) deoxycholic acid (d) ursodeoxycholic acid (e) lithocholic acid, each 
expressed as a per cent of the total.  
Based on studies in the literature, the initial fecal sample is expected to have an increase in the 
proportion of conjugated bile acids and non-conjugated cholic and chenodeoxycholic acid with 
absent  deoxycholic, lithocholic and ursodeoxycholic acid. 
 
Subsequent stool specimens are all expected to contain ursodeoxycholic acid and therefore 
a reduction in the proportion of conjugated bile acids. The “key” data will be the increase in the 
proportion of deoxycholic and lithocholic acid and decrease in chenodeoxycholic and cholic acids 
which will only occur with the return of the normal enteric bacterial flora (confirmed via 
microbiome analyses). 
 
The percent of patients with return toward a normal fecal bile acid pattern will be the criterion for 
evaluating the success of urso treatment. If all subjects remain symptom-free during the study 
then urso may be considered as a surrogate for FMT. Return of the endogenous deoxycholic 
acid pool in 20% or more of subjects would indicate they probably will not need FMT therapy and 
are protected from recurrent CDI.  
 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 13 
6.3 Subject Population(s) for Analysis 
In addition to the C. difficile negative stool specimens, only subjects that have completed the two month 
period and provided 5 stool samples will be included in the data analysis. C. difficile negative stool 
samples and initial fecal samples from C. difficile positive subjects that did not complete the study will be 
used to compare to literature reports on the fecal bile acid patterns of individuals with recurrent  C. difficile 
infection. 
7 Safety and Adverse Event 
 
Adverse Event 
 
Based on published experience with the use of ursodeoxycholic acid, it is possible that some patients 
may develop loose bowel movements at a total dose of 600 mg/day. In this event, the daily dose will be 
lowered to 300 mg/day and the subject remain in the study. 
 
Serious Adverse Event 
The recurrence of symptoms together with evidence of recurrent C. difficile infection during the 
two month period would indicate the emergence of a resistant strain of bacterium that will require medical 
care beyond the scope of the study.  However, such an event will be included in the final published report. 
 
7.1 Recording of Adverse Events 
At each contact with the subject, the study team member 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 by the study team 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. 
7.2 Reporting of Serious Adverse Events and Unanticipated Problems 
The sponsor-investigator must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that 
must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 7.1).   
 
For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 14 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as 
serious 
• 
Investigator assessment of the association 
between the event and study treatment 
7.2.1 Investigator reporting: notifying the sponsor-investigator (Principal Investigator) 
 
The following describes events that must be reported to the sponsor-investigator in an expedited fashion. 
 
Initial Report: within 24 hours: 
The following events must be reported to the study sponsor by telephone within 24 hours of awareness of 
the event:  recurrence of symptoms to be evaluated by the physician lowering dose of urso 
• 
Unanticipated problems related to study participation, loss of urso medication 
• 
Serious adverse events, recurrence of C. difficile infection  
 
Follow-up report: within 48 hours: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated device event or the unanticipated 
problem in the form of a written narrative.  This should include a copy of the completed Unanticipated 
Problem form, and any other diagnostic information that will assist the understanding of the event.  
Significant new information on ongoing unanticipated adverse device effects shall be provided promptly to 
the sponsor-investigator. 
 
Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both sponsor-investigator and IRB approval before they 
are initiated. Any protocol deviations initiated without sponsor-investigator and IRB approval that 
may affect the scientific soundness of the study, or affect the rights, safety, or welfare of study 
subjects, must be reported to the sponsor-investigator and IRB as soon as a possible, but no 
later than 5 working days of the protocol deviation. 
 
• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB notification of withdrawal 
of approval. 
7.2.2 Sponsor-Investigator reporting: notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, 
though Investigators at participating sites are responsible for meeting the specific requirements of their 
IRB of record.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 15 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be 
caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a 
more severe or frequent side effect; Other research finds arm of study has no therapeutic value; 
FDA labeling change or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB via: “Reportable New Information” 
submission or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form 
and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
7.3 Data Safety Monitoring Plan  
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 as follows: Dr. Michael Poles, M.D., Ph.D. , Associate Professor of Medicine, Microbiology and 
Immunology at NYU  School of  Medicine who is a Gastroenterologist and conducted his own 
research programs will review the fecal bile acid data and ask  providers about the recurrence of 
symptoms in subjects at two week intervals. Recurrence of symptoms that are confirmed to be 
attributable to CDI in a subject with ursodeoxycholic acid in the stool sample will be an indication for 
withdrawing from the study. Recurrence of symptoms confirmed to be related to CDI and failure to 
find  increasing amounts of deoxycholic acid in the initial 4 subjects would be an indication for 
suspending, modifying or stopping the study.  Summarized reports of these reviews will be submitted 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 16 
to the IRB after 10 subjects have completed the study.  Additional summarized reports will be 
submitted after 20 subjects have completed the study, and after all subjects have completed the 
study. Other reports will be submitted if untoward events occur and/or the monitor determines the 
study needs to be suspended, modified, or stopped. 
7.4 Confidentiality 
The only research data collected will be fecal bile acid analysis which will be entered on Excel data 
sheets with study numbers instead of identifiers. Only study team members will be able to relate the study 
number to a specific patient. All data will be stored on password protected computers within the NYU 
medical center secure network and de-identified data sheets sent only to physicians listed in the study 
with e-mail addresses at nyumc.org. 
 
For stool specimens collected during the study, the specimen ID (subject # and specimen collection #  i.e. 
1234-F1, 1234-F2, etc.) will be used to identify the sample and no personal identifiers will be used.   
 
7.5 Confidentiality and HIPAA 
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. 
7.6 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. 
7.7 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. 

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 17 
7.8 Records Retention 
It is 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 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.  
 
8 Study Monitoring, Auditing, and Inspecting 
8.1 Study Monitoring Plan 
This study will be monitored according to the following monitoring plan: Dr. Michael Poles, the data safety 
monitor will ensure regulatory compliance and proper protocol conduct at 2 week intervals.  
The investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), 
and has adequate space to conduct the monitoring visit. 
8.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, 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. 
9 Ethical Considerations 
 
This study is to be conducted 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 a properly constituted Institutional Review Board 
(IRB)) in agreement with local legal prescriptions, for formal approval of the study conduct.  The decision 
of the 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-investigator before commencement of this study along with a 
list of IRB members.   
 
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. This consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  The formal 
consent of a subject, using the IRB -approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject and the investigator-
designated research professional obtaining the consent.  

 
 
 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Pg 18 
10 Study Finances 
10.1 Funding Source 
This study will be funded by the Division of Gastroenterology using funds designated for research 
purposes. 
10.2 Conflict of Interest 
Any study team member who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed 
by a properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict 
management plan that has been reviewed and approved by the study sponsor prior to participation in this 
study.  All NYULMC study team personnel will follow the applicable University conflict of interest policies. 
10.3 Subject Stipends or Payments:  
There are no subject stipend/payments. Ursodiol will be provided without cost.  Subjects and/or their 
insurance plans will not be billed for study-related stool samples. 
11 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the principal investigator.  Any study team member involved 
with this study is obligated to provide the principal investigator with complete test results and all data 
derived from the study.  The principal investigator will prepare a manuscript for and circulate it for 
comments and approval to all study participants prior to submission for publication 
12 References 
1. Greathouse, KL. Harris CC, Bultman SJ. 2014: Dysfunctional families: Clostridium scindens 
and secondary bile acids inhibit the growth of clostridium difficile. Cell metabolism 21:9- 
2. Weingarden AR, Chen C., Zhang, N., Graiziger, et. Al. Ursodeoxycholic acid inhibits 
Closridium difficile Spore Germination and Vegetative growth, and prevents the recurrence of 
ileal pouchitis associated with infection 2015. J. clin. Gastoenterol 00, 00, early publication 
3. Lessa F. Mu Y, Bamberg WM et al: 2015: Burden of Clostridium difficile Infection in the 
United States. N. Engl J Med 372: 825-34 
4. Surawicz CM and Alexander J. 2011: Treatment of refractory and recurrent Clostridium 
Infection. Nat. Rev. Gastroenterol Hepatol 8:330-339. 
5. Giovanni C, Gianluca  I and Gasbamini A. 2014. Fecal Microbiota Transplantation for   
the treatment of Clostridium difficile infection: A Systematic Review. Journal of Clinical 
Gastroenterology 48(8):693-702. 
6. Buggie CG, Bucci V, Stein RR et al:2015.Precision microbiome restoration of bile-acid 
mediated resistance to Clostridium difficile. Nature 517:205-208 
7. Hardiosn WG and Grundy S.1984. Effect of ursodeoxycholate and its taurine conjugate 
on bile acid synthesis and cholesterol absorption.Gastroenterology 87:130-5.