Teduglutide for Treatment of Enterocutaneous Fistula (ECF) - a Pilot Study to Demonstrate Safety and Feasibility
Phase: PHASE2
Conditions: Postoperative Fistula
Sponsor: Daniel Dante Yeh

IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 1 of 28
1)
Protocol Title:
Teduglutide for treatment of enterocutaneous fistula (ECF) – a pilot study to demonstrate 
safety, efficacy, and feasibility
Principal Investigator:
D. Dante Yeh, MD, FACS, FCCM, FASPEN
Associate Professor of Surgery
Associate Program Director of General Surgery Residency
Division of Trauma and Surgical Critical Care
The DeWitt Daughtry Family Department of Surgery
Ryder Trauma Center / Jackson Memorial Hospital
Miller School of Medicine
University of Miami
1800 N.W. 10th Avenue, T-215
Miami, Florida 33136
Office: 305-585-1822
FAX: 305-326-7065
Research Facility:
Miller School of Medicine, University of Miami,  
Crohns & Colitis Center, Motility and Infusion Center
1295 NW 14th Street South Bldg, Suite A
Miami, FL, 33136
IRB:
Human Subject Research Office
Dominion Tower, 1400 NW 10th Avenue 12th Floor (M809)
Miami, FL, 33136
2)
Objectives
To demonstrate the safety, efficacy, and feasibility of teduglutide in patients with ECF; to 
evaluate quality of life in patients with ECF receiving teduglutide
Hypothesis
We hypothesize that administration of teduglutide to patients with ECF is safe, feasible, and 
effective in reducing fistula output by 20% and improving quality of life. 
Design
Open label cross-over pilot study to determine safety and efficacy of teduglutide in patients 
with ECF.  Our planned sample size is 10 subjects randomized and treated with at least 1-
dose of study drug .
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 2 of 28
The primary efficacy end point will be decrease in fistula volume by 20% from baseline 3-
day average, as measured by the patient.
The secondary efficacy end points will be cessation of fistula output altogether and health-
related quality of life questionnaire score as assessed by the questionnaires (see below) at 
time points Study Visit 5, 10, and 11 (3 months after end-of-treatment).
Subjects that complete both arms of the study who have a favorable (but incomplete) 
response and are deemed to be reliable (both as determined by the principal investigator) 
will be offered an open-label extension during which they will continue to receive 
teduglutide for up to another 12 months or permanent fistula closure, whichever occurs 
first.
3)
Background
Enterocutaneous fistula is (ECF) defined as an abnormal connection between the 
gastrointestinal tract and the skin, or an open abdomen (enteroatmospheric fistula, EAF).  
This disease is highly morbid and associated with significant ICU length of stay, hospital 
stay, and average hospital charges >$500,000 [1]. Death and complication rates are 
disproportionately high, with mortality rates commonly reported between 6 to 48% [2].  
Survivors with ECF have lower health-related quality of life [3].
The treatment of ECF is challenging and often requires a multi-disciplinary approach 
including gastroenterologists, surgeons, wound care specialists, and nutritionists.  
Intestinal rehabilitation for ECF is directed at decreasing ECF output (completely, if 
possible) and achieving independence from artificial nutrition (enteral or parenteral).  
There are few pharmacologic options for the treatment of ECF.  Somatostatin and its 
analogues (ex: octreotide) have been the most widely studied, but results are conflicting, 
with significant effects being found only on meta-analysis [4].
Glucagon-like peptide 2 (GLP-2) is an endogenous hormone secreted by L cells in the 
intestine which has trophic effects.  Exogenous GLP-2 administration stimulates intestinal 
blood flow, decreases gastric acid secretion, and improves nutrient and fluid absorption in 
animal models and human studies [5-7]. 
Teduglutide is a GLP-2 analogue with a much longer half-life than GLP-2.  An open label 
pilot study of teduglutide demonstrated improvements in enteral absorption.  At the 
microscopic level, improvements were seen in small bowel villus height, crypto depth, and 
mitotic index [8].  In two phase III randomized, placebo-controlled studies, 24 weeks of 
administration of teduglutide led to significant decreases in PN/IV volume requirements [9, 
10].  Small bowel villus height and plasma citrulline (a marker for enterocyte mass) were 
both significantly improved in the teduglutide groups [9].  This efficacy was not only 
maintained, but also increased, in long-term extension studies with continued gains and 
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 3 of 28
additional patients achieving PN/IV independence.  OF the 19 non-responders in the 
original 24-week study, 11 became responders in the extension study [11]. 
Approved by the FDA in 2012 for the treatment of adults with short bowel syndrome with 
intestinal failure (SBS-IF), teduglutide is well-tolerated and common adverse events are 
mild and related to gastrointestinal symptoms such as abdominal pain, nausea, and 
vomiting [12].  
It is easy to conceive that the results of teduglutide treatment could be extrapolated to 
patients with ECF.  For example, SBS-IF patients treated with GLP-2 experienced a 
reduction in fecal wet weight of approximately 33% (from 3.0 kg/day to 2.0 kg/day) [7].  
Similar changes in ECF could convert high-output fistulas (>500 mL/day) to medium- (200-
500 mL/day) or low-output fistulas (<200 mL/day), significantly simplifying 
fluid/electrolyte management, or even resolve low-output fistulas completely.
4)
Entry Criteria
Inclusion criteria
a) Age >18
b) Enterocutaneous fistula (ECF) that could be secondary to volvulus, injury, prior 
trauma or surgery, or vascular ischemia
Exclusion criteria
a) Perianal fistula
b) History of radiation enteritis or sprue (as defined by history)
c) Active (<1 year) alcohol or drug abuse
d) Significant hepatic, or cardiac diseases as defined as:
i. Hepatic: aspartate aminotransferase (AST) > 2 times upper limit of normal (10-
40 U/L)
ii. Cardiac: unstable angina or evidence of active myocardial ischemia (elevated 
troponin level drawn by clinical suspicion)
e) Severe renal dysfunction: serum creatinine > 2 times upper limit of normal (0.6-1.5 
mg/dL)
f)
Received IV glutamine less than 4 weeks prior to screening
g) Receiving growth factors (erythropoeitin, granulocyte colony-stimulating factor, 
granulocyte-macrophage colony stimulating factor, and human growth hormone)
h) Pregnancy or lactation (women of childbearing age will be excluded if they do not 
agree to either complete sexual abstinence during the study or if they refuse to use 
at least two forms of highly effective contraception such as oral contraception, 
injectable or implantable contraception, vaginal rings, or intrauterine devices (IUD))
i)
Active malignancy or suspicion for gastrointestinal malignancy on CT scan obtained 
during standard clinical care, if available
j)
Not capable of understanding or not willing to adhere to the study visit schedule and 
drug administration requirements
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
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k) First degree relative with history of intestinal malignancy (gastric, small intestine, 
colon) 
l)
Personal or first degree relative with history of hereditary non-polyposis colorectal 
cancer, familial adenomatous polyposis, first degree relative with colon cancer
m) Positive hemoccult (per rectum) obtained during standard clinical care, if available
n) Abnormal baseline electrocardiogram (ECG) suggestive of congestive heart failure 
or underlying cardiac disease
o) Taking oral benzodiazepines, barbiturates, or phenothiazines
5)
Procedures Involved
Study team will screen the inpatient census and clinic roster of the “Surgical Nutrition” 
team at the University of Miami Hospital and identify potentially eligible subjects with 
enterocutaneous fistulas.  If the patient meets all inclusion/exclusion criteria, a member of 
the study team will then approach the patient or surrogate. Re-screening of patients can be 
made at the PI’s discretion, if the patient meets all of the inclusion, and none of the 
exclusion criteria.
Eligibility Screening Visit(s):
Screening procedures can be completed over several visits
Obtain informed consent
Demographics
Medical and surgical history
Review prior and concomitant medications
Collect Physical exam
Collect Vital signs measurements
ECG
Chemistry Panel (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine 
glucose) if not done in the last 90 days
Liver Function tests (total bilirubin, direct bilirubin, alkalkine phosphatase, alanine 
aminotransferase, aspartate aminotransferase, lipase, amylase) if not done in the last 90 
days
Serum pregnancy test if applicable
Collect Concomitant medical review
Collect Nutritional assessment
3-day average fistula output
Enrollment within 2 months of signing consent
Inclusion/Exclusion criteria
Vital signs measurements
Nutritional assessment
3-day average fistula output
Complete quesionnaires (see additional documents):
1. ASCQ-Me Short Form v2.0 - Social Functioning Impact
2. ASCQ-Me v2.0 - Sleep Impact Short Form
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 5 of 28
3. Global Health Scale v1.2
4. PROMIS Scale v1.0 - GI Belly Pain
5. PROMIS Scale v1.0 - GI Diarrhea
6. PROMIS Scale v1.0 - GI Nausea and Vomiting
7. PROMIS SF v2.0 - Ability to Participate
Teaching of self-administration of medication
After study enrollment, the subject will be randomly assigned (by  a computerized method, 
using the site ‘www.sealedenvelope.com’) to begin teduglutide treatment immediately or to 
continue standard of care (SOC) treatment. The randomization will be performed by a 
member of the study that is not involved in the informed consent process, and will be 
enclosed in sequentially numbered opaque envelopes. The envelopes will be given to the PI 
prior to the enrollment visit. At study visit 5 (day 56), the subject will then cross-over to 
the opposite treatment assignment.  The half-life of teduglutide is 2-3 hours.  During the 
period the subjects are on the “SOC only” treatment arm, the subjects will be given the 
option to replace some Study visits with Telephone Calls for their convenience. If study 
visits overlap due to the time window, either visit may be skipped or completed on the 
same day. Please see information below, and the Study schema.
Study Visit 1 or Telephone Call as applicable (Day 7) (+/- 3 days)
Collect physical examination if during visit
Collect Vital Signs measurements if during visit
Monitor severe adverse events (SAE) and adverse events (AE)
Collect concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit) from the Diaries
Collect adjustment of medications and fluids if recorded
Study Visit 2 or Telephone Call as applicable (Day 14) (+/- 3 days)
Collect physical examination if during visit
Collect Vital Signs measurements if during visit
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit) from the Diaries
Collect adjustment of medications and fluids if recorded
Telephone Call 1 (Day 21) (+/- 3 days)
Monitor severe adverse events (SAE) and adverse events (AE)
Nutritional Assessment
3-day average fistula volume (3 days immediately preceding telephone call)
Adjustment of medications and fluids if necessary
Study Visit 3 (Day 28) (+/- 1 week)
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 6 of 28
Collect physical examination
Collect Vital Signs measurements
Chemistry Panel (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine 
glucose)
Liver Function tests (total bilirubin, direct bilirubin, alkalkine phosphatase, alanine 
aminotransferase, aspartate aminotransferase, lipase, amylase)
Plasma PK (Pharmacokinetics) 

Processed according to separate “Sample Processing Procedure”
Serum pregnancy test
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Telephone Call 2 (Day 35) (+/- 3 days)
Monitor severe adverse events (SAE) and adverse events (AE)
Nutritional Assessment
3-day average fistula volume (3 days immediately preceding telephone call)
Adjustment of medications and fluids if necessary
Study Visit 4 or Telephone Call as applicable (Day 42) (+/- 1 week)
Collect physical examination if during visit
Collect Vital Signs measurements if during visit
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Telephone Call 3 (Day 49) (+/- 3 days)
Monitor severe adverse events (SAE) and adverse events (AE)
Nutritional Assessment
3-day average fistula volume (3 days immediately preceding telephone call)
Adjustment of medications and fluids if necessary
Study Visit 5, Cross-over, (Day 56) (+/- 1 week)
Collect physical examination
Collect Vital Signs measurements
Chemistry Panel (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine 
glucose)
Liver Function tests (total bilirubin, direct bilirubin, alkalkine phosphatase, alanine 
aminotransferase, aspartate aminotransferase, lipase, amylase)
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 7 of 28
Plasma PK (Pharmacokinetics) 

Processed according to separate “Sample Processing Procedure”
Serum pregnancy test
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Fistula closure (y/n)
Complete Questionnaires (see additional documents)
Study Visit 6 or Telephone Call as applicable (Day 63) (+/- 1 week)
Collect physical examination if during visit
Collect Vital Signs measurements if during visit
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Study Visit 7 or Telephone Call as applicable (Day 70) (+/- 1 week)
Collect physical examination
Collect Vital Signs measurements
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Telephone Call 4 (Day 77) (+/- 3 days)
Monitor severe adverse events (SAE) and adverse events (AE)
Nutritional Assessment
3-day average fistula volume (3 days immediately preceding telephone call)
Adjustment of medications and fluids if necessary
Study Visit 8 or Telephone Call as applicable (Day 84) (+/- 1 week)
Collect  physical examination if during visit
Collect Vital Signs measurements if during visit
Chemistry Panel (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine 
glucose)
Liver Function tests (total bilirubin, direct bilirubin, alkalkine phosphatase, alanine 
aminotransferase, aspartate aminotransferase, lipase, amylase)
Plasma PK (Pharmacokinetics) 

Processed according to separate “Sample Processing Procedure”
-       Study #: 20170189        Effective Date: 6/16/2021

IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 8 of 28
Serum pregnancy test
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Telephone Call 5 (Day 91) (+/- 3 days)
Monitor severe adverse events (SAE) and adverse events (AE)
Nutritional Assessment
3-day average fistula volume (3 days immediately preceding telephone call)
Adjustment of medications and fluids if necessary
Study Visit 9 or Telephone Call as applicable (Day 98) (+/- 1 week)
Collect physical examination
Collect Vital Signs measurements
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Telephone Call 6 (Day 105) (+/- 3 days)
Monitor severe adverse events (SAE) and adverse events (AE)
Nutritional Assessment
3-day average fistula volume (3 days immediately preceding telephone call)
Adjustment of medications and fluids if necessary
Study Visit 10, End of Treatment (EOT), (Day 112) (+/- 1 week)
Collect physical examination
Collect Vital Signs measurements
Chemistry Panel (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine 
glucose)
Liver Function tests (total bilirubin, direct bilirubin, alkalkine phosphatase, alanine 
aminotransferase, aspartate aminotransferase, lipase, amylase)
Plasma PK (Pharmacokinetics) 

Processed according to separate “Sample Processing Procedure”
Serum pregnancy test
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
3-day average fistula volume (3 days immediately preceding study visit)
Collect adjustment of medications and fluids if recorded
Fistula closure (y/n)
Complete Questionnaires (see additional documents)
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
Page 9 of 28
Study Visit 11, Long-Term Follow-up Visit, 3 months after EOT (-2 weeks/+3 months)
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
Chemistry Panel (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine 
glucose)
Liver Function tests (total bilirubin, direct bilirubin, alkalkine phosphatase, alanine 
aminotransferase, aspartate aminotransferase, lipase, amylase)
Plasma PK (Pharmacokinetics) 

Processed according to separate “Sample Processing Procedure”
3-day average fistula volume (3 days immediately preceding study visit)
Fistula closure (y/n)
Complete Questionnaires (see additional documents)
Open-Label Extension Study Visit (up to 12 additional visits) to occur monthly (+/- 1 
week)
*Visits may be conducted virtually due to the Covid-19 outbreak.
Collect physical examination results
Collect Vital Signs measurement results
Collect most recent Chemistry Panel results approximately every 3 months (sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen, creatinine glucose)
Collect Liver Function test results approximately every 3 months (total bilirubin, direct 
bilirubin, alkalkine phosphatase, alanine 
aminotransferase, aspartate aminotransferase, lipase, amylase)
Collect Serum pregnancy test results every 3 months if completed
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medications
Collect Nutritional Assessment if completed
Collect approximate daily average fistula volume 
Collect adjustment of medications and fluids if recorded
Open-Label Extension Telephone Visit to occurevery 2 weeks (+/- 3 days) alternating 
with Open-Label Extension Study Visits 
Monitor severe adverse events (SAE) and adverse events (AE)
Collect Concomitant medication review
Collect Nutritional Assessment
Collect approximate daily average fistula volume 
Collect adjustment of medications and fluids if recorded
Drug Administration, Dispensation and Disposition
Once consent is obtained and necessary baseline data collected, the subject will begin 
receiving teduglutide (0.05 mg/kg/d, for moderate renal impairment defined as serum 
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
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creatinine > 1.5 times the upper limit of normal, the dose will be reduced to 0.025 
mg/kg/d), administered once daily subcutaneously into the abdomen, thigh, or arm (at 
approximately the same time each day) for 8 weeks. For enrolled subjects demonstrating a 
favorable trend and are deemed to be reliable  (both as determined by the PI) but still have 
a fistula at the end of treatment (EOT) or long-term follow-up, the subject will be offered an 
“open-label” extension whereby they will continue to receive teduglutide at the previous 
dose for up to another 12 months or permanent fistula closure, whichever occurs first. 
Immediately prior to initiating the 8-week period of drug administration, the subject will 
receive training on how to safely reconstitute and administer the medication.  The volume 
of reconstituted study drug to be administered is a fixed dose of 0.005 mL/kg body weight.  
Each day, the injection site should be changed.  The subject should be dosed at 
approximately the same time each day.  If a subject forgets to take drug, that day’s dose 
should be administered as soon as possible, even if this is later in the day or evening.  
Consecutive doses should be separated by approximately 12 hours.  Dates of days with 
missed or incomplete doses are to be reported in the diary. The subject is going to be 
instructed to bring back all used and unused IP.  The IP will then be disposed of per 
pharmacy SOP.  University of Miami Research Pharmacy will be receiving, storing, 
dispensing, keeping inventory, and disposing the IP for this study as per their standard 
operating procedures.
Study drug will be packaged, labeled, and delivered to the clinical center by the sponsor or 
designee.  Each study drug kit will contain labeling with the general dosage instructions, 
storage conditions, expiration date, kit number, and company name.  All medication 
supplied to be used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice (GMP).  Ancillary 
supply kits containing syringes with needles for injection and reconstitution, sterile water, 
and alcohol swabs will also be provided.
The Principle Investigator or designee will conduct an inventory upon receipt of the clinical 
supplies and will acknowledge receipt of the supplies to the sponsor.  A copy of the 
shipping documents will be maintained for records.  Study drug will be kept at controlled 
room temperature (15°-25°C, 59°–77°F) in a secure location until dispensed to the subject.  
Subjects will be instructed to keep study drug at controlled room temperature.  The sterile 
water diluent should be stored at controlled temperature.
Study drug kits will be dispensed to subjects at each of the office visits during the 8 weeks 
of dosing and up to an additional 52 weeks of “open-label” extension  at which the subject 
is required to be at the clinic.  Each study drug kit is sufficient for a treatment period of 4 
weeks (depending on visit  #).  The PI will keep a current record of the inventory and 
dispensing of all clinical supplies.  This record will be made available to the sponsor’s 
monitor for the purpose of accounting for all clinical supplies.  Any discrepancy or 
deficiency will be recorded, with an explanation.  All supplies sent to the investigator will 
be accounted for and in no case will clinical supplies be used in an unauthorized situation.
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
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Subject compliance will be checked at every visit (and telephone call) by asking the 
subjects if they have taken their study drug according to instructions and by reviewing the 
subject diary if available and to perform drug accountability.  Compliance is considered to 
be achieved if the subject reports (by diary or discussion) 80% of the planned doses 
administered. The hierarchy of source documentation is the Diary as primary, and if not 
available then followed by study staff documentation of weekly visits and lastly 
documentation of monthly visits.
At present, the standard of care (SOC) for ECF involves source control treatment of intra-
abdominal infection, nutritional support via enteral nutrition (EN), parenteral nutrition 
(PN), or oral intake, careful fluid and electrolyte management, and occasionally surgical 
repair.  Subjects enrolled in this study will still receive SOC in addition to 8 weeks of 
teduglutide therapy and up to an additional52  weeks of open-label extension when this 
applies.
Unless contraindicated by clinical condition, enrolled patients will undergo colonoscopy 
within 6 months prior to starting the drug. 
6)
Data and Specimen Banking*
All subjects will undergo laboratory assessment (sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen, creatinine, glucose,  aspartate aminotransferase, alanine 
aminotransferase, total bilirubin, direct bilirubin, alkaline phosphatase, lipase, amylase) 
before starting teduglutide and subsequent laboratory tests will be performed as stated in 
the schedule below.  These labs are normally drawn during the course of clinical care.  
Specifically, the labs which will be assessed in this study are:
Total bilirubin ( normal 0.0 – 1.0 mg/dL)
Alkaline phosphatase (normal 45 -115 U/L)
Lipase (normal 13 – 60 U/L)
Creatinine (normal 0.6-1.5 mg/dL)
Data Fields
Age
BMI
Gender
Charlson Comorbidity Index
Questionnaires (see additional documents)
Cause of major intestinal resection: trauma, emergency operation, elective operation, 
inflammatory bowel disease, other
Location of fistula: stomach, duodenum, jejunum, ileum, colon
Days since last operation
Days since fistula diagnosis
Type of nutrition: per os (PO), enteral nutrition (EN), parenteral nutrition (PN), PO + EN, 
PO + TPN, EN + PN, PO +EN + PN
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IRB Study Number: 20170189
NCT02889393
Version Date:   
June 16, 2021
PI: 
Daniel Dante Yeh, MD
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Concomitant medications: antidiarrheals, antisecretory agents
3-day average fistula volume (continuous variable)
Output of fistula >500 mL/day (Y/N)
Because of the expected increase in luminal absorption, subjects will be closely monitored 
for increased oral medication absorption, particularly opioids and sedating medications.  
Subjects will be assessed for pinpoint pupils and lethargy.  If clinical evidence of increased 
oral medical absorption is discovered, the doses will be accordingly decreased.  If clinical 
evidence of fluid overload is discovered (such as breathlessness, subjective dyspnea, new-
onset pitting peripheral edema, change in body weight, jugular venous distention, and rales 
on lung ascultation), then EN and PN prescription will be decreased accordingly.
Additionally, subjects will be monitored for clinical evidence of volume depletion.  Clinical 
signs suggestive of volume depletion include dry mucus membranes, poor skin turgor, 
decreased urine output, or rapid body weight loss.
Fluid and volume status will be assessed according to the usual clinical signs and 
symptoms: breathlessness, subjective dyspnea, new-onset pitting edema, change in body 
weight, and rales on lung auscultation.  This will be assessed both in person at the time of 
study visit as well as by self report from the subject during phone calls.
Criteria for discontinuation of teduglutide in patients who experience fluid overload 
include: decrease in room-air oxygen saturation > 5% from baseline, significant worsening 
of peripheral edema resulting in functional limitation, severe dyspnea resulting in 
functional limitation, and hospitalization for congestive heart failure.
Data will be de-identified and stored on password-protected  network accessible only to 
research staff. Data will be retained for at least six years following conclusion of the study 
on this network.
7)
Biostatistical Analysis
Because this is a pilot study enrolling only 10 subjects, no sample size or power calculation 
was performed.  The primary endpoint (decrease in fistula volume by 20%) was chosen 
based on previous studies in a different population.
Continuous outcome variables that are normally distributed will be presented as mean ± 
Standard Deviation (SD) while continuous outcome variables that are not normally 
distributed will be presented as median and interquartile range (IQR).   In calculating the 
difference in fistula volume between baseline and final measures, a two-sample t-test for 
independent samples will be used.  A p value of <0.05 will be considered significant.
8)
Risks to Subjects*
Because of its intestinotrophic mechanism of action, teduglutide may theoretically increase 
the risk of neoplastic growth, though this has never been proven in clinical trials.  For this 
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Version Date:   
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PI: 
Daniel Dante Yeh, MD
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reason, patients with evidence or suspicion of active gastrointestinal malignancy will not 
be enrolled.  Abdominal computed tomography scans obtained during the course of routine 
clinical care will be reviewed for evidence of gastrointestinal malignancy and any patients 
with concerning findings (as described by the final Radiologist’s interpretation) will be 
excluded.  Additionally, patients with a familial history of intestinal malignancy (gastric, 
small intestine, colon) will be excluded.
For patients meeting American College of Gastroenterology (ACG) colon cancer screening 
criteria based on age (age 50, or age 45 years in African Americans) who have not had a 
negative colonoscopy in the 5 years preceding study enrollment, a screening CT 
colonography will be offered.  All enrolled patients will be advised of the potential for 
acceleration of neoplastic growth included in the Gattex (teduglutide) label’s Warnings and 
Precautions, as well as the recommendation for colonoscopy with removal of polyps prior 
to initiating treatment with Gattex. CT colonography will be offered as an alternative 
method of screening.  Patients with abnormal findings concerning for malignancy will be 
excluded.
Additional possible safety risks with teduglutide identified in the previous trials also 
include gastrointestinal obstruction; gallbladder, biliary tract, and pancreatic disease; 
increased absorption of fluids leading to fluid overload in patients with cardiovascular 
disease; and increased absorption of oral medications with narrow therapeutic index.
The grades of adverse events described below are taken from the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.3.0.
Intestinal obstruction occurred in 3.9% (n=6) of patients receiving teduglutide in the prior 
studies, with an onset between 6 days and 19 months.  Only 1 patient required surgical 
intervention.  Subjects will be monitored clinically for signs and symptoms of GI 
obstruction.  For those patients who develop obstruction, teduglutide will be temporarily 
discontinued while the patient is clinically managed and restarted when the obstructive 
presentation resolves, if clinically indicated.
Biliary symptoms of cholecystitis and gallstones/sludge occurred in 7.5% (n=13) of 
patients in previous teduglutide studies, though almost half of them had a history of biliary 
disease prior to enrollment.  None of the biliary events necessitated study withdrawal.
Pancreatitis developed in 1.7% (n=3) of all teduglutide-treated patients in previous trials, 
though all three patients had a history of pancreatitis prior to enrollment.  None of the 
events required study withdrawal.
Fluid overload developed in 13.3 % (n=23) of all teduglutide-treated patients in pooled 
Phase III studies.  Subjects will be closely monitored for increased oral medication 
absorption, particularly opioids and sedating medications.  Subjects will be assessed for 
pinpoint pupils and lethargy.  If clinical evidence of increased oral medical absorption is 
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discovered, the doses will be accordingly decreased.  If clinical evidence of fluid overload is 
discovered (such as breathlessness, subjective dyspnea, new-onset pitting peripheral 
edema, change in body weight, and rales on lung auscultation), then EN and PN 
prescription will be decreased accordingly.  
During weekly assessments, if the patient is on PN and there are clinical signs or suspicion 
of fluid overload, the PN volume will be decreased by 10% to 30% in coordination with the 
PN Pharmacy.  We will then continue monitoring and adjust PN/IV volume accordingly to 
maintain clinical nutrition and volume status.
Criteria for discontinuation of teduglutide in patients who experience fluid overload 
include: decrease in room-air oxygen saturation > 5% from baseline, significant worsening 
of peripheral edema resulting in functional limitation, severe dyspnea resulting in 
functional limitation, and hospitalization for congestive heart failure.
Because of the laboratory safety monitoring, the subjects will require blood draws before 
teduglutide initiation, at the mid-point of treatment (week 4), after the completion of the 8 
week trial, and at long-term follow up (3 months after end of treatment).  Patients with 
persistently abnormal laboratory results and ongoing adverse reactions will be followed 
until resolution and will undergo repeat laboratory testing as necessary to ensure 
resolution of all abnormal laboratory results potentially attributable to study drug.  For 
patients receiving parenteral nutrition, this will not impact them as they will be getting test 
performed as part of routine care.  However, for patients not requiring parenteral nutrition, 
this entails additional minimal blood loss and the discomfort of needle stick.
The most common adverse events identified in the previous trial (Jeppesen 2012, 
Teduglutide reduces need for parenteral support among patients with short bowel 
syndrome with intestinal failure) are mild and related to gastrointestinal symptoms such 
as abdominal pain (31%), nausea (29%), and abdominal distension (21%).  
9)
Adverse Event (AE) Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product.  An AE does not necessarily 
have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding, for example), symptom, or disease temporarily 
associated with the use of a medicinal product (investigational or marketed), whether or 
not considered related to treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is 
detected or diagnosed after study drug administration
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
Pretreatment or post-treatment events that occur as a result of protocol-mandated 
procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the 
disease or disorder, unless there is worsening of the condition of the disease or 
disorder

A pre-existing disease or condition, present at the start of the study, that does not 
worsen.
Although an overdose of the study drug or concomitant medication without any clinical 
sign or symptom is not technically an AE, it will be captured as an AE to provide valuable 
safety data on higher untested doses of study drug.
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported, obtained through non-leading questioning, 
or noted during examination of a subject.  Adverse events will be recorded from the signing 
of informed consent through the last dose of study drug.  Serious adverse events will be 
recorded from the signing of informed consent through 30 days after the last dose of study 
drug.
At each visit, new AEs are recorded sequentially on the Adverse Event log.  The AE term 
will note the diagnosis whenever possible, not the individual signs or symptoms (eg., 
myocardial infarction will be recorded rather than chest pain, elevated cardiac enzymes, 
and abnormal ECT).  Also recorded are:

Start and stop date and time

Whether or not the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild: usually transient, requiring no special treatment and generally not 
interfering with usual daily activities
o
Moderate: usually ameliorated by simple therapeutic maneuvers and impairs 
usual activities
o
Severe: requires vigorous therapeutic intervention and interrupts usual 
activities.  Hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if 
a causal relationship between the investigational product and an AE is at least a 
reasonable possibility (i.e. the relationship cannot be ruled out).

Whether or not the AE is serious (i.e. an SAE).  If identified as an SAE, the AE will be 
reported as an SAE.

Actions taken (none, study drug dose interrupted, study drug discontinued, other 
medication change, non-drug therapy, change in parenteral nutrition or IV fluids).  

Outcome (resolved, severity or frequency increased, ongoing, fatal).  An individual 
AE receives only one outcome.
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Adverse events not resolved at the end of treatment will be followed until resolution or 
until the AE is judged by the investigator to have stabilized.

Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations will be reported as AEs if they:

Are considered clinically significant by the investigator

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study
Serious Adverse Events
An event that is serious will be recorded on the Serious Adverse Event log.  SAEs will be 
recorded from the signing of informed consent through 30 days after the last dose of study 
drug.
The most common adverse events are mild and related to gastrointestinal symptoms such 
as abdominal pain, nausea, and vomiting.  If these occur, they will be noted in the adverse 
event tracking log and reported to the IRB during Continuing Review.
More serious adverse events and any unexpected adverse events will be recorded as per 
UM HSRO policies and procedures. 
Events Necessitating Withdrawal from Study
The occurrence of any of the following events may necessitate premature withdrawal of a 
subject from the study:

Development of any of the following Inclusion/Exclusion criteria:
o
Significant, active, uncontrolled cardiac, hepatic, or renal dysfunction as 
defined by the Inclusion/Exclusion criteria

New diagnosis of inflammatory bowel disease

Use of any excluded medication

Pregnancy

Occurrence of a serious adverse event (SAE) thought to be related to study drug and 
not alleviated by symptomatic treatment

Unwillingness to continue in the clinical study

Death of the subject

Principal Investigator decision (i.e. subject non-compliance with study procedures)

Significant AE or medical decision that precludes the subject from adhering to study 
requirements
Readmission to the hospital for fistula-related complications (ex: cellulitis, intra-abdominal 
abscess, dehydration, etc.) is common and is likely to occur during the study treatment and 
follow-up period.  Unless one of the above “Events Necessitating Withdrawal” occurs, the 
subject will remain enrolled in the study during hospitalization.
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10)
Potential Benefits to Subjects
Based on the encouraging results in studies of teduglutide for patients with short bowel 
syndrome, we expect a clinically significant decrease in daily ECF volume of about 20% 
magnitude.  This could convert high-output fistulas (>500 mL/day) to medium- (200-500 
mL/day) or low-output fistulas (<200 mL/day), significantly simplifying fluid/electrolyte 
management, allow for liberation from parenteral nutrition, or even resolve low-output 
fistulas completely.  It is reasonable to expect an improvement in quality of life.
11)
Vulnerable Populations*
We will not routinely enroll pregnant women, prisoners, children, or cognitively impaired 
adults.
12)
Resources Available
The PI has many years of experience conducting and being trained for clinical research. All 
study personnel will be trained on the protocol by the investigator or designee and 
complete CITI training. Those obtaining consent will also have prior experience 
communicating with patients.
13)
Prior Approvals
None
14)
Recruitment Methods
Recruitment Procedures
The Study Staff will perform a daily screen of the inpatient census of the “Surgical 
Nutrition” team at the University of Miami Hospital as well as the outpatient census of the 
Surgical Nutrition clinic for adults with ECF.  In order to screen for eligible patients, the 
study team is requesting partial HIPAA waiver.  When a patient is found to be eligible, the 
primary health provider team (usually a physician or nurse practitioner) who is known to 
the potential subject will be contacted for approval for the patient to be contacted for 
research purposes.  This provider will initially introduce the study to the patient and 
verbally obtain the patient’s permission to be contacted by study staff.  The patient will 
then be approached for discussion of the trial and informed consent, as outlined in the 
consent procedures below. 
Potential subjects will not be contacted by phone for recruitment.  Recruitment will not 
involve restrictions on sociodemographic factors including gender or ethnic characteristics. 
Recruitment will be devoid of any procedures which could be construed as coercive. 
If the potential subject is the Investigator’s own patient, the Investigator will ask a 
physician colleague to initially explain the study and also recommend that the patient 
discuss participation with other health care providers.  These colleagues will stress that 
participation is voluntary, that they do not have to participate, and the decision not to 
participate will not affect their care, now or in the future.
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15)
Local Number of Subjects:
10
16)
 
Monitoring And Quality Assurance
Study Staff will maintain the data in an electronic database stored in a secure location on 
password-protected computer system. The consent forms will be kept in files which will be 
stored in a secure location. De-identified data will be uploaded  to VELOS electronic 
database.  The PI will confirm the completeness of data being entered in the electronic 
database
In order to protect all subjects’ confidentiality, we will store data on a password-protected 
network. Subjects will receive a study-specific unique identifier and the medical record 
number (MRN) will be uncoupled from the data.  The decoder key for study identifier and 
MRN will be stored in a separate, password-protected file. 
Trial Monitoring, Auditing, and Inspecting
The investigator will permit trial-related monitoring, quality audits, and inspections by, 
government regulatory authorities, of all trial-related documents (e.g., source documents, 
regulatory documents, data collection instruments, case report forms).  The investigator 
will ensure the capability for inspections of applicable trial-related facilities.  The 
investigator will ensure that the trial monitor or any other compliance or QA reviewer is 
given access to all trial-related documents and trial-related facilities.  
Participation as an investigator in this trial implies the acceptance of potential inspection 
by government regulatory authorities. 
In addition to the Clinical Monitoring component of this protocol, Quality Assurance (QA) 
to assess compliance with GCP and applicable regulatory requirements.  Data or 
documentation audited shall be assessed for compliance to the protocol, accuracy in 
relation to source documents and compliance to applicable regulations.
17)
Confidentiality
The protected health information collected for the purpose of this research study will be 
assigned a research code number and any obvious patient identifiers (name, social security 
number, hospital record number) will be removed from this information. Both the 
confidential health information and the information linking the research code numbers to 
the patients’ identities will be stored in a secure manner (e.g., locked file cabinet, password 
protected database) accessible only to the research study personnel. The information 
linking the research code numbers to the patients’ identities will be stored separate from 
the confidential health information.
Clinical data will be collected for no longer than one year after the patient has had the 
initial surgery. Data will be de-identified and stored on a password-protected network 
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accessible only to research staff. Data will be retained for at least six years following 
conclusion of the study on this network. 
18)
Provisions to Protect the Privacy Interests of Subjects
Access to patients and their protected health information along with the collection and 
analysis is necessary in order to conduct this research study. Consistent with the 
“minimum necessary standard” of the HIPAA privacy rule, we will only access and collect 
the specific health information necessary to complete this research study.
Some of the research investigators who will access and use the protected health 
information may also be involved directly in the care of the respective patients, thus 
obviating the privacy and confidentiality concerns.
Authorization to obtain protected health information will be obtained from the patient or 
their proxy as soon as possible. It is nearly impossible to provide authorization during a 
crisis situation in critical care areas during the workup of a critically ill patient. Generally, 
these patients are intubated, sedated, and hemodynamically compromised, especially 
during the initial days after admission.
The protected health information collected for the purpose of this research study will be 
assigned a research code number and any obvious patient identifiers (name, social security 
number, etc) will be removed from this information. Both the confidential health 
information and the information linking the research code numbers to the patients’ 
identities will be stored in a secure manner (e.g., locked file cabinet, password protected 
database) accessible only to the research study personnel. 
19)
Consent Process
19a. Remote Consenting will include the following:
•
Send a copy of the consent document via secure email or U.S. Mail.
•
Arrange for a witness to attend and witness the consent discussion.
•
Let the participant know that a witness will join the consent meeting.
•
Set up a video meeting or 3-way call and send an invitation to the attendees.
We will ask the participant to scan or take a picture of each page of the documents and 
email the signed/dated documents to the study team. As an alternative, we may establish a 
secure network location for uploading the consent document.
During meeting:

Identify everyone on the call.

Review the informed consent with the participant, answer the participant’s questions 
and ask questions of the participant to confirm comprehension.

Ask the participant if s/he consents to participate/continue participation.

If the participant agrees, ask him/her to sign and date the consent document.

If using 3-way call, ask the participant to confirm s/he signed & dated the document.
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We will ask the participant to scan or take a picture of each page of the documents and 
email the signed/dated documents to the study team. As an alternative, the research could 
establish a "UM Box" location for uploading the consent document.
If the person is unable to take a picture, we will document the circumstances. 
The person conducting the consent process will sign and date a copy of the consent 
document.
The witness will sign & date on the witness line of a copy of the consent document.
The person conducting the consent process will document the purpose for the remote 
consent (COVID-19), and each step of the process.  The note will explain why the research 
team doesn’t have the signed and dated document. 
Documenting the Remote Consent process
The originals of the informed consent document signed by the investigator (and possibly 
the witness) will be placed in the participant’s research record.
The person obtaining consent will document how s/he confirmed that the patient 
consented and signed the consent form. The note will include a statement indicating why 
the informed consent document signed by the participant was not retained, (e.g., due to 
contamination of the document by infectious material.)
If the participant cannot send a picture of the signed document, the person obtaining 
consent will document why a copy of the signed document is not available. See example 
below.
Example:
Informed consent was obtained on Date at Time.  The participant could not come to the site 
for the consent process due to COVID-19 social distancing requirements.  A copy of the 
consent document was emailed to the prospective participant before the consent 
discussion
The consent process was performed by phone/ZOOM.  The individuals attending the 
discussion were: (list the names of the individuals). The person obtaining consent 
explained the research to the participant and answered the participant’s questions.  The 
person obtaining consent asked the participant questions to ascertain whether the s/he 
understood the study, and the participant was able to answer the questions.  The 
participant voluntarily agreed to participate.  The subjest/LAR signed and dated the 
consent document. The research was not able to obtain a copy of the signed original 
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consent document because consent was obtained remotely, and the document may 
transmit the COVID-19 infection.   
After signing the consent document, the participant took a picture and sent it to the 
research team/ OR The participant was unable to send a picture of the document. A witness 
observed the entire process.
The consenter will then add similar documentation about the HIPAA authorization.
19b. In person consenting:
The patient will be approached in the clinic area by a member of the research staff. Any of 
the staff members listed on the protocol will discuss the risks and benefits of participation. 
If the staff member is not fluent in the patient's native language, they will use a translator 
to obtain informed consent in a document written in the patient's native language. 
Initiating this process may also occur over the phone and during scheduling and may 
include mailing of the consent form to allow for more time to read and understand prior to 
coming into clinic.
Subject/Proxy will be given an ICF in their native language (English/Spanish only). They 
will be given ample time to review the ICF with family, clergy, friends or primary 
physicians. Once they have agreed they will be required to sign ICF before any study 
procedures can be done on the subject. A copy of the ICF will be given to the subject/proxy 
and one will be placed in the medical records. The original will stay in the subject’s source 
documentation folder located in the Trauma Research Office.
Patients who are incapacitated or unable to sign their own consent will not be enrolled in 
the study, as compliance is less likely and compromise the study.
Non-English Speaking Subjects
A translated written informed consent document will be provided in a language 
understandable to the participant. This will be an accurate translation of the IRB-approved 
English version of the full informed consent document.
20)
Process to Document Consent in Writing
We will document consent with a translated written informed consent document in a 
language understandable to the participant. If subjects who do not speak English are 
eligible, we ensure that the oral and written information provided to those subjects will be 
in that language either by research personnel fluent in that language or by an institutional 
translator. We will pursue approval of the consent documents in Spanish as a significant 
portion of the subject population may speak Spanish.  We also request permission to utilize 
the short forms for documentation of consent and translation into other than the English or 
Spanish for the rare circumstance that the subject or proxy cannot communicate in either 
of those languages.
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21)
Publication policy/ Results Reporting/Progress and Final Reports
ClinicalTrials.gov requirements (registration/results publication)
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study 
may be requested from other researchers 1 years after the completion of the primary 
endpoint by contacting the PI
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22) 
REFERENCES
1. Teixeira, P.G., et al., Enterocutaneous fistula complicating trauma laparotomy: a major 
resource burden. Am Surg, 2009. 75(1): p. 30-2.
2. Campos, A.C., et al., A multivariate model to determine prognostic factors in 
gastrointestinal fistulas. J Am Coll Surg, 1999. 188(5): p. 483-90.
3. Visschers, R.G., et al., Health-related quality of life in patients treated for enterocutaneous 
fistula. Br J Surg, 2008. 95(10): p. 1280-6.
4. Rahbour, G., et al., A meta-analysis of outcomes following use of somatostatin and its 
analogues for the management of enterocutaneous fistulas. Ann Surg, 2012. 256(6): p. 
946-54.
5. Brubaker, P.L., et al., Intestinal function in mice with small bowel growth induced by 
glucagon-like peptide-2. Am J Physiol, 1997. 272(6 Pt 1): p. E1050-8.
6. Jeppesen, P.B., et al., Glucagon-like peptide 2 improves nutrient absorption and 
nutritional status in short-bowel patients with no colon. Gastroenterology, 2001. 120(4): 
p. 806-15.
7. Jeppesen, P.B., et al., Short bowel patients treated for two years with glucagon-like 
Peptide 2: effects on intestinal morphology and absorption, renal function, bone and body 
composition, and muscle function. Gastroenterol Res Pract, 2009. 2009: p. 616054.
8. Jeppesen, P.B., et al., Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant 
glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome 
patients. Gut, 2005. 54(9): p. 1224-31.
9. Jeppesen, P.B., et al., Randomised placebo-controlled trial of teduglutide in reducing 
parenteral nutrition and/or intravenous fluid requirements in patients with short bowel 
syndrome. Gut, 2011. 60(7): p. 902-14.
10. Jeppesen, P.B., et al., Teduglutide reduces need for parenteral support among patients 
with short bowel syndrome with intestinal failure. Gastroenterology, 2012. 143(6): p. 
1473-1481 e3.
11. O'Keefe, S.J., et al., Safety and efficacy of teduglutide after 52 weeks of treatment in 
patients with short bowel intestinal failure. Clin Gastroenterol Hepatol, 2013. 11(7): p. 
815-23 e1-3.
12. Jeppesen, P.B., Pharmacologic options for intestinal rehabilitation in patients with short 
bowel syndrome. JPEN J Parenter Enteral Nutr, 2014. 38(1 Suppl): p. 45S-52S.
13. Berghofer, P., et al., Development and validation of the disease-specific Short Bowel 
Syndrome-Quality of Life (SBS-QoL) scale. Clin Nutr, 2013. 32(5): p. 789-96.
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Appendix B
Appendix C
MEDICATION GUIDE FOR PATIENTS
Medication Guide for 
patients.pdf
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Appendix D
Charlson Comorbidity Index
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Appendix E                  Treatment Schema
Treatment
Cross-
over
Eligibility
/ 
Screening
Enrollment
Day 7 
Study 
Visit 1 
+/- 3 
days
Day 14 
Study 
Visit 2 or 
Telephone 
+/- 3 days
Day 21  
Telephone 
Call 1      
+/- 3 d
Day 28  
Study 
Visit 3 
+/- 1 
week
Day 35  
Telephone 
Call 2      
+/- 3 days 
Day 42 
Study 
Visit 4 or 
Telephone  
+/- 1 week
Day 49 
Telephone 
Call 3      
+/- 3 d
Day 56 
Study 
Visit 5       
+/- 1 
week
Informed Consent
X
X
Inclusion and exclusion 
criteria
X
X
Demographics
X
Medical and surgical history
X
Review prior and concomitant 
medications
X
Complete Physical ExamA
X
X
X
X
X
X
Vital signs measurementsB
X
X
X
X
X
X
X
Self-administration of 
medication and teaching if 
needed
X
X
X
X
X
X
X
X
X
IP Dispensation and 
Accountability
X
X
X
X
X
X
Chemistry panel
X
X
X
Liver function tests
X
X
X
Plasma PK*
X
X
Serum pregnancy test
X
X
X
ECG
X
Monitor SAE/AEC
X
X
X
X
X
X
X
X
Concomitant medication 
review
X
X
X
X
X
x
Nutritional assessmentD
X
X
X
X
X
X
X
X
X
X
3- day fistula output
X
X
X
X
X
X
X
X
X
X
Questionnaires
X
X

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Treatment
End-of-
Treatment
Long-
Term 
Follow-
up
Day 63 
Study 
Visit 6 or 
Telephone 
+/- 1 week
Day 70  
Study 
Visit 7 or 
Telephone 
+/- 1 week 
Day 77  
Telephone
Call 4      
± 3 d
Day 84 
Study 
Visit 8 ± 
1 week
Day 91   
Telephone 
Call 5  
± 3 d
Day 98   
Study Visit 
9 or 
Telephone 
+/- 1 week 
Day 105  
Telephone 
Call 6      
± 3 d
Day 112   
Study Visit 
10              
±1 week
Study 
Visit 11   
(3 months 
after EOT) 
-2wks to  
+3 mos.
Informed Consent
Inclusion and exclusion criteria
Demographics
Medical and surgical history
Review prior and concomitant 
medications
Complete Physical ExamA
X
X
X
X
X
Vital signs measurementsB
X
X
X
X
X
Self-administration of medication 
and teaching if needed
X
X
X
X
X
X
X
IP Dispensation and Accountability
X
X
X
X
XE
Chemistry panel
X
X
X
Liver function tests
X
X
X
Plasma PK*
X
X
X
Serum pregnancy test
X
X
X
Monitor SAE/AEC
X
X
X
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
Nutritional assessmentD
X
X
X
X
X
X
X
X
X
3- day fistula output
X
X
X
X
X
X
X
X
X
Questionnaires
X
X

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Open-Label Extension (up to 12 additional Study Visits and 12 additional Telephone Calls)
Extension Study 
Visit 1
 +/- 1 week
Extension Study 
Telephone Call 1 to End
± 4 d
Extension Study 
Visit 2 to End 
+/- 1 week
Informed Consent
X
Collect Complete Physical Exam ResultsA
X
X
Collect vital signs measurementsB
X
X
Self-administration of medication and 
teaching if needed
X
X
X
IP Dispensation and Accountability
X
X
Collect chemistry panel results**
X
X
Collect liver function test results**
X
X
Collect serum pregnancy test (if applicable)
X
X
Monitor SAE/AEC
X
X
X
Collect concomitant medication review
X
X
X
Nutritional assessmentD
X
X
X
Approx. average daily  fistula output
X
X
X
Questionnaires
XF
A. A complete physical examination during an applicable study visit will include an assessment as per clinical judegment.
B. Vital sign measurements during an applicable study visit will include body temperature, heart rate, respiratory rate, and blood pressure.  Height will 
be obtained at Screening only; weight will be measured at screening and during applicable study visits.
C. Patients will be monitored for non-serious adverse events and serious adverse events from the time when informed consent is obtained at Screening 
up to and including 30 days for SAEs and throught the Long Term Follow Up (Study Visit  11) for AEs. 
D. May include adjustment of parenteral nutrition (PN) volume as per pre-defined weaning protocol.
E.  IP accountability only at visit 10
F. Questionnaires for the Open-Label Extension Study will only be administered at the End of the study
*   PK = Pharmacokinetics, processed according to separate “Sample Processing Procedure”
** Laboratory test results for the Open-Label Extension Study may be collected every 3 months if completed clinically