Yield of Diagnostic Tests and Management of Crofelemer for Chronic Idiopathic Diarrhea In Non-HIV Patients: A Pilot Study
Phase: PHASE4
Conditions: Chronic Diarrhea of Unknown Origin
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-18-0990 
IRB APPROVAL DATE: 12/06/2023 
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Yield of Diagnostic Tests and Management of Crofelemer for Chronic Idiopathic Diarrhea In Non-
HIV Patients: A Pilot Study 
 
NCT03898856 
 
Version Date: 12/06/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Yield of Diagnostic Tests and Management of Crofelemer for Chronic Idiopathic Diarrhea In Non-HIV Patients: A 
Pilot Study 
 
 
Principal Investigator 
 
Brooks D. Cash, MD 
 
Chief - Division of Gastroenterology, Hepatology and Nutrition 
Sterling Professor of Medicine 
University of Texas Health Science Center at Houston 
Co-Director, Ertan Digestive Disease Center 
 
 
 
 
 
 
 
 
 
 
 
 
Co-Investigator 
 
Shruti Khurana, MD 
 
PGY-2 (Second Year Resident) 
Department of Internal Medicine/Pediatrics 
University of Texas Health Science Center at Houston 
 
 
 
 
Co-Investigator 
 
Asha Kuruvila, MD 
PGY-5 (Clinical Fellow) 
Division of Gastroenterology, Hepatology and Nutrition 

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University of Texas Health Science Center at Houston 
 
 
 
 
Collaborators/ Sponsors 
 
1. Napo Pharmaceuticals 
 
 
San Francisco, CA 94105 
 
 
 
 
 
 
Study Coordinator 
 
Cecilia Lara, MBA 
 
Sr. Clinical Trial Program Manager 
Department of Internal Medicine 
 
 
 
 
 
 
 
 
Principal Clinical Site 
 
Ertan Digestive Disease Center (EDDC) 
 
University of Texas Health Science Center at Houston (UTHealth)/ Memorial Hermann Healthcare System (MHHS) 
 
 
 
 

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Study Population 
 
Males and females between age 18-75 years with chronic functional diarrhea (defined as 3 non-bloody loose stools 
per day or more than 20 non-bloody loose stools per week for ≥ 4 weeks) without an obvious cause after evaluation 
for organic causes presenting to Ertan Digestive Diseases Center (EDDC) in Houston. 
Sample Size 
 
Up to 100 Subjects 
 
Study Duration 
 
Approximately one year from institutional review board (IRB) approval 
 
Subject Duration 
 
Approximately 3 to 4 months per subject 
 
Tentative Dates of Study 
 
Estimated commencement date of the study: Nov 2019 
Estimated completion date of the study: May 2021 
Type of Study 
Pilot Study; Non-Blinded Clinical Trial 
 
Amount of Product Required 
 
2 tablets x 28 days x 25 patients = 1,400 crofelemer tablets 
 
No placebo needed. The drug will be used solely to conduct the study and all safety and regulatory reporting 
obligations will be followed. Any unused drug will be returned to Napo Pharmaceuticals within 90 days of study 
completion. 

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Background and Rationale 
 
Chronic Diarrhea and Epidemiology 
 
Chronic diarrhea is a common complaint of patients presenting to family practitioners, internists and is one of the 
most common reasons for referral to gastroenterologists. It is estimated that the prevalence of chronic idiopathic 
diarrhea in developed countries (including the US) is approximately 3-5% [1-3]. It has a significant negative effect 
on health-related quality of life (HRQOL) and causes high economic burden on patients and society. The American 
Gastrointestinal Association Burden of Illness study showed that the estimated annual direct and indirect costs 
associated with chronic diarrhea is up to $524 million per year and $136 million per year, respectively [3]. 
Diagnostic Evaluation of Chronic Diarrhea 
 
There are many causes of chronic diarrhea known to man and several algorithms have been created for the 
evaluation chronic diarrhea [2-4]. Over the last 10 years, additional diagnostic tools have become available that may 
increase the identification of heretofore unappreciated causes of chronic diarrhea. In addition to traditional stool 
analyses and lower gastrointestinal endoscopy, breath testing for specific carbohydrate maldigestion, stool multiplex 
examinations for gastrointestinal infection, and assays for carbohydrate and bile acid malabsorption have become 
available in routine clinical practice. As a consequence, clinical awareness of the conditions diagnosed by these 
emerging assays has increased, but prevalence values for these conditions and the relative importance of their 
contributions to the symptoms of chronic diarrhea remain unknown. For instance, recent estimates have placed the 
prevalence of bile acid malabsorption (BAM) in patients with irritable bowel syndrome (IBS) with diarrhea between 
25-50%. Up until recently, there has been no diagnostic test available outside research institutions for BAM and 
treatment for this condition has been empiric bile acid sequestrant therapy, which can interfere with the absorption 
of other medications. The availability of the serum 7C4 test for BAM may be an important development in the 
management of patients with chronic diarrhea, but outcomes data are lacking. 
Congenital sucrase-isomaltase enzyme deficiency (CSID) is an often unrecognized, autosomal recessive disorder 
with wide phenotypic heterogeneity with symptoms such as chronic diarrhea, bloating, abdominal pain, and 
flatulence that are non-specific and commonly associated with other digestive disorders. This results from 
maldigestion of sucrose and starches in the diet, release of water secondary to high intraluminal osmolality, and 
subsequent bacterial fermentation [5]. Recent work has shed some light on the hypothesis that CSID may be more 
prevalent than we previously believed with estimates ranging from 9.3% to 21% [6,7]. Demonstration of normal 

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duodenal or jejunal mucosal histology and low to absent sucrase activity detected by enzyme assay remains the gold 
standard for diagnosis of CSID [8-11]. An evolution of the H2 BT introduced in the early 1970’s was the 
measurement of isotope-labeled CO2 in breath using 13C or 14C [12]. These tests depend on measurement of changes 
in isotope labeled breath via infrared mass-dispersion spectrophotometry which is simple and has a short turnaround 
time [13-15]. Since the introduction of mass spectrometers for the detection of the stable isotope of 13C in expired 
air the BT technique has been adapted for the study of malabsorption with collection systems that are well tolerated 
and widely reproducible. 13C Breath testing is a non-invasive, 90-minute test that can be easily administered by the 
patient at home. An 8 hour fast is required after which the patient collects a baseline sample and then 20 gram of 13C 
Sucrose is administered orally. The patient collects breath samples 30 minutes apart by blowing through a straw into 
labeled, screw-cap glass tubes. These tubes are then mailed to the analyzing lab and results are obtained within 24 
hours. 
Management of Chronic Diarrhea 
 
Despite the advances in the medical field, in a substantial number of cases, no organic or functional etiology can be 
determined. In those circumstances and in cases where no specific treatment is available or specific treatment fails to 
affect the cure, symptomatic treatment of diarrhea remains the mainstay of management. Variable success has been 
seen with pharmacological agents including anti-secretory (octreotide), anti-motility (loperamide and diphenoxylate 
atropine), and adsorbent medications along with adjunctive non-pharmacologic measures such as dietary 
modifications (fiber supplements like psyllium or absorbents like kaolin) [2]. 
About Crofelemer 
 
Crofelemer is a novel compound isolated from the plant Croton lechleri (family Euphorbiaceae) found in the 
western Amazonian regions of South America. (Attachment 6) This naturally occurring extract is an acid-labile, 
proanthrocyanidin oligomer found in the red latex of the plant [16]. Native populations of South America have used 
the sap of the plant for self-treatment of chronic diarrhea for many years. Crofelemer is primarily composed of (+)– 
catechin, (–)–epicatechin, (+)–gallocatechin, and (–)–epigallocatechin monomer units linked in random sequence 
(Figure 1). 
 
The mechanism of action of crofelemer is through dual inhibition cyclic adenosine monophosphate (cAMP)- 
stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl) channel, and the calcium- 
activated Cl channels (CaCC) at the luminal membrane of enterocytes [17,18]. This structurally unrelated inhibition 

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of intestinal chloride channels normalizes the flow of Cl and water in the GI tract, leading to anti-secretory effects of 
crofelemer. Systemic absorption is minimal and concentrations of crofelemer in plasma remained below the level of 
quantitation (50 ng/mL) in studies. There are no active metabolites identified and the route of elimination is 
unknown. 
 
Previously, crofelemer has been investigated for the treatment of several types of chronic diarrhea, including 
traveler’s diarrhea [19], AIDS-associated diarrhea [20], and infectious diarrhea such as cholera [21]. Crofelemer has 
also been studied in patients with diarrhea-predominant IBS (IBS-D) [22]. Crofelemer has also been evaluated as a 
topical application in patients with AIDS for the treatment of recurrent genital and perianal herpes lesions. 
Due to its large chemical structure, crofelemer has minimal systemic absorption when given orally, irrespective of 
concomitant food intake or duration of exposure. It has demonstrated a good safety profile and is well tolerated in 
current published studies [23]. In a study performed in 2002 on 184 travelers returning from Mexico, Jamaica, and 
the United States-Mexico border, De Cesare et al. demonstrated a 21% reduction in the duration of traveler’s 
diarrhea in more than 90% of the individuals with crofelemer [19]. Holodniy et. al conducted a multicenter, phase II, 
randomized, double blind, placebo-controlled study [20]. 26 patients with AIDS received a 4-day course of 
crofelemer with marked reduction in stool frequency and stool weight compared to placebo. Crofelemer has also 
been efficacious in reducing pain and discomfort in female patients with IBS-D. This was shown by Mangel et al. in 
a placebo-controlled trial in 2008 [22]. The phase 3 ADVENT trial lead by McArthur et al. used a 2-stage design 
[23]. The first stage included a placebo-controlled phase with approximately 200 HIV-seropositive patients on 
HAART therapy, randomized to receive crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. After a 
responsiveness analysis, crofelemer 125mg twice daily was used in a placebo controlled second stage trial. Clinical 
response was defined as ≤2 watery stools per week during ≥2 of the 4 weeks of the placebo-controlled phase. 
Crofelemer provided a 17.6% response rate compared to only 8.0% in the placebo group. It decreased the number of 
daily watery bowel movements and daily stool consistency score, but was ineffective in controlling urgency, 
abdominal pain, and incontinence. Both clinical trial stages were followed by 20-week open label trial with weekly 
response-assessment. In this trial the placebo-response rate rose for weekly responders to 56%. More pronounced 
crofelemer treatment effects were observed in patients with diarrhea of greater severity (≥2 watery stools per day) or 
duration (>2 years) or who had used multiple (≥2) antidiarrheal medications prior to the study. 

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Formerly known as Fulyzaq, crofelemer was approved by US-FDA in December 2012 for symptomatic treatment of 
HIV-related diarrhea in the dose of 125mg tablets taken two times a day [24]. It was the first botanical therapy to 
receive FDA approval and is now marketed under the name of Mytesi®. The most common adverse reactions for 
crofelemer that occurred in at least 2% of patients in the ADVENT trial at a higher incidence than placebo were 
upper respiratory tract infection, bronchitis, dry cough, flatulence and increased bilirubin [23](Table 1). Adverse 
reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of crofelemer were abdominal 
pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood 
bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, 
nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood 
cell count. 
 
There are no absolute contraindications reported for crofelemer use. It is a white, oval, enteric-coated 125 mg 
delayed-release tablet. The inactive ingredients of crofelemer are - microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, and magnesium stearate. The coating ingredients are - ethylacrylate and 
methylacrylate copolymer dispersion, talc, triethyl citrate, and white dispersion, which contains xanthan gum, 
titanium dioxide, propyl paraben, and methyl paraben. Since there is no known relation between food intake and 
drug administration, crofelemer can be taken with or without meal. However, it should not be crushed or chewed 
and is intended to be swallowed whole. It is marketed as a bottle of 60 tablets and should be stored at 20°C-25°C 
(68°F-77°F); excursions are permitted between 15°C-30°C (59°F-86°F) (Attachment 6 and 7). 
 
With the increasing interest in discovering uses of crofelemer in other spectrum of diarrheal disease, objective of 
this study will be to evaluate the efficacy of crofelemer in non-HIV patients with chronic idiopathic diarrhea. With 
most patients relying on anti-motility agents or other adjunct therapies with variable success, there is a promise in 
crofelemer for future studies. 
 
Chronic Diarrhea and Health-Related Quality of Life 
 
 
Chronic diarrhea can result in a decline in nutritional status and subsequent decline in functional status and overall 
quality of life. HRQOL is a multidimensional construct that consists of three broad domains − physical, 
psychological, and social functioning − that are affected by one’s disease and/or treatment [25]. The measures of 

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quality of life may be influenced by factors unrelated to the health status of the patient including change in their 
 
expectations and aspirations as circumstances change, values patients place on life, their risk aversion, or their 
attitude towards certain type of medical intervention [26]. Understanding how chronic diarrhea affects HRQOL is 
still very limited and restricted to specific population studies largely focusing on people living with AIDS and IBS 
[27-29]. There is no HRQOL questionnaire specifically developed, or validated for, chronic idiopathic diarrhea. 
Short-Form 36 (SF-36) is a generic questionnaire developed in the early 1990’s to evaluate HRQOL in illness and 
make comparisons with the background population or between different diseases. It is a self-administered, general 
questionnaire comprising 36 items, which is well validated and accepted. Thirty-five of the items are grouped into 
eight scales: physical function (PF), role limitations due to physical disability (RP), bodily pain (BP), general health 
perception (GH), vitality (VT), social function (SF), role limitation due to emotional problems (RE), and mental 
health (MH). The results are presented as scale scores ranging from 0 (worst possible health state) to 100 (best 
possible health state) following the standard SF-36 scoring algorithm [30-32]. With our study, we aim to shed some 
light on the perception of health and quality of life in patients with chronic idiopathic diarrhea. In addition, we will 
also look at any change in that perception after administration of crofelemer for 4 weeks. 
Objectives 
 
Primary Objective – Assess the efficacy of crofelemer in adult, non-HIV patients with idiopathic chronic diarrhea 
 
Secondary Objectives - 
 
1. 
Determine the prevalence of identifiable causes of chronic diarrhea in a non-HIV patients 
 
2. 
Assess the diagnostic yield, in terms of identification of treatable etiologies, of commercially available 
diagnostic evaluations in adult, non-HIV patients with chronic idiopathic diarrhea; i.e., evaluate which 
tests, among the standard diagnostic tests commonly conducted as part of the evaluation of chronic 
idiopathic diarrhea, are most likely to identify a treatable cause of the diarrhea. 
3. 
Assess the usefulness of CSID testing in adults with chronic idiopathic diarrhea via 
sucrase enzyme level testing on small intestinal biopsies, and 13C-SBT. 
4. 
Analyze the relationship between chronic idiopathic diarrhea and health-related quality of life and assess 
the impact of crofelemer treatment on health-related quality of life 
Details of the Study 

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Definition of Chronic Diarrhea - Persistent increase in bowel movement frequency (≥ 3 bowel movements per day 
or ≥ 20 bowel movements per week) AND decrease in consistency of >50% stools (liquid or watery-Bristol Stool 
Form Scale type 6 or 7) for more than 4 weeks [33]. 
Outcome measures 
 
Primary Response to crofelemer- A 50% decrease in mean stool count per week by the end of week 4 
 
Secondary Responses to crofelemer- An improvement (decrease) in stool consistency by more than 2 levels in the 
Bristol stool scale (Figure 2) [34,35]. 
2. Changes in HRQOL at T0 and at T+4 weeks 
 
3. Descriptive analysis of the frequency of identified etiologies of chronic diarrhea and the frequency of abnormal 
diagnostic test results leading to the identification of those etiologies 
Treatment Failure/Non-responder - 
 
1. 
Failure to meet the primary response definition 
 
2. 
Medication non-compliance: Subjects who missed more than a total of four doses over the 4-week course. 
 
3. 
Subjects who fail to record at least 80% of the daily symptom diary. 
 
Inclusion Criteria 
 
Males and females between age 18-75 years with chronic diarrhea (defined as 3 non-bloody loose stools per day or 
more than 20 non-bloody loose stools per week for more ≥ 4 weeks) and Bristol Stool Form Scale for stool 
consistency of 6/7 with >50% stool without an obvious cause after evaluation for organic etiologies. Patients of all 
ethnicities will be included in the study. 
Exclusion Criteria 
 
Since the study focuses on chronic idiopathic diarrhea, subjects who may have other organic pathologies or co- 
morbidities that may explain the cause of diarrhea will be excluded. 
1. 
Hematochezia (potentially related to an organic cause). 
 
2. 
Subjects less than 18 years of age more than 75 years of age (safety and effectiveness of crofelemer has not 
been established in these age groups). 
3. 
Pregnant females (crofelemer is a Category C drug due to lack of well-controlled studies to study its effects 
in this population). 

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4. 
Lactating females (it is unknown if crofelemer is excreted in the human milk and thus may have unknown 
adverse effects on the nursing infants). 
5. 
HIV positive individuals. 
 
6. 
Persons within ability to provide consent and understand the study 
 
7. 
Persons with history of alcohol abuse or binge drinking. 
 
8. 
Persons with history of surgical bowel resection or bariatric surgery in the past 12 months. 
 
9. 
Persons who have undergone cholecystectomy (open or laparoscopic) in the past 3 months. 
 
10. Persons receiving antibiotics currently or have received antimicrobials in the past 4 weeks. 
 
11. Persons with end-organ failures including end-stage renal disease, end-stage liver disease, or severe heart 
failure. 
12. Persons with metastatic hematologic and oncologic malignancies. 
 
13. Persons receiving chemo-radiation or immune-modulators for oncologic or rheumatologic conditions. 
 
14. Persons with any other known organic gastrointestinal or non-gastrointestinal disease process in which 
diarrhea is a recognized clinical feature. 
15. Gluten free diet for previous 3 months and refusal to ingest gluten. 
 
Recruitment strategy 
 
1. 
Prospective recruitment of patients referred to the Gastroenterology division of UTHealth/MHHS for 
evaluation and management of chronic diarrhea. 
2. 
Furthermore, presentations will be given to faculty members in the Department of Gastroenterology, 
Hepatology and Nutrition and Internal Medicine at UTHealth/MHHS to discuss the study and facilitate 
recruitment of subjects. 
3. 
Inclusion of study criteria and description of study procedures on the research page for the 
UTHealth/MHHS Gastroenterology Division. 
4. 
Poster advertisements at UTHealth/MHHS bulletin boards with contact information. 
 
Phases of the study 
 
1. 
Screening period of 4-8 weeks for each patient to undergo diagnostic evaluation to determine eligibility to 
participate in the study 
2. 
Treatment period of 4 weeks for collection of efficacy data on crofelemer 

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3. 
Post-Treatment follow-up for drug efficacy, safety assessment, and overall quality of life analysis 
 
Based on estimated prevalence of identifiable causes of chronic diarrhea in approximately 50% of adult patients and 
an estimated non-eligibility prevalence of up to 75% of prospective patients, to enroll 25 patients who meet the 
eligibility criteria for the study, we are estimating that approximately 100 patients will be required to undergo 
evaluation for this pilot study. This will be achieved over a period of 12-18 months starting from Fall 2019. 
Since this is a pilot study with limited data available of the effect of the drug on the specified population, a sample 
size of 25 subjects is considered safe and feasible to inform potential future randomized controlled trials. 
Criteria for termination of trial: 
 
1. 
Severe unanticipated adverse effects of the drug in the participants 
 
2. 
Inability to enroll stipulated number of participants over the anticipated study time 
 
3. 
Withdrawal of more than 50% of the selected subjects from the study. Please note that subjects may 
withdraw voluntarily from the study at any time of the subject duration. He/she will be required to write a 
written request addressed to the PI, explaining the reason for withdrawal. New subjects will be enrolled to 
the study after the screening period, if possible during the total study duration. 
4. 
Enrollment of 25 subjects into the treatment phase or 100 patients in the diagnostic phase, whichever 
occurs first. 
Number of visits/encounters 
 
Four clinic visits at EDDC 
 
1. Pre-screening assessment of subjects (4-8 weeks prior to treatment phase) 
 
2. Discussion of the results of diagnostic tests and evaluations; initiation of treatment with crofelemer 125 
mg tablets twice daily (BID) (Day 1) (Attachment 7) 
3. Mid-study follow-up (Day 14) for symptomatic evaluation of diarrhea and any adverse events 
 
4. Final post-treatment follow-up on Day 29 OR the first business day after completion of treatment 
 
PHASE 1: SCREENING PERIOD 
 
A careful, detailed and comprehensive medical, surgical, and social history will be obtained to categorize the 
diarrhea and rule out obvious organic causes of diarrhea. All of these diagnostic tests are considered standard of care 
for the evaluation of chronic idiopathic diarrhea. 

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The order in which these investigations will be performed will be tailored on a case-to-case basis (patient education 
for each test is added as an attachment and mentioned in parenthesis)– 
1. Complete Blood Count (CBC) 
 
2. Comprehensive Metabolic Panel (CMP) 
 
3. HIV Screening – To screen patients for the study as our study focuses on non-HIV patients only (if not 
done in previous 6 months) 
4. Esophagogastroduodenoscopy (Attachment 8) and Colonoscopy (Attachment 9)– (performed by PI) 
with random and (if required by endoscopic findings) targeted biopsies of the UGI (duodenum) and 
LGI (colon) tract mucosa sent to the department of pathology for analysis as well testing for CSID 
(duodenal biopsies) 
5. Stool multiplex panel for the following gastrointestinal pathogens: 
 
 
Campylobacter 
Cryptosporidium 
E. coli O157 
 
Enterotoxigenic E.coli (ETEC) 
 
Shiga Toxin-producing E. coli (STEC) 
Giardia lamblia 
Norovirus GI/GII 
Rotavirus A 
Salmonella 
Shigella 
Adenovirus 40/41 
Entamoeba histolytica 
Vibrio cholera 
Yersinia enterocolitica 
Clostridium difficile 
 
6. Urine Pregnancy Test when clinically indicated 
 
7. Thyroid Panel: Thyroid stimulating hormone and free T4 
 
 
 
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8. Tissue transglutaminase and IgA 
 
9. C-reactive protein 
 
10. Serum 7C4 
 
11. Gastrin Level 
 
12. Calcitonin Level 
 
13. VIP Level 
 
14. Stool osmolality 
 
15. Stool Qualitative Stool Fat 
 
16. Stool Reducing Substances 
 
17. Stool calprotectin 
 
18. Stool elastase 
 
19. Lactulose Hydrogen Breath Test 
 
20. 13C-Sucrose Breath Test 
 
21. HRQOL (SF-36) baseline - This is a questionnaire that consists of 36 questions and asks subjects’ 
views about their health. Subjects will fill this form two times during the total duration of study – at the 
initial visit prior to starting treatment and once at the end at the post-treatment follow-up (Attachment 
5a and 5b). 
 
We estimate that it may take from 4 weeks up to 8 weeks to obtain and complete all the above-mentioned tests. 
Patients will be updated by a call from the study coordinator to discuss the results and scheduled the pre-treatment 
clinic visit. 
 
Diagnostic tests will be denoted as normal, abnormal, or unable to be performed (in the event of insufficient sample, 
non-compliance, or lab error). Descriptive statistics will be used to denote the percentage of patients with any 
abnormal diagnostic tests and the frequency of abnormal results for each test, relative to other diagnostic tests, will 
be computed and recorded for the cohort. 
 
 
 
 
 
 
 
 
 
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In accordance with good clinical and standard practice, abnormal tests will be evaluated and acted upon as indicated. 
Any diagnosis of a causative medical condition identified as a result of the standardized diagnostic evaluation will 
be recorded, as will patient response to appropriate therapy for any identified medical conditions, if any. 
 
PHASE 2: TREATMENT PERIOD 
 
Consecutive patients completing the diagnostic phase who are not identified as having a proven etiology of their 
chronic diarrhea symptoms will be invited to participate in the treatment phase. With the evidence supporting 125 
mg BID dosing of crofelemer as the appropriate dose for response as shown by the ADVENT study, we will be 
administering the same dose of 125 mg tablets taken by mouth twice daily for our subjects. 
We will provide the subjects with a total of 56 tablets for the 28-day course. An IND has not been sought for this 
study because the study meets the exemption criteria as stated in 21 CFR 312.2(b): investigations using a marketed 
drug or biologic do not require submission of an IND if all six conditions below are met: 
 
1. 
It is not intended to be reported to FDA in support of a new indication for use or to support any other 
significant change in the labeling for the drug. 
2. 
It is not intended to support a significant change in the advertising for the product. 
 
3. 
It does not involve a route of administration or dosage level, use in a subject population, or other factor that 
significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the 
drug. 
4. 
It is conducted in compliance with the requirements for Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) review and informed consent. 
5. 
It is conducted in compliance with the requirements concerning the promotion and sale of drugs. 
 
6. 
It does not intend to invoke 21 CFR 50.24 (exception from informed consent for emergency research). 
 
 
As there is effect of food intake on the drug’s absorption, it can be taken with or without meal. Subjects will be 
advised to remain on a regular diet and limit major dietary modifications during the study period. Patients will be 
advised to follow their regular routine including average level of daily activity and there are no restrictions to travel 
with emphasis on compliance with the medication. Women of childbearing age will be advised to use at least one 
method of contraception including barrier method, hormonal therapies with pills, implants or IUDs. In case, a 

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subject misses a period or has a positive home urine pregnancy test, she will be advised to call the study coordinator 
or PI’s office immediately. 
Use of rescue medications i.e. loperamide will be allowed in order to prevent hesitation of participants to enter the 
study. However, the use will be monitored and limited to fourteen 2mg doses per week. 
Symptom Diary maintenance has been used previously for IBS-D studies [62]. This not only improves compliance 
and accurate data collection, but also provides a sense of control to the patient as a participant in the study. 
Therefore, each subject will be asked to maintain a Daily Symptom Diary with the following information 
(Attachment 3) - 
1. 
Time of bowel movements per 24-hour period (midnight to midnight) 
 
2. 
Number of loose stools per 24-hour period 
 
3. 
Consistency of each bowel movement (according to Bristol Stool Form Scale) (Figure 2) 
 
4. 
Presence of urgency with each bowel movement (0-4 VAS scale; 0-none, 1-mild, 2-moderate, 3-severe, 4- 
incontinence) 
5. 
Supportive Anti-diarrheal medication taken (Yes/No) 
 
6. 
Dose of supportive anti-diarrheal medication taken 
 
7. 
Number of Anti-diarrheal medications taken per 24-hour period 
 
8. 
Daily time of administration of crofelemer (AM/PM) 
 
9. 
Any other new symptoms noted 
 
 
Participants will be provided with the Daily Symptom Diary on their second visit, prior to treatment initiation. It will 
be a notebook with the above questions printed on each page with a total of 30 entries and 5 extra pages in the back 
for any other information that the participant may wish to include (Attachment 3). The completeness of entries and 
pattern of symptoms will be assessed on the subsequent visits on Day 14 and Day 29. All information will then be 
noted and uploaded to the study database subsequently. Participants will need to have at least 80% completed entries 
i.e. 22 diary entries throughout the study period. Any missing entry will be considered as no bowel movements for 
that day. Any subject with insufficient data entry of less than 22 entries will be categorized a non-responder. No 
patient identifiers will be included in the diary, other than subject number that corresponds to the master study 

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enrollment log, which will be maintained electronically. Patients will be given sequential study ID numbers (1 up to 
 
100) upon enrollment into the study. 
 
PHASE 3: POST-TREATMENT FOLLOW-UP 
 
A post-treatment follow-up visit would be scheduled with the PI on Day 29 or the first business day after completion 
of the crofelemer course. The following variables will be obtained and analyzed for the study - 
1. Age (in years) 
 
2. Gender (Male/Female/Other) 
 
3. Ethnicity (Caucasian/Hispanic/African American/Native American/Asian/Other) 
 
4. BMI (in kg/m2) 
 
5. Number of weeks/years of diarrhea fulfilling entry criteria 
 
6. Number of stools per day (Day 0) 
 
7. Number of stools per day (Day 14) 
 
8. Number of stools per day (Day 28) 
 
9. Total number of stools per week (Week 1, 2, 3, and 4) 
 
10. Average consistency of stools (Day 0) 
 
11. Average consistency of stools (Day 14) 
 
12. Average consistency of stools (Day 28) 
 
13. Previous use of other anti-diarrheal agents (Yes/No) 
 
14. Average number of anti-diarrheal agents used per week (Day 0) 
 
15. Average number of anti-diarrheal agents used per week (Day 14) 
 
16. Average number of anti-diarrheal agents used per week (Day 28) 
 
17. Abdominal Pain yes or no and scored from 0 to 10 (0-no pain, 10-worst abdominal pain imaginable) 
 
18. Urgency (according to 0-4 VAS scale) 
 
19. Fecal Incontinence (Yes/No) 
 
20. Other comorbid diagnoses 
 
21. Concomitant medications and dosing 
 
22. HRQOL (SF-36) Post-treatment (Attachment 5b) 

IRB NUMBER: HSC-MS-18-0990 
IRB APPROVAL DATE: 12/06/2023 
17 
 
Data and Safety Monitoring 
 
Adverse Events Reporting – Adverse events are not expected. However, in the event of any unanticipated medical 
occurrence in a subject directly caused by the drug, it is the responsibility of the Investigator to record all relevant 
information regarding the medical occurrence on the Sample Collection Study Incident Case Report Form and 
provide it to the IRB and study sponsors promptly. The Investigator will be responsible for the proper reporting of 
any potential adverse events (AE) or serious adverse events (SAE) (as defined by general medical standards) to the 
appropriate authorities. AEs/SAEs related to medication treatment(s) will be reported directly to the manufacturer of 
the medication product. The investigator will be responsible for ensuring that adequate medical care is provided to a 
subject for any untoward medical occurrence resulting from this clinical protocol. 
Statistics 
 
Since this is a pilot study, simple descriptive statistics will be used to denote outcomes and findings from diagnostic 
evaluations and treatment. For the diagnostic outcomes, this will include the prevalence of organic gastrointestinal 
disorders identified as a result of diagnostic testing. For the treatment outcomes, responder and non-responder rates 
will be described as well as the incidence of adverse effects. Changes in HRQOL will be described in standard 
fashion. 
Ethics 
 
1. 
IRB approval will be sought from CPHS for initiation of the study. The protocol and related documents 
will be submitted for review to the UTHealth institutional ethics committee. 
2. 
A written informed consent will be obtained from the participants prior to initiation of the study. Consent 
will be made available in English. 
3. 
All participants will be provided with the study coordinator’s office phone number and fax number for 
correspondence and answering any queries regarding the study, treatment or any other concerns. 
Data handling and record keeping 
 
1. 
Data will be collected through accessing the individual participant’s electronic medical records in the 
Memorial Hermann Hospital Care4 (inpatient) and UTHealth AllScripts (outpatient) and recorded in the 
password-protected database electronically. 

IRB NUMBER: HSC-MS-18-0990 
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18 
 
2. 
All identifying personal health information will be kept confidential as per HIPAA compliance 
requirements. 
3. 
Source documents will be accessed only by the principal and co-investigator and will be used solely for the 
purpose of this study. The records will be accessible for inspection and copying by authorized authorities. 
4. 
All data will be stored electronically in a PIN-protected USB drive and data transfer will be performed 
through encrypted emails between investigators and staff (if necessary) using institutional email addresses. 
5. 
Patient diaries will be maintained by the patient until the end of study and will be turned in at the end of 
study to the investigators for abstracting into the study database. Once abstracted, the diaries will be stored 
with any other had copy study materials in a secured storage container in a locked room maintained by 
study coordinator personnel. 
6. 
We will share de-identified demographics and results of CSID testing with investigators from the 
University of Michigan who are performing a similar study aimed and determining the prevalence of CSID. 
(Attachment 11) 
Quality control and assurance 
 
1. 
The investigators will meet every month to review the data collected and assess the progress of the project. 
 
2. 
Study sponsors will be provided with a quarterly report of the progress of the ongoing research including 
adverse events (if any). 
Publication Plan 
 
1. 
We plan to publish the results of the study in an internationally recognized scientific journal. 
 
2. 
Napo pharmaceuticals will be provided with the finalized manuscript prior to submission as part of the 
Grant Agreement. 
3. 
We will make the results of the study available to the participants within 8 weeks of final analyses. It will 
either be handed to them on their next routine follow up or sent to them by mail, whichever is earlier. 
Funding 
 
1. 
 
 
2. 
The remainder of the diagnostic evaluations are considered standard of care and patients will be billed 
through their insurance in accordance with standard operating procedures for these tests and procedures. 

IRB NUMBER: HSC-MS-18-0990 
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19 
 
3. 
Pre-authorization for insurance coverage for these tests will be sought to ensure that you will not be 
billed later because test was done but insurance later informed you that the test wasn't covered. If 
specific tests or evaluations are not covered by insurance/Medicare, patients will be given the choice of 
not undergoing that testing or covering the cost out of pocket. 
 
 
Conflicts of Interest 
 
The authors disclose no conflicts of interest. 
 
Limitations of the study 
 
1. 
Participants will not be monitored as inpatients during the study period. This introduces the possibility of 
confounding factors including variation in diets and excessive use of other rescue medications for 
symptomatic relief 
2. 
Small sample size of 25 patients for the pilot treatment (crofelemer) arm 
 
3. 
Short follow up period of 4 weeks to assess effects of the crofelemer will limit any longer-term 
observations or conclusions regarding chronic therapy with this medication 
Based on the results of this pilot study, a randomized control multi-center clinical trial may be warranted with a 
larger cohort and longer treatment and follow up duration. We are hoping that this study would set up a base for 
future investigators to explore the potential uses of crofelemer from chronic idiopathic diarrhea given the 
prevalence of the condition and the absence of FDA approved therapies. 
Attachments 
 
1. Curriculum Vitae of the Principal Investigator 
 
2. Written Informed Consent Form to participate in the clinical trial with HIPAA authorization 
 
3. Template of Sample Entry of Daily Symptom Diary 
 
4. Written Informed Consent Form Esophagoduodenoscopy and Colonoscopy 
 
5. SF-36: Health-related Quality of Life Questionnaire Form Pre-Treatment Survey (5a) and Post-Treatment 
Survey (5b) 
6. Crofelemer Package Insert 
 
7. Patient Education Sheet on Crofelemer 
 
8. Patient Education Sheet on Esophagogastroduodenoscopy procedure 

IRB NUMBER: HSC-MS-18-0990 
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20 
 
9. Patient Education Sheet on Colonoscopy procedure 
 
10. University of Michigan CSID Protocol 
 
 
Figure 1. A Chemical Structure of crofelemer. 
 

identified 
Adult patients with uninvestigated chronic diarrhea 
without exclusion criteria 
Figure 2. Bristol Stool Scale Chart (Reproduced by permission of the late Dr K W Heaton, Reader in Medicine at 
the University of Bristol. © 2000 Norgine Pharmaceuticals Ltd.) [61] 
 
 
 
 
 
 
 
 
 
Figure 3. Schematic Design of the Study 
 
 
 
 
 
 
 
Organic disorder 
explaining diarrh IRB NUMBER: HSC-MS-18-0990 
21 
IRB APPROVAL DATE: 12/06/2023 
Diagnostic testing (4-8 weeks) 
Organic disorder 
explaining diarrhea 
identified 

IRB NUMBER: HSC-MS-18-0990 
IRB APPROVAL DATE: 12/06/2023 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Adverse Reactions Occurring in at Least 2% of Patients in the 125 mg Twice Daily Group 
 
 
Adverse Reaction 
Crofelemer 125 mg BID*N = 
229 n(%) 
Placebo N = 274 n(%) 
Upper respiratory tract 
infection 
13 (5.7) 
4 (1.5) 
Bronchitis 
9 (3.9) 
0 
Cough 
8 (3.5) 
3 (1.1) 

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23 
 
Flatulence 
7 (3.1) 
3 (1.1) 
Increased bilirubin 
7 (3.1) 
3 (1.1) 
Nausea 
6 (2.6) 
4 (1.5) 
Back pain 
6 (2.6) 
4 (1.5) 
Arthralgia 
6 (2.6) 
0 
Urinary tract infection 
5 (2.2) 
2 (0.7) 
Nasopharyngitis 
5 (2.2) 
2 (0.7) 
Musculoskeletal pain 
5 (2.2) 
1 (0.4) 
Hemorrhoids 
5 (2.2) 
0 
Giardiasis 
5 (2.2) 
0 
Anxiety 
5 (2.2) 
1 (0.4) 
Increased alanine 
aminotransferase 
5 (2.2) 
3 (1.1) 
Abdominal distension 
5 (2.2) 
1 (0.4) 
* Twice daily 
 
 
Abbreviations 
 
AE - Adverse Event 
 
BAM - Bile Acid Malabsorption 
BID - Twice Daily 
BSS - Bristol Stool Scale 

IRB NUMBER: HSC-MS-18-0990 
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24 
 
13C-SBT - 13C-Sucrose Breath Test 
 
CSID - Congenital Sucrase-Isomaltase Deficiency 
EDDC - Ertan Digestive Disease Center 
EGD - Esophagoduodenoscopy 
FDA - Food and Drug Association 
H2 BT - Hydrogen Breath Testing 
HRQOL - Health-related Quality of Life 
 
IBS - Irritable Bowel Syndrome 
IRB - Institutional Review Board 
MGAM - Maltase-Glucoamylase Complex 
PI - Principal Investigator 
QOL - Quality of life 
SI - Sucrase-Isomaltase 
UTHealth/MHHS - University of Texas Health Science Center at Houston/ Memorial Hermann Healthcare System 
VIP - Vasoactive Inhibitory Peptide 

IRB NUMBER: HSC-MS-18-0990 
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25 
 
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