Crofelemer for Functional Diarrhea
Phase: PHASE4
Conditions: Diarrhea
Sponsor: Beth Israel Deaconess Medical Center

NCT Number:  
NCT04486326 
Official Title: 
Crofelemer for Functional Diarrhea 
Document Type: 
Study Description and SAP 
Document Date: 
01/25/2022 

(CCI) Committee on Clinical Investigations 
Page 1 of 8 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
Crofelemer for functional diarrhea 
Principal Investigator 
Anthony Lembo, MD 
 
B1. 
PURPOSE OF PROTOCOL 
The primary objectives of this study are:  
 
To evaluate the clinical response of patients with diarrhea to crofelemer relative to placebo.  
 
To evaluate the overall safety and tolerability of croflemer in the treatment of diarrhea.  
 
The secondary objective of this study is assess whether improvement in bowel function with crofelemer is 
more effective in subjects without evidence of bile acid malabsorption (i.e., elevated C4 level).   
 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Irritable bowel syndrome (IBS) is a gastrointestinal condition defined by abdominal pain and altered 
bowel habits in the absence of another disease that can account for these symptoms (1). IBS is the 
most commonly diagnosed gastrointestinal condition and has a population prevalence of up to 12% 
in North America (1–3). IBS is more prevalent in women than in men (4). Depending on diagnostic 
criteria and study methodology, anywhere from 0.8-50% of IBS patients in the United States suffer 
from the diarrhea-predominant IBS subtype (IBS-D), in which altered bowel habits are most 
frequently diarrhea (5). Patients with IBS-D and IBS in general report significantly reduced quality of 
life, higher indirect costs, and greater impairments in daily and work activities (6–10). Limited 
medication options are available for treatment of diarrhea symptoms associated with IBS-D. 
 
 
Crofelemer is a potent  antisecretory agent and has promising therapeutic properties for 
functional diarrhea patients. Crofelemer is an active compound extracted from the latex of the 
Western South American plant Croton lechleri. The latex has been used for medicinal purposes for 
centuries by indigenous peoples, with its active properties attributable to the crofelemer compound 
(11). Crofelemer has an inhibitory effect on cAMP-mediated secretion of chloride ions in T84 and 
Caco-2 epithelial cells, resulting in antisecretory effects in the colon that may alleviate diarrhea and 
related symptoms (12). Crofelemer has been shown to improve traveler’s diarrhea and HIV-
associated diarrhea (13,14). It’s applicability to symptoms of functional diarrhea is still unclear. 
 
 
In a Phase II randomized trial, Mangel & Chaturvedi observed the effects of crofelemer in the 
setting of IBS-D (15). While they did not meet the primary endpoint of altering stool consistency in 
IBS-D patients, they did find upon further analysis that crofelemer significantly reduced the number 
of pain- and discomfort-free days in female patients with IBS-D. This study warrants further 
investigation of the effects of crofelemer in treating symptoms of functional diarrhea. 
  
1.  
Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA 2015;313:949–958. 
2.  
Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta -analysis. Clin. 
Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2012;10:712-721.e4. 
3.  
Mearin F, Badía X, Balboa A, et al. Irritable bowel syndrome prevalence varies enormously depending on the 
employed diagnostic criteria: comparison of Rome II versus previous criteria in a general population. Scand. J. 
Gastroenterol. 2001;36:1155–1161. 
4.  
Lovell RM, Ford AC. Effect of gender on prevalence of irritable bowel syndrome in the community: systematic 

(CCI) Committee on Clinical Investigations 
Page 2 of 8 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
review and meta-analysis. Am. J. Gastroenterol. 2012;107:991–1000. 
5.  
Guilera M, Balboa A, Mearin F. Bowel habit subtypes and temporal patterns in irritabl e bowel syndrome: 
systematic review. Am. J. Gastroenterol. 2005;100:1174–1184. 
6.  
Buono JL, Carson RT, Flores NM. Health-related quality of life, work productivity, and indirect costs among 
patients with irritable bowel syndrome with diarrhea. Health Qual . Life Outcomes 2017;15:35. 
7.  
Nellesen D, Yee K, Chawla A, et al. A systematic review of the economic and humanistic burden of illness in 
irritable bowel syndrome and chronic constipation. J. Manag. Care Pharm. JMCP 2013;19:755–764. 
8.  
Paré P, Gray J, Lam S, et al. Health-related quality of life, work productivity, and health care resource utilization 
of subjects with irritable bowel syndrome: baseline results from LOGIC (Longitudinal Outcomes Study of Gastrointestinal 
Symptoms in Canada), a naturalistic study. Clin. Ther. 2006;28:1726–1735; discussion 1710-1711. 
9.  
Hulisz D. The burden of illness of irritable bowel syndrome: current challenges and hope for the future. J. Manag. 
Care Pharm. JMCP 2004;10:299–309. 
10.  
Dean BB, Aguilar D, Barghout V, et al. Impairment in work productivity and health-related quality of life in 
patients with IBS. Am. J. Manag. Care 2005;11:S17-26. 
11.  
Fischer H, Machen TE, Widdicombe JH, et al. A novel extract SB-300 from the stem bark latex of Croton lechleri 
inhibits CFTR-mediated chloride secretion in human colonic epithelial cells. J. Ethnopharmacol. 2004;93:351–357. 
12.  
Gabriel SE, Davenport SE, Steagall RJ, et al. A novel plant-derived inhibitor of cAMP-mediated fluid and chloride 
secretion. Am. J. Physiol. 1999;276:G58-63. 
13.  
DiCesare D, DuPont HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 
(Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am. J. Gastroenterol. 
2002;97:2585–2588. 
14.  
Holodniy M, Koch J, Mistal M, et al. A double blind, randomized, placebo-controlled phase II study to assess the 
safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS. Am. J. 
Gastroenterol. 1999;94:3267–3273. 
15.  
Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel 
syndrome patients. Digestion 2008;78:180–186. 
 
 

(CCI) Committee on Clinical Investigations 
Page 3 of 8 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
This is a randomized, double-blind, placebo-controlled, parallel group, study is designed to evaluate the 
efficacy and safety of orally administered crofelemer in patients with diarrhea. The study will consist of a 2-
week screening phase, a 4-week double-blind treatment phase, followed by a 4 week open-label extension for 
both groups.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1  
 
Informed Consent 
 
Baseline demographics, medical and treatment history 
 
Baseline questionnaires via RedCap 
 
Vitals (height, weight, blood pressure, temperature, heart rate) 
 
Blood draw for bile acid malabsorption (BAM); mast cell activation, i.e C4, tryptase, histamine; and 
storing of blood for future studies. BAM is a send-out lab performed by Prometheus Labs. Mast cell 
activation will be done at a research laboratory at BIDMC.  
 
Subjects meeting the inclusion and exclusion criteria will enter a screening period of up to 2 weeks 
during which time subjects will complete daily diary assessment of their bowel symptoms including 
bowel frequency and use of loperamide via RedCap.  
 
At the conclusion of the screening period, subjects will be evaluated to determine if they met study 
entry criteria related to diary compliance, loperamide rescue medication use, and stool consistency 
(i.e., Bristol Stool Score). 
 
Visit 2 (Day 0) 
 
Adverse event assessment 
 
Vitals (weight, blood pressure, temperature, heart rate) 
 
Subjects who meet all conditions for study entry will be randomized into the 4-week double-blind 
treatment phase.  Subjects will be randomized (1:1) to receive crofelemer 125 mg BID or placebo BID 
for 4 weeks. Approximately 80 patients will be randomly assigned (in a 1:1 ratio) to 125mg crofelemer 
bid vs. placebo.   
 
Subjects will continue to complete daily diary assessments of their bowel symptoms and use of 
loperamide during the 4-week treatment period via RedCap. 
 
Visit 3 (Week 4) 
 
Adverse event assessment 
Screening 
                  Treatment                      Open-Label Extension 
-2 weeks                Day 0                                             Week 4                                Week 8
Screening 
125mg crofelemer bid 
125mg crofelemer bid 
placebo bid 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
 
Vitals (weight, blood pressure, temperature, heart rate) 
 
Blood draw for mast cell activation, i.e C4, tryptase, histamine; and storing of blood for future studies 
 
Subjects will return their unused study drug to the study team for IP accountability. 
 
Subjects completing the 4 week double-blind treatment phase will be eligible to enter an open-label 
extension for 4 weeks during which all subjects will receive crofelemer 125 mg BID.  
 
Subjects will continue to complete daily diary assessments of their bowel symptoms and use of 
loperamide during the 4-week treatment period via RedCap. 
 
Visit 4 (Week 8) 
 
Adverse event assessment 
 
Vitals (weight, blood pressure, temperature, heart rate) 
 
Subjects will return their unused study drug to the study team for IP accountability 
 
Concomitant Medications 
Subjects will be allowed and advised to continue with their current diarrhea treatments as long as it was at a 
stable dose for 30 days prior to randomization.  
 
Protected Health Information 
As the study is not industry-sponsored, no protected health information will be provided to any outside 
sources, excluding Prometheus Laboratories which is BIDMC’s send out for BAM. 
 
Questionnaires/Efficacy Assessments  
Throughout the study subjects will be required to access their electronic diary every day via RedCap, 
preferably at the same time each day, to record bowel symptoms and rescue medication use. 
 
Bristol Stool Score (BSS) 
Patients will be asked to rate the BSS most representative of the past 24 hours. The patient-reported 
BSS consistency score is based on a 1 to 7 scale where 1 corresponds to a hard stool and 7 
corresponds to watery diarrhea.  
 
Frequency, Urgency and Incontinence  
Patients will be asked to record the number of bowel movements, number of incontinence episodes 
and the number of urgency episodes over the past 24 hours.  
 
Diarrhea - Adequate Relief  
Once per week patients will be asked whether they have experienced adequate relief of their 
diarrheal symptoms. The IBS-adequate relief (IBS-AR) score is a dichotomous single item used to 
assess adequate relief of IBS symptoms. 
 
Diarrhea - Quality of Life 
Patients will be asked to assess the impact of their IBS-like symptoms on their quality of life using the 
IBS-Quality of Life instrument (Patrick et al, 1998). The IBS-QoL will be completed at the study center 
at all visits.  The IBS-QoL will be completed at the beginning of the applicable study visits before all 
other evaluations, especially discussion of AEs or the patient’s medical condition. 
 
Worst Abdominal Pain Score  
Patients will be asked to rate their worst abdominal pain in the past 24 hours. The patient-reported 
worst abdominal pain will be recorded on a 0 to 10 scale, where 0 corresponds to no pain and 10 
corresponds to worst imaginable pain.  
 
Abdominal Discomfort Score  
Patients will be asked to rate their abdominal discomfort in the past 24 hours. The patient-reported 
abdominal discomfort will be recorded on a 0 to 10 scale, where 0 corresponds to no discomfort and 
10 corresponds to worst imaginable discomfort.  
 
Abdominal Bloating Score  

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
Patients will be asked to rate their abdominal bloating in the past 24 hours. The patient-reported 
abdominal bloating will be recorded on a 0 to 10 scale, where 0 corresponds to no bloating and 10 
corresponds to worst imaginable bloating.  
 
Rescue Medication for Uncontrolled Diarrhea 
Subjects will be allowed to take loperamide rescue medication for the acute treatment of uncontrolled 
diarrhea.  Loperamide at a unit dose of 2 -4 mg may be taken once approximately every 6 hours with the 
following guidelines:  
• 
No more than 4 unit doses over a continuous 24-hour time period (8 mg/day)  
• 
No more than 7 unit doses over a continuous 48 hour time period (14 mg over 2 days)  
• 
No more than 11 unit doses over a continuous 7-day time period 
 
Loperamide will not be provided to the subjects by the study team as it is standard of care for functional 
diarrhea.   
 
Blood Collection  
Any blood that is remaining after the analysis is completed will be stored frozen indefinitely at BIMDC for use in 
future studies.  The sample will remain de-identified, but be labeled with the unique subject code. Information 
related to the subject’s diagnosis, treatment, and study results will be retained and possibly used in future analysis 
and more information becomes identified regarding functional bowel disorders. PHI related to the stored samples 
will not be used in the future analysis and will be kept on BIDMC’s secure server.  Any samples that may be shared 
with collaborators will contain the subject code, but will not have any identifiable information or PHI. 
 
Placebo Tablets 
Placebo tablets are matching film-coated [white] tablets that contain standard FDA approved excipients that are 
used for Mytesi tablets and are identical in size, shape and weight. They will be provided and produced by the 
manufacturer of Mytesi (crofelemer).  
 
B. 
Statistical Considerations 
Sample Size Justification:  
This study aims to recruit 120 subjects until 80 subjects are enrolled.  This sample size is based on a 85% 
power calculation assuming placebo response is 40%. 
 
Data Analysis:  
All continuous variables will be tested for normality using the Shapiro-Wilk test. Normally distributed 
continuous data will be presented as mean ( SD) and will be compared pre-and post- interventions using 
paired Student’s t-test. Continuous data which are not normally distributed will be presented as median 
(range) and compared using Wilcoxon signed-rank test. Proportions will be expressed as percentages and 
compared using chi-square test or fisher exact test as appropriate. 
 
C. 
Subject Selection 
Inclusion Criteria 
1. Patient is a man or woman aged 18 to 65 years, inclusive, at Screening.  
2. Patient has functional diarrhea defined by the Rome IV criteria as loose (mushy) or watery stools ≥25% 
and hard or lumpy stools <25% of bowel movements  
3. Patient has had a colonoscopy performed:  
a. Within 10 years prior to Prescreening if patient is at least 50 years of age (alternatively, a 
flexible sigmoidoscopy, double contrast barium enema, or CT colonography within the past 5 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
years is acceptable [see recommendations of the American Cancer Society])  
b. Since the onset (if applicable) of any of the following alarm features for patients of any age 
(see Spiller and Thompson, 2010 – i.e. Patient has documented weight loss within the past 6 
months; Patient has nocturnal symptoms; Patient has a familial history of colon cancer; or 
patient has blood mixed with their stool (excluding any blood from hemorrhoids).  
4. Patient has an average daily stool consistency score (BSS) of ≥5.0 on days without the use of an anti-
diarrheal and at least 3 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to 
randomization.  
5. Patient has completed the daily diary on at least 6 of the 7 days during the week prior to 
randomization AND at least 11 of the 14 days during the 2 weeks prior to randomization.  
6. Patient has not used loperamide rescue medication more than 4 days during the screening period.  
7. Patient is not planning to change his/her usual diet and lifestyle during the course of the study.  
8. Patient is willing to be compliant with study procedures including completing the daily diary during the 
screening period and throughout the study.  
9. Patient must sign an informed consent document before the initiation of any study-related procedures 
indicating that he or she understands the purpose of and procedures required for the study and is 
willing to participate in the study.  
 
Exclusion Criteria  
1. Patient has a history of inflammatory or immune-mediated GI disorders including inflammatory bowel 
disease (ie, Crohn's disease, ulcerative colitis, microscopic colitis) and celiac disease.  
2. Patient has a predominant symptom of abdominal pain. 
3. Patient has a history of diverticulitis within 3 months prior to screening. Patients with a history of 
diverticulosis are candidates for the study.  
4. Patient has a history of intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal 
impaction, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal 
circulation (eg, aortoiliac disease).  
5. Patient has any of the following surgical history:  
a. Any abdominal surgery within the 3 months prior to screening; or  
b. Patient has a history of major gastric, hepatic, pancreatic, or intestinal surgery 
(appendectomy, cholecystectomy, hemorrhoidectomy, or polypectomy greater than 3 months 
are allowed). For the purposes of this study, laparoscopic surgeries without complication are 
considered minor and non-exclusionary, provided the condition for which the surgery was 
performed was not exclusionary.  
6. Patient has an unstable renal, hepatic, metabolic, or hematologic condition.  
7. Patient has a history of human immunodeficiency virus infection.  
8. Patient has a history of DSM-IV-TR-defined substance dependency, excluding nicotine and caffeine, 
within 2 years prior to Prescreening.  
9. Patient has a history of alcohol abuse as defined by DSM-IV-TR, binge drinking as defined by the 
National Institutes on Alcohol Abuse and Alcoholism, or any medical treatment for alcohol-related co-
morbidities, within 5 years prior to Prescreening. Recovered alcoholics who have not consumed 
alcohol over the 5 years prior to Prescreening are candidates for the study.  
10. Patient has current (within 14 days of randomization) or expected use of any narcotic or opioid 
containing agents, tramadol 
11. Patient is unable to swallow solid, oral dosage forms whole with the aid of liquid (patients may not 
chew, divide, dissolve, or crush the study drug).  
12. Patient has received an investigational drug or used an investigational medical device within 30 days 
prior to randomization. 
13. Patient has a known pregnancy or is breastfeeding. 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
 
 
  
B4. 
POSSIBLE BENEFITS 
Subjects may experience improvement in their functional diarrhea symptoms. 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
Safety 
Possible risks of crofelemer include upper respiratory tract infection, bronchitis, cough, flatulence, increased 
bilirubin, nausea, back pain, arthralgia, UTI, nasopharyngitis, musculoskeletal pain, hemorrhoids, giardiasis, 
anxiety, increased alanine aminotransferase, abdominal distention. 
 
There is a possible risk of loss of confidentiality, however every effort will be made to ensure patient 
confidentiality which includes but is not limited to only discussing medical information in a private clinical 
setting and collecting information necessary to accomplish the research purpose.  Physical data will be kept in 
a locked room that only the research team have access to. Electronic data will be kept on the secure server 
with access granted only to the individuals on the research staff. 
 
The risk/benefit ratio of the study is favorable for the patient due to the limited options for treating functional 
diarrhea. 
 
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
Recruitment 
Patients will be identified in the following ways:  
 
Clinical practice of the Center for Functional Bowel Disorders and GI Motility at BIDMC 
 
GI referrals from BIDMC  
 
Review of medical records, data repositories, and appointment logs 
 
Clinical Query 2 
 
Advertisements  
 
Potential study participants (obtained from the means listed above) will be contacted by phone and a brief phone 
screening will be initiated to assess subject’s eligibility before scheduling the office visit. 
 
Potential study participants identified through Clinical Query 2 or appointment logs will be mailed a letter or 
postcard with opt-in information.  
 
Consent 
During the screening visit the Investigator will fully explain the purpose of the study to the patient and all 
questions and concerns regarding the study will be addressed as well (informed consent process) in a private 
area in the Division of Gastroenterology.   
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date: 1/25/2022 
B7. 
STUDY LOCATION 
Privacy  
Every effort will be made to ensure the patient’s privacy which includes but is not limited to only discussing 
medical information in a private clinical setting and collecting information necessary to accomplish the 
research purpose. 
 
Physical Setting 
Study visits will be conducted in the Division of Gastroenterology 
 
 
B8. 
DATA SECURITY 
Physical data will be kept in a locked room that only the research team has access to. Electronic data will be 
kept on BIDMC server. 
 
B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No  
 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 
 
 
B10 
Dissemination of Research Results 
Subjects will be thanked for their participation following their participation in the study and informed of the 
possibility of future publications.