Safety and Efficacy of Crofelemer in Adult Patients With Short Bowel Syndrome and Intestinal Failure (SBS-IF) Without Colon-in-continuity (CIC) (CRO-SBS-IF)

A Phase 2, Placebo-Controlled, Randomized, Double-Blind Study of 2 Doses of Crofelemer for the Treatment of Adult Patients With Short Bowel Syndrome and Intestinal Failure (SBS-IF) Without Colon-in-continuity (CIC)

A 24-week, randomized, placebo-controlled, double-blind study to evaluate the efficacy, safety and tolerability of crofelemer in patients with Short Bowel Syndrome and Intestinal Failure (SBS-IF) without colon-in-continuity (CIC) requiring parenteral support (PS).

Blinded study drug will be administered orally (or enterally) three times daily (TID) as a novel crofelemer formulation, Crofelemer Powder for Oral Solution, or a matching placebo powder formulation for oral solution.

Patients will be randomized in a 1:1:1 ratio to crofelemer 3 mg/kg/dose TID, crofelemer 10 mg/kg/dose TID or placebo and randomization will be stratified by baseline PS volume (≤4 or >4 L/week).

Study Overview

• Status: Recruiting
• Conditions: Malabsorption Syndromes; Functional Gastrointestinal Disorders; Short Bowel Syndrome; Post-Op Complication; Short Gut Syndrome
• Intervention / Treatment: Drug: Crofelemer Powder for Oral Solution; Drug: Matched Placebo Powder for Oral Solution

Detailed Description

This is a 24-week, randomized, placebo-controlled, double-blind study to evaluate the efficacy, safety and tolerability of crofelemer in patients with Short Bowel Syndrome and Intestinal Failure (SBS-IF) without colon-in-continuity (CIC) requiring parenteral support (PS).

After an up to 4-week screening period and a PS stabilization period that will last from 2 to 12 weeks, eligible patients who have meet the stabilization requirements will be randomized 1:1:1 to the following treatment groups and entered into the 24-week double-blind treatment period:

• Crofelemer 3 mg/kg/dose TID, morning, midday and evening;
• Crofelemer 10 mg/kg/dose TID, morning, midday and evening;
• Matched placebo TID, morning, midday and evening.

Visits during the 24-week treatment period will be performed at baseline (Day 0) and after 1, 2, 4, 8, 12, 16, 20 and 24 weeks of treatments.

At the end of the 24-week treatment period, patients will be followed up for 4 weeks for safety.

For the primary and secondary objectives, changes between the two crofelemer and placebo arms will be assessed over the 24-week treatment period versus baseline.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sara Papetti, MA; Phone Number: +39 3397978779; Email: spapetti@napo.eu
• Study Contact Backup: Name: Sabriye Duran; Phone Number: +49 089 89558070; Email: sabriye.duran@alirahealth.com

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Not yet recruiting
    • Universitäatsklinik RWTH
    • Principal Investigator: Martin von Websky, MD
  • Berlin, Germany, 10117
    • Not yet recruiting
    • Charite Universitatsmedizin
    • Principal Investigator: Elisabeth Blüthner, MD
  • Essen, Germany, 45147
    • Not yet recruiting
    • Universitätsklinikum
    • Principal Investigator: Christoph Schramm, MD
  • Hamburg, Germany, 20099
    • Not yet recruiting
    • Asklepios Klinik St. Georg
    • Principal Investigator: Ulrich-Frank Pape, MD
  • Rostock, Germany, 18057
    • Not yet recruiting
    • Universitätsmedizin
    • Principal Investigator: Georg Lamprecht, MD
• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi
    • Principal Investigator: Anna Simona Sasdelli, MD
  • Napoli, Italy, 80131
    • Recruiting
    • Azienda Ospedaliera Universitaria Federico II
    • Principal Investigator: Fabrizio Pasanisi, MD
  • Padova, Italy, 35128
    • Not yet recruiting
    • Ospedale Università di Padova
    • Principal Investigator: Edoardo Savarino, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Patients will be enrolled in the study if they meet all the following criteria:

1. Patients must understand and provide written informed consent before they can participate in the study. They must understand the study procedures and be willing to complete the required assessments;
2. Male and female patients aged ≥ 18 years;
3. SBS patients with intestinal failure and without colon-in-continuity who are not eligible or not willing to receive an approved marketed GLP-2;
4. Patients with history of SBS resulting in intestinal failure caused by a major intestinal resection (e.g., injury, cancer*, Crohn's disease, vascular disease, volvulus) without colon-in-continuity (patients with duodenostomy, Jejunostomy or Ileostomy). Intestinal failure will be defined according to the recommendations of the European Society for Clinical Nutrition and Metabolism (ESPEN), i.e., a reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous (IV) supplementation is required to maintain health and/or growth. *Patients with history of cancer, should be in remission for the last 6 months and with not ongoing anticancer therapy (long-term hormonal therapy is allowed).
5. Minimum remaining length of 100 cm of small bowel;
6. At least 6 months elapsed since last surgical bowel resection;
7. No restorative surgery planned during the entire study period;
8. Patients with at least 4 continuous months of PS dependency (parenteral nutrition and/or intravenous fluids);
9. Chronic non-infectious diarrhoea defined as passage of at least 1 loose watery stool per day for more than 4 consecutive weeks.
10. Patients receiving stable parenteral support (fluids, electrolytes and/or nutrients) at least three days per week and a minimum of 2 liters of PS per week, to meet caloric, fluid or electrolytes needs;
11. Patients with Crohn's disease will have to be in clinical remission for ≥ 12 weeks;
12. Patients must be able to ingest solid or semi-solid foods and drink fluids;
13. If taken at screening, use of antimotility and antidiarrheal agents (loperamide, diphenoxylate, codeine and other opiates), H2-receptor antagonists, proton pump inhibitors, bile sequestering agents, oral glutamine, diuretics and oral rehydration solutions is required to be at stable average weekly doses for at least 4 weeks prior to screening evaluations;
14. If female and of child-bearing potential, the patient must use an "acceptable effective contraceptive measure" for the entire study duration and for 4 weeks after the last dose. Acceptable birth control methods that result in a failure rate of more than 1% per year include: progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action male or female condom with or without spermicide cap, diaphragm or sponge with spermicide (A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered acceptable). Male patients must agree to use an acceptable form of birth control and to not donate sperm during the study and for 4 weeks after the last dose.
15. If female and child-bearing potential, the patient must have a negative urine pregnancy test prior the first administration of the investigational product;
16. Satisfactory general health status as determined by the investigator based on current medical status, medical history and physical examination.

Exclusion criteria

Patients cannot be enrolled in the study if they meet any of the following criteria:

1. Body mass index (BMI) <17.5 or >30 kg/m2;
2. Presence of clinically significant intestinal adhesions and/or chronic abdominal pain that can interfere with the conduct of the study;
3. Patients with radiological (Radiography and/or CT) signs of bowel dilatation or pseudo-obstruction;
4. Active Crohn's disease as evaluated by standard procedures employed by the investigator;
5. Inflammatory bowel disease (IBD) that required immunosuppressant therapy that has been introduced or changed within last 3 months or treatment with biologics within the last 6 months;
6. Intestinal or other major surgery scheduled within the time frame of the study;
7. Visible blood in the stool within the last 12 weeks;
8. Ongoing radiation enteritis or the presence of damaged enteral tissue due to radiation enteritis, scleroderma, celiac disease, refractory or tropical sprue;
9. Compromised immune system (e.g., acquired immune deficiency syndrome [AIDS], severe combined immunodeficiency);
10. Inadequate hepatic function: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or total bilirubin and/or alkaline phosphatases > 2 times the patient's average relative values in the last 3 months;
11. Inadequate renal function: serum creatinine or blood urea nitrogen > 2 times the Upper Normal Limit (UNL);
12. Urine sodium <20 mmol/day;
13. More than four SBS-related hospital admissions (unless one or more admissions were to rule out line sepsis) within the past 12 months or hospital admission within the last 4 weeks;
14. Concurrent or past use of infliximab, growth hormone or growth factors such as native glucagon-like peptide-2 (GLP-2) or other biological therapy within the last 12 weeks;
15. Use of systemic corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, octreotide, intravenous glutamine within the last 4 weeks;
16. Use of antibiotics within the last week or active infection;
17. History of alcohol abuse (Drinking more than 12 g/day of alcohol for women and 24 g/day of alcohol for men) or drug abuse within the last year;
18. Pregnant or lactating women;
19. History of psychiatric illnesses which lead to consider the patient as incapacitated and prevent him/her to provide informed consent;
20. History of any other uncontrolled chronic or acute concomitant disease which, in the Investigator's opinion, would contraindicate study participation or confound interpretation of the results;
21. Patient not capable of understanding or not willing to adhere to the study visit schedules and other protocol requirements;
22. Participation in any other interventional clinical study within five times the half-life of the investigational medicinal product / relevant metabolites (of the previous clinical study) or 4 weeks (whichever is longer) prior to screening;
23. Known hypersensitivity/allergy to any component of the IP.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Crofelemer 3 mg/kg/dose three times daily (TID); Participants randomized to the Crofelemer 3 mg/kg/dose arm will receive Crofelemer 3 mg/kg/dose by oral route three times per day (TID) morning, midday, and evening for 24 weeks.	Drug: Crofelemer Powder for Oral Solution; Crofelemer Powder for Oral Solution
Experimental: Crofelemer 10 mg/kg/dose three times daily (TID); Participants randomized to the Crofelemer 10 mg/kg/dose arm will receive Crofelemer 10 mg/kg/dose by oral route three times per day (TID) morning, midday, and evening for 24 weeks.	Drug: Crofelemer Powder for Oral Solution; Crofelemer Powder for Oral Solution
Placebo Comparator: Matched Placebo three times per day (TID); Participants randomized to the matched placebo arm will receive matched placebo by oral route three times per day (TID) morning, midday, and evening for 24 weeks.	Drug: Matched Placebo Powder for Oral Solution; Matched Placebo Powder for Oral Solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Frequency of Treatment-Emergent-Adverse Events	24 weeks
Safety and Tolerability	Frequency of IP interruption and/or discontinuation considered related to the study drug	24 weeks
Preliminary Efficacy	Change in weekly parenteral support (PS: parenteral nutrition (PN) and/or intravenous (IV) fluid volume) from baseline, by recording PS volume in the patient daily diary	24 weeks
Preliminary Efficacy	Change in weekly stool volume from baseline, by measuring and recording daily stool volume in the patient daily diary	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in parenteral support volume	Change from baseline in weekly PS volume at different study timepoints, as recorded in the patient daily diary	24 weeks
Change in parenteral support calories intake	Change in total number of calories administered, as detailed on the PS prescription written by the study doctor	24 weeks
Change in parenteral support electrolytes intake	Change in total number of electrolytes administered, as detailed on the PS prescription written by the study doctor	24 weeks
Change in weekly oral fluid volume intake	Change from baseline in weekly oral fluid volume intake, as recorded in the patient daily diary	24 weeks
Proportion of patients with change in number of days/week of PS	Proportion of patients with at least one day reduction in weekly PS	24 weeks
Number of days/week of PS	Change in number of days/week of PS requirements from baseline	24 weeks
Change in volume of loose/watery stool	Change from baseline in weekly loose/watery stools as measured by the volume in the ostomy bag or other measuring devices and recorded in the patient daily diary	24 weeks
Changes from baseline in stool consistency	Recording stool consistency of each stool using the 7-point Bristol Stool Scale in the patient daily diary	24 weeks
Changes in laboratory parameters	Changes from baseline of individual lab values within a chemistry and metabolic panel analysis	24 weeks
Changes in physical examination	Changes from baseline in physical examination findings (such as head, ears, eyes, nose, mouth, skin, heart, lung, lymph nodes, gastrointestinal, skeletal, and neurological signs and symptoms)	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Quality of life (QoL)	Measuring Quality of Life through administration of SBS-QoL questionnaire (17 questions to be responded with a visual analog scale) together with additional daily diary questions	24 weeks

Collaborators and Investigators

• Sponsor: Napo Therapeutics, S.p.A.

Publications and helpful links

General Publications

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• Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, Swinburn P, Busschbach J. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res. 2013 Sep;22(7):1717-27. doi: 10.1007/s11136-012-0322-4. Epub 2012 Nov 25.
• Jeppesen PB. Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. JPEN J Parenter Enteral Nutr. 2014 May;38(1 Suppl):8S-13S. doi: 10.1177/0148607114520994. Epub 2014 Jan 31.
• Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010 Jan;77(1):69-78. doi: 10.1124/mol.109.061051. Epub 2009 Oct 6.
• Jeppesen PB, Gilroy R, Pertkiewicz M, Allard JP, Messing B, O'Keefe SJ. Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut. 2011 Jul;60(7):902-14. doi: 10.1136/gut.2010.218271. Epub 2011 Feb 11.
• Holodniy M, Koch J, Mistal M, Schmidt JM, Khandwala A, Pennington JE, Porter SB. 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 Nov;94(11):3267-73. doi: 10.1111/j.1572-0241.1999.01535.x.
• Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion. 2008;78(4):180-6. doi: 10.1159/000185719. Epub 2008 Dec 18.
• Nee J, Salley K, Ludwig AG, Sommers T, Ballou S, Takazawa E, Duehren S, Singh P, Iturrino J, Katon J, Lee HN, Rangan V, Lembo AJ. Randomized Clinical Trial: Crofelemer Treatment in Women With Diarrhea-Predominant Irritable Bowel Syndrome. Clin Transl Gastroenterol. 2019 Dec;10(12):e00110. doi: 10.14309/ctg.0000000000000110.
• Jeppesen PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O'keefe SJ, Forbes A, Heinze H, Joelsson B. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012 Dec;143(6):1473-1481.e3. doi: 10.1053/j.gastro.2012.09.007. Epub 2012 Sep 11.
• Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F; ESPEN. ESPEN Guidelines on Parenteral Nutrition: surgery. Clin Nutr. 2009 Aug;28(4):378-86. doi: 10.1016/j.clnu.2009.04.002. Epub 2009 May 21.
• Vanderhoof JA, Langnas AN. Short-bowel syndrome in children and adults. Gastroenterology. 1997 Nov;113(5):1767-78. doi: 10.1053/gast.1997.v113.pm9352883.
• Guillen B, Atherton NS. Short Bowel Syndrome. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK536935/
• Guy MK, Teixeira A, Lalani AS et al. Effects of oral on neratinib-induced diarrhea in beagle dogs. Cancer Res 2020;80(16) Supplement (Abstract#580).
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• Jeppesen PB. Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome. Therap Adv Gastroenterol. 2012 May;5(3):159-71. doi: 10.1177/1756283X11436318.
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• Capriati T, Mosca A, Alterio T, Spagnuolo MI, Gandullia P, Lezo A, Lionetti P, D'Antiga L, Fusaro F, Diamanti A. To Wean or Not to Wean: The Role of Autologous Reconstructive Surgery in the Natural History of Pediatric Short Bowel Syndrome on Behalf of Italian Society for Gastroenterology, Hepatology and Nutrition (SIGENP). Nutrients. 2020 Jul 18;12(7):2136. doi: 10.3390/nu12072136.
• Camilleri M. Intestinal secretory mechanisms in irritable bowel syndrome-diarrhea. Clin Gastroenterol Hepatol. 2015 Jun;13(6):1051-7; quiz e61-2. doi: 10.1016/j.cgh.2014.07.020. Epub 2014 Jul 17.
• Cagir B. Short Bowel Syndrome. Clinical Presentation. emedicine Medscape 2017.
• Berghofer P, Fragkos KC, Baxter JP, Forbes A, Joly F, Heinze H, Loth S, Pertkiewicz M, Messing B, Jeppesen PB. Development and validation of the disease-specific Short Bowel Syndrome-Quality of Life (SBS-QoL) scale. Clin Nutr. 2013 Oct;32(5):789-96. doi: 10.1016/j.clnu.2012.12.001. Epub 2012 Dec 12.
• Pironi L, Arends J, Bozzetti F, Cuerda C, Gillanders L, Jeppesen PB, Joly F, Kelly D, Lal S, Staun M, Szczepanek K, Van Gossum A, Wanten G, Schneider SM; Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group of ESPEN. ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr. 2016 Apr;35(2):247-307. doi: 10.1016/j.clnu.2016.01.020. Epub 2016 Feb 8.

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2025
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: March 10, 2025
• First Submitted That Met QC Criteria: March 25, 2025
• First Posted (Actual): April 1, 2025

Study Record Updates

• Last Update Posted (Actual): June 12, 2025
• Last Update Submitted That Met QC Criteria: June 9, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Short Bowel Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Intestinal Diseases; Disease; Intestinal Failure; Gastrointestinal Diseases; Digestive System Diseases; Syndrome; Postoperative Complications; Short Bowel Syndrome; Malabsorption Syndromes; Pharmaceutical Solutions
• Other Study ID Numbers: NP303-501; 2024-511994-31-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No