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

Official title

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)

Overview

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.

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.

Interventions

• Drug Crofelemer Powder for Oral Solution
  Crofelemer Powder for Oral Solution
• Drug Matched Placebo Powder for Oral Solution
  Matched Placebo Powder for Oral Solution

Primary outcome measures

• Safety and Tolerability [Time frame: 24 weeks]
• Safety and Tolerability [Time frame: 24 weeks]
• Preliminary Efficacy [Time frame: 24 weeks]
• Preliminary Efficacy [Time frame: 24 weeks]

Secondary outcome measures (10)

• Change in parenteral support volume [Time frame: 24 weeks]
• Change in parenteral support calories intake [Time frame: 24 weeks]
• Change in parenteral support electrolytes intake [Time frame: 24 weeks]
• Change in weekly oral fluid volume intake [Time frame: 24 weeks]
• Number of days/week of PS [Time frame: 24 weeks]
• Proportion of patients with change in number of days/week of PS [Time frame: 24 weeks]
• Change in volume of loose/watery stool [Time frame: 24 weeks]
• Changes from baseline in stool consistency [Time frame: 24 weeks]
• Changes in laboratory parameters [Time frame: 24 weeks]
• Changes in physical examination [Time frame: 24 weeks]

Eligibility criteria

Inclusion criteria

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

• 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;
• Male and female patients aged ≥ 18 years;
• SBS patients with intestinal failure and without colon-in-continuity who are not eligible or not willing to receive an approved marketed GLP-2;
• 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).
• Minimum remaining length of 60 cm of small bowel;
• At least 6 months elapsed since last surgical bowel resection;
• No restorative surgery planned during the entire study period;
• Patients with at least 4 continuous months of PS dependency (parenteral nutrition with or without intravenous fluids);
• Chronic non-infectious diarrhoea defined as passage of at least 1 loose watery stool per day for more than 4 consecutive weeks.
• Patients receiving parenteral support (fluids, electrolytes and/or nutrients) for at least three days per week and a minimum of 6 liters of PS per week, to meet caloric, fluid or electrolytes needs;
• Patients with Crohn's disease will have to be in clinical remission for ≥ 12 weeks;
• Patients must be able to ingest solid or semi-solid foods and drink fluids;
• 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;
• 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.
• If female and child-bearing potential, the patient must have a negative urine pregnancy test prior the first administration of the investigational product;
• 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:

• Diagnosis of celiac disease or active or refractory tropical sprue;
• Presence of clinically significant intestinal adhesions and/or chronic abdominal pain that can interfere with the conduct of the study;
• Patients with current radiological (Radiography and/or CT) evidence of bowel dilatation or pseudo-obstruction;
• Active Crohn's disease as evaluated by standard procedures employed by the investigator;
• 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;
• Intestinal or other major surgery scheduled within the time frame of the study;
• Visible blood in the stool within the last 12 weeks;
• Clinical evidence of active radiation enteritis or scleroderma, contributing to the patient's stool volume;
• Compromised immune system (e.g., acquired immune deficiency syndrome \[AIDS\], severe combined immunodeficiency);
• 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;
• Inadequate renal function: serum creatinine or blood urea nitrogen > 2 times the Upper Normal Limit (UNL);
• Urine sodium <20 mmol/day;
• 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;
• 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;
• Use of systemic corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, octreotide, intravenous glutamine within the last 4 weeks;
• Use of antibiotics within the last week or active infection;
• 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;
• Pregnant or lactating women;
• History of psychiatric illnesses which lead to consider the patient as incapacitated and prevent him/her to provide informed consent;
• 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;
• Patient not capable of understanding or not willing to adhere to the study visit schedules and other protocol requirements;
• 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;
• Known hypersensitivity/allergy to ANY component of the IP.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Germany · 5 centers

• Universitäatsklinik RWTH — Aachen
• Charité Universitätsmedizin — Berlin
• Universitätsklinikum — Essen
• Asklepios Klinik St. Georg — Hamburg
• Universitätsmedizin — Rostock

Italy · 3 centers

• Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi — Bologna
• Azienda Ospedaliera Universitaria Federico II — Naples
• Ospedale Università di Padova — Padova

Publications

• Guillen B, Atherton NS. Short Bowel Syndrome. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK536935/ PMID 30725620
• 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).
• Wales PW, Christison-Lagay ER. Short bowel syndrome: epidemiology and etiology. Semin Pediatr Surg. 2010 Feb;19(1):3-9. doi: 10.1053/j.sempedsurg.2009.11.001. PMID 20123268
• 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. PMID 9352883
• 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. PMID 19808995
• Thompson JS. Short Bowel Syndrome and Malabsorption - Causes and Prevention. Viszeralmedizin. 2014 Jun;30(3):174-8. doi: 10.1159/000363276. PMID 26288591
• Terrin G, Scipione A, De Curtis M. Update in pathogenesis and prospective in treatment of necrotizing enterocolitis. Biomed Res Int. 2014;2014:543765. doi: 10.1155/2014/543765. Epub 2014 Jul 17. PMID 25147804
• Tappenden KA. Pathophysiology of short bowel syndrome: considerations of resected and residual anatomy. JPEN J Parenter Enteral Nutr. 2014 May;38(1 Suppl):14S-22S. doi: 10.1177/0148607113520005. Epub 2014 Feb 5. PMID 24500909

Identifiers

NCT: NCT06904872 · NP303-501 · 2024-511994-31-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗