Safety and Efficacy of Crofelemer in 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).

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.

Eligibility Criteria:
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.