The Role of Secondary Bile Acids in Intestinal Inflammation

The cause of Inflammatory bowel disease (IBD) is unknown, but intestinal bacteria-involved in the production of molecules that impact health-are widely accepted to play a key role. A significant proportion of IBD patients with pouches (surgically created rectums after the diseased colon is removed) continue to have inflammation similar to their previous disease.

Only a few microbes are known to have the capability to modify primary bile acids (PBAs) made by the liver to secondary bile acids (SBAs). SBAs are some of the most common metabolites in the colon and play key roles in several diseases.

In this study the investigators will investigate if ursodeoxycholic acid (UDCA) may reduce inflammatory markers and improve quality of life (as assessed by validate survey) in those subjects with active antibiotic refractory or antibiotic dependent pouchitis.

Study Overview

• Status: Recruiting
• Conditions: Ulcerative Colitis; Pouchitis
• Intervention / Treatment: Drug: ursodiol (ursodeoxycholic acid, UDCA)

Detailed Description

The cause of Inflammatory bowel disease (IBD) is unknown, but intestinal bacteria-involved in the production of molecules that impact health-are widely accepted to play a key role. A significant proportion of IBD patients with pouches (surgically created rectums after the diseased colon is removed) continue to have inflammation similar to their previous disease.

Only a few microbes are known to have the capability to modify primary bile acids (PBAs) made by the liver to secondary bile acids (SBAs). SBAs are some of the most common metabolites in the colon and play key roles in several diseases.

In previous study, the investigators examined bile acid levels in stool from pouches (surgically-created "rectums" made of small bowel) in colectomy-treated patients with ulcerative colitis (UC) versus colectomy-treated controls without inflammatory disease. This comparison revealed that certain SBAs are significantly decreased in stool from UC compared to control pouches.

In this study the investigators will investigate if ursodeoxycholic acid (UDCA) may reduce inflammatory markers and improve quality of life (as assessed by validate survey) in UC pouch patients (colectomy-treated patients with ulcerative colitis) with active antibiotic refractory or antibiotic dependent pouchitis.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Sidhartha Sinha, MD; Phone Number: 6507365555; Email: sidsinha@stanford.edu
• Study Contact Backup: Name: Aida Habtezion, MD; Phone Number: 6507365555; Email: aida.habtezion@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University
      • Contact: Sidharta Sinha, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent;
2. Male or female subjects, ≥18 years of age who have undergone an ileal pouch-anal anastomosis (IPAA) for UC.

3. History of pouchitis

   Documented evidence of active pouchitis, based on endoscopy, symptoms and histopathology, as follows:

4. Endoscopic score >=2 on the endoscopic component of a modified Mayo endoscopic score (where friability is scored as >2) Note: the area within 1 cm of the pouch staple, or pouch suture line, is not considered evaluable

5. Symptomatic disease (stool frequency):

   Subjects must demonstrate increased stool frequency compared to what is considered "normal" after their IPAA operation ("baseline"). Stool frequency must be an absolute value of > 6 stools per day, and > 3 stools per day above the post-IPAA "baseline". Note: The measurement of stool frequency will be a 7-day average rounded to the nearest integer. The most recent 7 days of data will be used to calculate the average.

6. Histology: evidence of disease.
7. Modified PDAI (mPDAI) score >= 5. The mPDAI consists of the symptom (range: 0-6) and endoscopy (range: 0-6) subscores.
8. Must have chronic antibiotic refractory or antibiotic dependent pouchitis.

Exclusion Criteria:

1. Lack of effective contraception Women of childbearing potential may not participate unless they are surgically sterile or are using adequate contraception.

   The following contraceptive methods are acceptable: hormonal (eg oral, injection, transdermal patch, implant, cervical ring), barrier (eg condom or diaphragm with spermicidal agent), intrauterine system or intrauterine device. If hormonal contraceptives are used by female subjects, they must be established for 6 weeks before the first administration of test product. Male sterilization is considered an acceptable form of contraception if the appropriate post-vasectomy documentation (absence of sperm) is provided in the subject's medical notes. Sexual abstinence is considered acceptable if this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (eg calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

   Male subjects with female partners of child-bearing potential and female subjects who are neither surgically sterilized nor post-menopausal (defined as no menses for one year or a follicle-stimulating hormone value > 40 IU/L) will be required to use effective contraception throughout the study and for 30 days after.

2. Women who are pregnant or breastfeeding;

3. History of allergy or adverse event to UDCA;

   Stable use of concomitant medications for pouchitis is generally permitted, doses of concomitant medication, where taken, should be optimised in accordance with local/national practice guidelines, and dose levels and types of baseline medications for pouchitis will be documented and any changes during the study will be recorded. Changes in use of medications for pouchitis and high doses of oral steroids are not permitted. It is particularly important to maintain stable medication through to measurement of the primary end-point at Week 10. Criteria which would lead to exclusion of subjects from the study are described below:

4. Changes in dose to strong analgesia, such as opioid containing compounds within 4 weeks of the Screening Visit.
5. History of regular nonsteroidal anti-inflammatory drugs (NSAID) use.
6. Oral 5-aminosalicylate (5-ASA) compounds; exclude subjects who have discontinued or changed doses of oral 5-ASA within 4 weeks of the Screening Visit.
7. Oral budesonide > 6.0 mg/day is not permitted; exclude subjects who have received budesonide for < 6 weeks, or who have changed doses of budesonide within 4 weeks of the Screening Visit.
8. Oral steroids other than budesonide: exclude subjects who exceed a daily dose of 15 mg prednisolone or equivalent, who have received oral steroids for < 6 weeks, or who have changed dose within 4 weeks of the Screening Visit.
9. Use of rectal compounds is not permitted; these agents must be discontinued at the Screening Visit.
10. Immunosuppressant therapy (azathioprine, 6- mercaptopurine, methotrexate, cyclosporin); exclude subjects who have received treatment for < 12 weeks, or who have changed doses within 8 weeks of the Screening Visit.
11. Biological agents (Anti-tumour necrosis factor (anti - TNF) therapy, vedolizumab and / or ustekinumab); exclude subjects who have received biological agents for <6 months prior to the screening visit, or who changed doses of the biological agent within 6 months prior to the screening visit.
12. Previous use of UDCA is permitted: treatment course must have completed at least 12 weeks prior to the Screening Visit.

13. All other agents targeted to pouchitis, including experimental agents, must have been discontinued at least 8 weeks prior to the Screening Visit, or for a period equivalent to 5 half-lives (t1⁄2) of the agent (whichever is longer) It is acceptable to recruit subjects who remain on optimised, stable doses of oral 5-ASA, oral steroids (below the doses stipulated above) and immunosuppressants.

    It is acceptable to recruit subjects who terminated treatment with oral 5-ASA or oral steroids 4 weeks before the Screening Visit, or immunosuppressants 8 weeks before the Screening Visit.

    Note: Analgesic use should remain stable throughout the trial where possible. Paracetamol is the analgesic of choice.

    Note: VSL#3 probiotic treatment (and other probiotic treatments) will be permitted as long as maintained stable for 4 weeks prior to the Screening Visit, and maintained at a stable dose throughout the trial

    Also excluded are subjects with:

14. Anastomotic stricture
15. Unable to undertake endoscopic evaluation
16. Faecal incontinence due to anal sphincter dysfunction
17. Infections to cytomegalovirus or Clostridium Difficile
18. Faecal transplantation within 12 weeks of screening
19. Intestinal malabsorption
20. Pancreatic maldigestion
21. Suspected irritable pouch syndrome
22. Cuffitis (inflammation of the anal mucosa). Subjects with active antibiotic refractory pouchitis as the predominant condition, but who also have cuffitis, may be enrolled
23. Crohn's disease of the pouch; defined as either: a) complex perianal or pouch fistula and/or b) extensive pre-pouch ileitis with deep ulceration
24. Subjects with a history of neoplastic disease except for basal cell carcinoma or nonmetastatic squamous cell carcinoma of the skin
25. Subjects who are receiving or have received nasogastric/nasoenteric bottle feeding, an elemental diet, or total parenteral nutrition within the 2 weeks prior to Day 1
26. Subjects with a history of clinically significant and/or persistent haematologic, renal, hepatic, metabolic, psychiatric, central nervous system, pulmonary or cardiovascular disease; which in the investigator's opinion, would exclude entry into the study
27. Subjects with any laboratory tests considered clinically significant at screening
28. Subjects who may be unavailable for the duration of the trial, likely to be noncompliant with the protocol, or who are felt to be unsuitable by the Investigator for any other reason including, for example, inability to retain an enema formulation
29. Pelvic sepsis should be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ursodiol (ursodeoxycholic acid, UDCA); ursodiol (ursodeoxycholic acid, UDCA) 300 mg two times daily for 10 weeks to treat pouchitis in ulcerative colitis patients with antibiotic refractory or antibiotic dependent pouchitis	Drug: ursodiol (ursodeoxycholic acid, UDCA); ursodiol (ursodeoxycholic acid, UDCA) 300 mg two times daily for 10 weeks for UC pouchitis patients; Other Names: NDC 0591-3159-01 Ursodiol Capsules, USP 300 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects who achieve clinical response at week 10.	Clinical response is defined as reduction of mPDAI score by >=2 points.	change from screening to end of treatment (10 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects who achieve remission at week 10.	Remission is defined as mPDAI < 5 and reduction of mPDAI score by >=2 points.	change from screening at end of treatment (10 weeks)
Proportion of subjects who achieve endoscopic response at week 10.	Endoscopic response is defined as reduction of modified MAYO (mMAYO)score by >=1 point.	change from screening at end of treatment (10 weeks)
Proportion of subjects who achieve endoscopic remission at week 10.	Endoscopic remission is defined as mMAYO score <=1.	change from screening at end of treatment (10 weeks)
Proportion of subjects with a stool frequency represented by a Mayo subscore of <1 at Week 10.	Proportion of subjects with a stool frequency represented by a Mayo subscore of <1 at Week 10.	change from screening at the end of treatment (10 weeks)
Mean change in Cleveland Global Quality of Life (CGQL)	Cleveland Global Quality of Life questionnaire (including current quality of life [0 being the worst and 10 being the best] ; current quality of health [0 being the worst and 10 being the best]; current energy level [0 being the worst and 10 being the best])	change from screening, at week 6 and at end of treatment (10 weeks)
Mean change in erythrocyte sedimentation rate (ESR)	Mean change from baseline in erythrocyte sedimentation rate (ESR) at Week 6 and Week 10.	change from screening, at week 6 and at end of treatment (10 weeks)
Mean change in C-reactive protein (CRP)	Mean change from baseline in C-reactive protein (CRP) at Week 10.	change from screening, at week 6 and at end of treatment (10 weeks)
Mean change in fecal calprotectin	Mean change from baseline in fecal calprotectin at Week 10	change from screening, at week 6 and at end of treatment (10 weeks)

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Sidhartha Sinha, MD, Stanford University

Publications and helpful links

General Publications

• Weingarden AR, Chen C, Zhang N, Graiziger CT, Dosa PI, Steer CJ, Shaughnessy MK, Johnson JR, Sadowsky MJ, Khoruts A. Ursodeoxycholic Acid Inhibits Clostridium difficile Spore Germination and Vegetative Growth, and Prevents the Recurrence of Ileal Pouchitis Associated With the Infection. J Clin Gastroenterol. 2016 Sep;50(8):624-30. doi: 10.1097/MCG.0000000000000427.

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2019
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2050

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: October 26, 2018
• First Posted (Actual): October 30, 2018

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; Pouchitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Enteritis; Ileitis; Ileal Diseases; Inflammation; Colitis; Colitis, Ulcerative; Pouchitis; Gastrointestinal Agents; Cholagogues and Choleretics; Ursodeoxycholic Acid
• Other Study ID Numbers: IRB-47198

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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