The Role of Secondary Bile Acids in Intestinal Inflammation


Trial ID: NCT03724175


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.

Official Title

The Role of Secondary Bile Acids in Intestinal Inflammation

Stanford Investigator(s)

Sidhartha Sinha
Sidhartha Sinha

Assistant Professor of Medicine (Gastroenterology and Hepatology)


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


drug: ursodiol (ursodeoxycholic acid, UDCA)


Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Sidharta Sinha, MD