Ursodeoxycholic Acid for Pouchitis

Overseen By Sidhartha Sinha, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Stanford University

Must not be taking: NSAIDs, Immunosuppressants, Biologicals, others

Disqualifiers: Pregnancy, Allergy to UDCA, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 10 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial allows participants to stay on stable doses of certain medications for pouchitis, like oral 5-ASA, oral steroids (below specific doses), and immunosuppressants. However, changes in these medications close to the trial start are not allowed, and some medications must be stopped weeks before joining. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Ursodeoxycholic Acid (UDCA) for treating pouchitis?

Ursodeoxycholic Acid (UDCA) has been shown to inhibit the growth of Clostridium difficile, a bacteria that can cause infections like ileal pouchitis, and it is used to treat other conditions like primary sclerosing cholangitis and to prevent colorectal adenoma recurrence, suggesting it may help with pouchitis as well. ^{1 2 3 4 5}

Is ursodeoxycholic acid (UDCA) safe for humans?

Ursodeoxycholic acid (UDCA) is generally considered safe for humans and is used to treat various liver and gallbladder conditions. It has been described as a nontoxic bile acid and has been used in different medical treatments without significant safety concerns. ^{1 2 3 6 7}

How is the drug ursodeoxycholic acid (UDCA) unique for treating pouchitis?

Ursodeoxycholic acid (UDCA) is unique because it is a bile acid with immunomodulatory properties, which may help reduce inflammation in pouchitis. Unlike other treatments, UDCA is designed to be delivered specifically to the colon, potentially enhancing its effectiveness for this condition. ^{2 4 7 8 9}

Research Team

Sidhartha Sinha, MD

Principal Investigator

Stanford University

Eligibility Criteria

Adults over 18 with a history of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis, who have chronic antibiotic refractory or dependent pouchitis. They must show increased stool frequency and have evidence of disease through endoscopy and histology. Pregnant women, those allergic to UDCA, using certain medications or with significant other diseases are excluded.

Inclusion Criteria

My pouchitis hasn't improved with antibiotics or needs continuous antibiotics.

My internal exam shows significant inflammation.

My tests show signs of disease.

Exclusion Criteria

I regularly use NSAIDs for pain or inflammation.

My pancreas does not digest food properly.

I have a narrowing in my body where two sections were surgically connected.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ursodeoxycholic acid (UDCA) 300 mg two times daily for 10 weeks to treat pouchitis

10 weeks

Visits at baseline, week 6, and week 10

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ursodeoxycholic Acid (UDCA)

Trial Overview The trial is testing whether the drug ursodeoxycholic acid (UDCA) can reduce inflammation in patients with active antibiotic refractory or dependent pouchitis by altering bile acids in the intestine. The study will assess if UDCA improves inflammatory markers and quality of life.

Participant Groups

Group I: ursodiol (ursodeoxycholic acid, UDCA) Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Findings from Research

Ursodeoxycholic acid (UDCA) effectively inhibits the germination and growth of Clostridium difficile in all tested strains, suggesting its potential as a nonantibiotic treatment for C. difficile-associated pouchitis.

A patient with recurrent C. difficile infection (RCDI) pouchitis, who was unresponsive to multiple antibiotics and fecal microbiota transplantation, remained infection-free for over 10 months after treatment with oral UDCA, indicating its promising therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ursodeoxycholic Acid Inhibits Clostridium difficile Spore Germination and Vegetative Growth, and Prevents the Recurrence of Ileal Pouchitis Associated With the Infection. Weingarden, AR., Chen, C., Zhang, N., et al.[2020]

Ursodeoxycholic acid (UDCA) can be efficiently produced using a one-biocatalyst system with glucose dehydrogenase (GDH), achieving over 99.5% conversion of dehydrocholic acid (DHCA) to 12-keto-UDCA in just 4.5 hours on a liter scale.

This new method significantly improves the yield and efficiency of UDCA production compared to the traditional seven-step chemical process, which has an overall yield of less than 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-enzymatic one-pot reduction of dehydrocholic acid to 12-keto-ursodeoxycholic acid with whole-cell biocatalysts. Sun, B., Kantzow, C., Bresch, S., et al.[2013]

In a phase III trial involving 1285 participants, UDCA treatment showed a non-significant 12% reduction in overall colorectal adenoma recurrence compared to placebo, suggesting a potential benefit.

More importantly, UDCA significantly reduced the recurrence of high-grade dysplastic adenomas by 39%, indicating its potential role in preventing progression to colorectal cancer, especially in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. Alberts, DS., Martínez, ME., Hess, LM., et al.[2022]

In a study involving 20 healthy dogs, 6-8 weeks of ursodeoxycholic acid (UDCA) administration significantly increased fasting serum bile acids (SBA) levels, but these levels remained within the normal reference range for most dogs.

UDCA treatment did not affect liver enzyme activities, bilirubin, cholesterol, or triglyceride concentrations, indicating that it is safe for long-term use in healthy dogs without causing adverse biochemical changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of 6-8 weeks of oral ursodeoxycholic acid administration on serum concentrations of fasting and postprandial bile acids and biochemical analytes in healthy dogs. Deitz, KL., Makielski, KM., Williams, JM., et al.[2016]

In a placebo-controlled trial with 15 healthy volunteers, taking 900 mg/day of ursodeoxycholic acid (UDCA) significantly altered fecal bile acid composition, increasing levels of UDCA and lithocholic acid (LCA) while decreasing primary and secondary bile acids.

Despite these changes in bile acid composition, UDCA did not affect the cytolytic activity of fecal water, suggesting that UDCA supplementation does not provide a protective effect against colorectal cancer in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in bile acid composition and effect on cytolytic activity of fecal water by ursodeoxycholic acid administration: a placebo-controlled cross-over intervention trial in healthy volunteers. van Gorkom, BA., van der Meer, R., Boersma-van Ek, W., et al.[2019]

Ursodeoxycholic acid (UDCA) significantly reduces mucosal damage in a rat model of colitis induced by trinitrobenzene sulfonic acid (TNB), showing effectiveness in both acute and acute/chronic inflammation scenarios.

Treatment with UDCA led to improved body weight gain in rats with colitis, indicating a potential benefit in overall health during intestinal inflammation recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effect of ursodeoxycholic acid on mucosal damage in trinitrobenzene sulphonic acid-induced colitis. Kullmann, F., Arndt, H., Gross, V., et al.[2013]

In a study of 21 heart transplant recipients treated with ursodeoxycholic acid (UDCA) for cyclosporine-induced cholestasis, there was a significant reduction in acute rejection episodes compared to 31 control patients, with an average of 1.38 vs 2.74 episodes per patient.

The cumulative rejection severity score was also significantly lower in the UDCA group (2.38 vs 5.06), suggesting that UDCA may have beneficial immunomodulatory effects in the early phase after heart transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant treatment with ursodeoxycholic acid may reduce the incidence of acute cardiac allograft rejection. Bährle, S., Szabó, G., Stiehl, A., et al.[2013]

In a study involving 24 healthy subjects, the Canadian Ursofalk tablets showed significantly better bioavailability of ursodeoxycholic acid (UDCA) compared to other formulations, with higher mean area under the curve (AUC) and peak serum concentration (Cmax).

The Canadian UDCA tablets also had a shorter time to reach peak concentration (Tmax), indicating that they are absorbed more quickly than the capsule formulations, which may enhance their effectiveness in treating conditions like primary biliary cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability of four ursodeoxycholic acid preparations. Williams, CN., Al-Knawy, B., Blanchard, W.[2019]

UDCA-glutamate (Glu) significantly enhances the delivery of ursodeoxycholic acid (UDCA) to the colon compared to standard UDCA, as shown in a study with Fisher rats over 5 days, leading to higher amounts of UDCA found in feces.

The conjugation of UDCA to glutamic acid reduces its absorption in the small intestine, suggesting that UDCA-Glu could be a promising pro-drug for improving treatment outcomes in colonic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new amino acid derivative of ursodeoxycholate, (N-L-Glutamyl)-UDCA (UDCA-Glu), to selectively release UDCA in the colon. Asciutti, S., Castellani, D., Nardi, E., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ursodeoxycholic Acid Inhibits Clostridium difficile Spore Germination and Vegetative Growth, and Prevents the Recurrence of Ileal Pouchitis Associated With the Infection. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Multi-enzymatic one-pot reduction of dehydrocholic acid to 12-keto-ursodeoxycholic acid with whole-cell biocatalysts. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of 6-8 weeks of oral ursodeoxycholic acid administration on serum concentrations of fasting and postprandial bile acids and biochemical analytes in healthy dogs. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Changes in bile acid composition and effect on cytolytic activity of fecal water by ursodeoxycholic acid administration: a placebo-controlled cross-over intervention trial in healthy volunteers. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Beneficial effect of ursodeoxycholic acid on mucosal damage in trinitrobenzene sulphonic acid-induced colitis. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Adjuvant treatment with ursodeoxycholic acid may reduce the incidence of acute cardiac allograft rejection. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Bioavailability of four ursodeoxycholic acid preparations. [2019]

9. Greece pubmed.ncbi.nlm.nih.gov

A new amino acid derivative of ursodeoxycholate, (N-L-Glutamyl)-UDCA (UDCA-Glu), to selectively release UDCA in the colon. [2013]