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Ursodeoxycholic Acid

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Anti-Inflammatory Agents, Non-Steroidal

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Analgesics, Non-Narcotic

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Patients receive oral celecoxib twice daily and oral placebo twice daily

Patients receive oral celecoxib twice daily and oral ursodeoxycholic acid twice daily

Celecoxib: 400mg twice daily, orally, 6 months

Ursodeoxycholic acid: orally, 6 months, dosage based on body weight:

below 50 kg: 1000mg, divided in two daily doses; 50-70 kg: 1500mg, divided in two daily doses; over 70 kg: 2000mg, divided in two daily doses

Ursodeoxycholic acid

Placebo: orally, 6 months, dosage based on body weight:

below 50 kg: 1000mg, divided in two daily doses; 50-70 kg: 1500mg, divided in two daily doses; over 70 kg: 2000mg, divided in two daily doses

Placebo

Fokko M Nagengast, MD, Ph D

Bjorn WH van Heumen, MD

Wilbert HM Peters, Ph D

Ellen Kampman, Ph D

Duodenal carcinomas are the leading cause of mortality in patients with Familial Adenomatous Polyposis (FAP) who underwent prophylactic colorectal surgery. The purpose of this study is to determine wether celecoxib combined with ursodeoxycholic acid is an effective chemoprevention strategy to influence the progression of duodenal adenomas to carcinomas in patients with FAP.

Prevention of Progression of Duodenal Adenomas in Patients With Familial Adenomatous Polyposis

Prevention of Progression of Duodenal Adenomas to Cancer in Patients With Familial Adenomatous Polyposis (FAP)

Dutch Cancer Society

Radboud University Medical Center

Ursodeoxycholic acid during 2 years :

* between 40 and 50 kg : 500 mg/day
* between 51 and 75 kg : 750 mg/day
* between 76 and 100 kg : 1000 mg/day

During 2 years :

* between 40 and 50 kg : 500 mg/day
* between 51 and 75 kg : 750 mg/day
* between 76 and 100 kg : 1000 mg/day

During 2 years :

* between 40 and 50 kg : 2 tabs/day
* between 51 and 75 kg : 3 tabs/day
* between 76 and 100 kg : 4 tabs/day

Yann RA Parc, M.D., Ph.D.

Malignant transformation of adenomas of the duodenum is now the leading cause of death in familial adenomatous polyposis (FAP) patients who had a restorative proctocolectomy. Ursodeoxycholic acid (UDCA) modifies the biliary acid profile and could reduce the severity of duodenal adenomas and prevent such transformation.

We designed a randomized double blinded study to evaluate the efficiency of UDCA in the treatment of duodenal adenomas. One hundred patients are planned to be included. Fifty will receive UDCA and fifty a placebo. Three duodenoscopies are planned: one before inclusion, one at the end of the first year of follow-up and one after two years of follow-up at the end of the protocol. These duodenoscopies are associated to endoscopies of the ileal reservoir performed at the time of restorative proctocolectomy and are recorded numerically. Severity of the duodenal adenomas are evaluated according to the SPIGELMAN score. Patients are seen every 6 months. Before each endoscopy, blood samples are collected for biliary acid profile analysis. Moreover, during endoscopies, duodenal fluid and ileal fluid are collected for biliary acid profile analysis, also.

At the end of the follow-up of the last patients included (nov 2008), biliary acid profile analysis will be performed and statistical analysis of the results will be performed.

Ursodeoxycholic Acid in the Treatment of Duodenal Adenomas in Familial Adenomatous Polyposis (FAP) Patients

Efficiency of Ursodesoxycholic Acid in the Treatment of Duodenal Adenomas in Familial Adenomatous Polyposis Patients. URSOPAF

Axcan Pharma

Assistance Publique - Hôpitaux de Paris

Christophe Aucan

Infections

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Patients with ≥ 3 grade ir-hepatitis will be treated with high-dose steroids 2 mg/kg/day intravenously. A diagnostic liver biopsy will be taken. Patients with mixed or cholestatic liver injury patterns will be added UDCA. Treatment evaluation will be performed after 72 hours, patients in UDCA will be evaluated will be on day 7. Patients with sufficient steroid response defined as ≥ 20% reduction in ALT, AST, ALP or bilirubin at day 4 or day 7 will undergo steroid tapering with a transition to peroral steroids. Patients with initial insufficient treatment response, defined as less than \< 20% reduction in ALT, AST, ALP, or bilirubin, are considered as having a steroid-refractory condition and will be added MMF. In case of no response or increase of ALT, AST, ALP, or bilirubin during treatment with steroids plus MMF a third-line treatment may be introduced according to the individual treating hepatologist.

Patients who experienced relapse of ir-hepatitis of grade ≥2 during prednisolone tapering or within one months after ended tapering will be randomized to either 100% dose of current steroid dose or restart of steroid 0.5-1 mg/kg versus adding MMF (if the patient received prednisolone the tapering plan hereof is continued, prednisolone up to 25 mg can be added if clinical indicated). Treatment efficacy is evaluated after seven days, if sufficient response the patients continued treatment, in case of insufficient response a cross-over will be performed.

Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day

Mycophenolate Mofetil

Solu-Medrol

Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight

Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.

Prednisone tablet

Inge Marie Svane, M.D. Professor

Rikke B Holmstrøm, M.D

Rikke B Holmstrøm, MD

Ane S Teisner, MD

Eva Ellebaek, MD

Peter Holland-Fischer, Ph.d, MD

Niels Kristian Aagaard, Ph.d., DMsc, MD

Peter N Bjerring, Ph.D. MD

Annette D Fialla, Ph.d, MD

Inge M Svane

Rikke B Holmstrøm

This clinical trial is to clarify and investigate the patterns of immune-related hepatitis and the optimal treatment choice for patients who are steroid-dependent. The project aims to prospectively characterize the various histopathological, biochemical, and phenotypical liver injury patterns induced by immune checkpoint inhibitors and the treatment responses to corticosteroids. Furthermore, the effect of adding a second-line immunosuppressive drug, either MMF in steroid-refractory or steroid-dependent cases will be explored and compared.

The number of patients treated with immune checkpoint inhibitors (ICI) is expanding worldwide due to an increasing number of indications, including additional types of cancer, combination of ICI with other antineoplastic therapies and have recently moved into the adjuvant setting. According to clinical trial material, almost all patients in ICI treatment will eventually develop any grade of an adverse event, here, estimated in up to 90 percent of treated patients. Around 10-30 percent of ICI-treated patients will show signs of liver injury related to ICI treatment and will be diagnosed with immune-related hepatitis. The treatment hereof should include observation and medium-dose steroids in low-grade asymptomatic patients (grade ≤ 2 ir-hepatitis) and high-dose steroids in higher grades according to the current European and American guidelines. However, up to 25 percent of patients with ir-hepatitis may not respond properly to steroids due to primary resistance or relapse during tapering. These patients should be offered a second-line immunosuppressive treatment. The present recommendation for patients with steroid-dependent ir-hepatitis is based on the case series and includes immunosuppressive treatment with mycophenolate mofetil (MMF). To date, no evidence exists for which second-line treatment to choose.

However, in the clinic, the initiation of MMF may be delayed, meanwhile, patients are typically treated with an increased dose of steroids. In some cases, an increased dose of steroids with prolonged tapering can be sufficient. We want to explore if increased doses of steroids or adding MMF is the best strategy for relapse of hepatitis.

In addition, patients with signs of biliary or mixed liver injury may benefit from adding ursodeoxycholic acid (UDCA).

The aim is to enroll around 40 patients in Cohort A for prospectively characterize the various patterns of liver injury histopathologically, biochemically, and phenotypically that are induced by ICI, and the response to treatment (steroids and MMF).

Cohort B: 20 patients who experienced a relapse of ir-hepatitis (grade ≥2) during prednisolone tapering or within one month after ended tapering will be randomized to either 100% dose of current steroid dose or restart of steroid 0.5-1 mg/kg versus adding MMF (if the patient received prednisolone the tapering plan hereof is continued, prednisolone up to 25 mg can be added if clinical indicated). Treatment efficacy is evaluated after seven days, if sufficient response the patients continued treatment, in case of insufficient response a cross-over will be performed

Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis

A National Prospective Study of Patients With Hepatitis Induced by Immune Checkpoint Inhibitors; Characterization of Liver Injury, Outcome of Therapy and Randomization to Either Prednisolone or Mycophenolate Mofetil Treatment in Case of Relapse

Correlation of the baseline immune markers, genomics and other biomarkers in blood

Description of changes in the fecal microbiome and characterization of the prevalence of specific bacteria e.g. Faecalibacterium and Firmicutes

Treatment-assessed hepatitis response rates with steroids and steroids plus either mycophenolate mofetil or tacrolimus

Time to response or downgrading of liver injury in patients with ≥grade 3 ir-hepatitis measured as; Days to ≥20 percent reduction in liver specific transaminases (ALT/AST) or bilirubin Days to shift to peroral prednisolone and discharge

Percent of patients with relapse to grade ≥2 hepatitis during steroid or during steroid plus either mycophenolate mofetil or tacrolimus tapering.

Time to downgrading of hepatotoxicity from grade 4 to grade 3, to grade 2 and to grade 1, respectively, assessed by CTCAE v5.0

Number of patients with hepatocellular, cholestatic and mixed liver injury respectively, assessed by histological findings of predominant injury to hepatocytes, bile ducts or combined.

Incidence of abnormal laboratory test results in blood

Cumulated doses of corticosteroids and MMF respectively, during the study period of 6 months

Cancer progression free survival at 6 months

Inge Marie Svane

M.D. Professor

Gastroesophageal Reflux

Barrett Esophagus

Esophageal Motility Disorders

Esophageal Spasm, Diffuse

Deglutition Disorders

Esophageal Diseases

Precancerous Conditions

Bile Acids and Salts

All patients are treated with DCA and UDCA perfusion of the esophagus, one year apart, followed by 8 weeks of treatment with oral ursodeoxycholic acid 10 mg/kg qd. Then a final DCA perfusion of the esophagus.

8 weeks of oral UDCA treatment 10 mg/kg qd

Stuart J Spechler, MD

This study has two major goals:

1. To determine the effects of bile salts on causing DNA injury and activating signaling pathways that promote growth in cells from the esophagus of patients who have gastroesophageal reflux disease (GERD)
2. To determine whether changes in bile composition induced by treating patients with a bile salt called ursodeoxycholic acid (UDCA) can alter DNA injury, signaling pathway activation and other types of damage in cells from the esophagus of patients who have GERD.

Patients who have been scheduled for elective endoscopic examination at the Dallas VA Medical Center for the evaluation of GERD or Barrett's esophagus will be invited to participate in the study. Patients who provide written, informed consent will have a medical history taken.

Women of child bearing potential will have a pregnancy test. Eligible subjects will be treated with omeprazole 20 mg BID for at least four weeks before the scheduled endoscopic examination. Eight days before the endoscopy, patients will be instructed to discontinue any aspirin and other non-steroidal anti-inflammatory drugs (unless there is a contraindication to discontinuing those medications including a history of coronary artery disease, myocardial infarction, cerebrovascular accident or transient ischemic attacks). The endoscopic examination, which had been scheduled for clinical purposes, will be performed as usual, with biopsy specimens taken as required for clinical purposes.

When the clinical examination has been completed, a perfusion catheter will be passed through the biopsy channel and positioned 5 cm above the squamocolumnar junction in the distal esophagus. The distal esophagus will be perfused with 10cc of a 250 M solution of either deoxycholic acid (DCA) or ursodeoxycholic acid (UDCA) for 5 minutes. Odd-number patients enrolled in each of the two patient groups (GERD patients with and without Barrett's esophagus) will receive DCA, whereas even-number patients will receive UDCA. The catheter position, bile acid concentration and duration of bile acid perfusion are chosen to simulate a typical episode of gastroesophageal reflux.

In all patients, 12 biopsy specimens of the squamous epithelium will be taken using jumbo biopsy forceps at a level 2 cm proximal to the squamocolumnar junction at baseline (6 biopsies will be used to establish the primary cell cultures and six will be used for the molecular analyses); 6 more biopsy specimens will be taken at the same level immediately after bile acid perfusion for molecular analyses.

In the patients with Barrett's esophagus, 12 biopsy specimens of the specialized intestinal metaplasia also will be taken using jumbo biopsy forceps at a level 1 cm distal to the squamocolumnar junction at baseline (6 biopsies will be used to establish the primary cell cultures and six will be used for the molecular analyses); 6 more biopsy specimens will be taken a t the same level immediately after bile acid perfusion for molecular analyses. All endoscopic procedures will be performed by Dr. S.J. Spechler.

All patients will be maintained on omeprazole 20 mg BID for one year, after which the endoscopic examinations will be repeated. The endoscopies will be performed with bile acid perfusions and biopsy sampling exactly as described above, except that patients who received DCA during the first examination will receive UDCA and vice-versa.

After the second endoscopy, patients will be treated with UDCA in a dose of 10 mg/kg for 8 weeks, after which a final endoscopy will be performed.

During this endoscopy, DCA perfusion will be performed as described above. In all patients, 6 biopsy specimens of the squamous epithelium will be taken using jumbo biopsy forceps at a level 2 cm proximal to the squamocolumnar junction at baseline for the molecular analyses; 6 more biopsy specimens will be taken at the same level immediately after bile acid perfusion for molecular analyses.

In the patients with Barrett's esophagus, 6 biopsy specimens of the specialized intestinal metaplasia also will be taken using jumbo biopsy forceps at a level 1 cm distal to the squamocolumnar junction at baseline for the molecular analyses; 6 more biopsy specimens will be taken at the same level immediately after bile acid perfusion for molecular analyses.

Clinical Studies on Bile Acids in Barrett's Esophagus

p-H2AX levels are a measure of DNA damage. Our major outcome measure is the change in p-H2AX levels, expressed as relative densitometry units, after DCA perfusion in patients treated with oral UDCA. If UDCA protects against bile acid-induced DNA damage, then p-H2AX levels before and after perfusion should not change significantly.

US Department of Veterans Affairs

Esophageal biopsy: After the esophageal perfusions described above, 12 biopsy specimens of the squamous epithelium will be taken at a level 2 cm proximal to the squamocolumnar junction at baseline (6 biopsies will be used to establish primary cell cultures and six will be used for molecular analyses); 6 more biopsy specimens will be taken at the same level immediately after bile acid perfusion for molecular analyses. In patients with Barrett's esophagus, 12 biopsy specimens of the specialized intestinal metaplasia also will be taken at a level 1 cm distal to the squamocolumnar junction at baseline (6 biopsies will be used to establish primary cell cultures and six will be used for molecular analyses); 6 more biopsy specimens will be taken at the same level immediately after bile acid perfusion for molecular analyses.

Arm 1

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Stuart Spechler

Before DCA Perfusion

After DCA Perfusion

Patients with Barrett's esophagus, only metaplastic epithelium evaluated. No data were collected from squamous epithelium as originally planned because our in vitro studies subsequently showed that DCA exposure did not cause DNA damage in squamous cells and, therefore, oral UDCA treatment would be meaningless for squamous esophagus.

Protection Against DNA Damage by UDCA

Overall Study

Carcinoma

Neoplasm Metastasis

Liver Neoplasms

Neoplastic Processes

Vasodilator Agents

Platelet Aggregation Inhibitors

Fibrinolytic Agents

Anticoagulants

Pentoxifylline

Enoxaparin

Enoxaparin sodium

Phosphodiesterase Inhibitors

Radiation-Protective Agents

Antioxidants

Medication group with patients receiving the study medication according to the study protocol for 8 weeks after HDR brachytherapy.

Comparison group with patients receiving the standard therapy of HDR brachytherapy without the study specific medication.

Pentoxifylline is given for 8 weeks since the evening of the day of intervention with a dose of 400mg applied three times daily (morning, noon, evening).

Ursodeoxycholic acid is administered for 8 weeks since the evening of the day of intervention. Dosage is 250mg given three times daily (morning, noon, evening).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Prevention of Progression of Duodenal Adenomas in Patients With Familial Adenomatous Polyposis	NCT00808743	Familial Adenom... Duodenal Neopla... Duodenal Polyps	Celecoxib Ursodeoxycholic... Placebo	18 Years - 70 Years	Radboud University Medical Center
Ursodeoxycholic Acid in the Treatment of Duodenal Adenomas in Familial Adenomatous Polyposis (FAP) Patients	NCT00134758	Adenomatous Pol...	Ursodeoxycholic... Placebo	18 Years - 65 Years	Assistance Publique - Hôpitaux de Paris
Prevention of Progression of Duodenal Adenomas in Patients With Familial Adenomatous Polyposis	NCT00808743	Familial Adenom... Duodenal Neopla... Duodenal Polyps	Celecoxib Ursodeoxycholic... Placebo	18 Years - 70 Years	Radboud University Medical Center
Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis	NCT04810156	Hepatitis, Drug...	Mycophenolate M... Solu-Medrol Ursodeoxycholic... Prednisone tabl...	18 Years -	Herlev Hospital
Clinical Studies on Bile Acids in Barrett's Esophagus	NCT00858858	Gastroesophagea...	Ursodeoxycholic...	18 Years -	VA Office of Research and Development
Ursodeoxycholic Acid in the Treatment of Duodenal Adenomas in Familial Adenomatous Polyposis (FAP) Patients	NCT00134758	Adenomatous Pol...	Ursodeoxycholic... Placebo	18 Years - 65 Years	Assistance Publique - Hôpitaux de Paris
Preventive Effect of Enoxaparin, Pentoxifylline and Ursodeoxycholic Acid to Radiation Induced Liver Toxicity	NCT01149304	Colorectal Canc... Liver Metastase... Irradiation Dam... Radiation Induc...	Pentoxifylline Ursodeoxycholic... Enoxaparin	18 Years - 80 Years	University of Magdeburg
Preventive Effect of Enoxaparin, Pentoxifylline and Ursodeoxycholic Acid to Radiation Induced Liver Toxicity	NCT01149304	Colorectal Canc... Liver Metastase... Irradiation Dam... Radiation Induc...	Pentoxifylline Ursodeoxycholic... Enoxaparin	18 Years - 80 Years	University of Magdeburg
Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease	NCT02021110	Polycystic Live... Polycystic Kidn...	Ursodeoxycholic...	18 Years - 80 Years	Radboud University Medical Center
Clinical Studies on Bile Acids in Barrett's Esophagus	NCT00858858	Gastroesophagea...	Ursodeoxycholic...	18 Years -	VA Office of Research and Development

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