Evaluation of DHA for the Treatment of PSC

Primary Sclerosing Cholangitis Clinical Trial

Official title:

Evaluation of Docosahexaenoic Acid (DHA) for the Treatment of Primary Sclerosing Cholangitis (PSC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00325013
• Other study ID #: 2005P-000259 (DK71851)
• Secondary ID: R03DK071851
• Status: Completed
• Phase: Phase 1
• First received: May 10, 2006
• Last updated: March 10, 2015
• Start date: December 2005
• Est. completion date: May 2012

Study information

• Verified date: March 2015
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

The researches aim to study the effects of DHA (component of fish oil) on patients with Primary Sclerosing Cholangitis (PSC). Our hypothesis is that DHA might reverse the problems associated with PSC.

Description:

The etiology of Primary Sclerosing Cholangitis (PSC) is unknown. There are no proven effective therapies and no early markers of the disease to predict which patients with colitis may be at risk to develop PSC.

Our group has demonstrated an increased prevalence of CFTR alleles (the gene responsible for Cystic Fibrosis (CF)) in patients with PSC which was correlated with decreased CFTR function as measured by Nasal Potential Difference Testing. These data suggested that colitis in the setting of CFTR dysfunction may lead to bile duct inflammation and fibrosis. As proof of concept, we subsequently demonstrated in cftr-/- mice that (1) colitis leads to the development of bile duct injury and (2) this is prevented by correction of the CFTR related fatty acid defect with oral Docosahexaenoic Acid (DHA). Preliminary data in these mice indicates that low PPAR expression in the liver may predispose to inflammation. One mechanism by which DHA ameliorates the innate inflammatory response linked to CFTR dysfunction may be through an increase in PPAR expression.

Based on these data, we hypothesize that CFTR dysfunction may contribute to the pathogenesis of primary sclerosing cholangitis (PSC). Furthermore, correction of the fatty acid abnormality and changes in the innate immune response associated with CFTR dysfunction by oral administration of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, might be an effective therapy for patients with PSC.

Immediate Objectives:

To evaluate the effect of DHA therapy on patients with PSC, examining:

Primary Outcome:

• serum alkaline phosphatase

Secondary Outcomes:

• cholangiography

• liver biochemistry (ALT, AST, gamma-glutamyl transferase, bilirubin, albumin, prothrombin time,)

• fatty acid profile (docosahexaenoic acid, arachidonic acid)

• serum/plasma liver fibrosis markers (hyaluronic acid, tumor necrosis factor-α, transforming growth factor-ß, type III procollagen peptide)

• innate immune response (peripheral blood monocytes for assessment of cytokine secretion, lipoxins, and PPAR)

• clinical data on signs and symptoms

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: May 2012
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

Patients must have a diagnosis of primary sclerosing cholangitis. The diagnosis will require a chronic cholestatic liver disease of at least 6 months' duration; a serum alkaline phosphatase level at least 1.5 times the upper limit of normal; cholangiographic findings of intrahepatic or extrahepatic biliary-duct obstruction, beading, or narrowing consistent with PSC; and a liver biopsy in the previous 12 months with compatible findings.

Exclusion Criteria:

Age less than18 years or more than 80 years. Subjects must have no evidence of secondary cholangitis or other liver disease (primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, and chronic viral hepatitis). Subjects will be excluded if there is a history of previous bile duct surgery, previous choledocholithiasis, recurrent ascending cholangitis, previous history of variceal hemorrhage, or cholangiocarcinoma. Subjects with PSC stage III (fibrosis) or IV (cirrhosis) based on the criteria of Ludwig et al. will be excluded.

Participants will be excluded if there are pregnant.

Subjects will also be excluded if treatment with corticosteroids, cyclosporine or methotrexate has occurred within the preceding 3 months, or there is an anticipated need for liver transplantation within 1 year. No fish oil supplements will otherwise be allowed. Patients on 5-aminosalicylate preparations or azathioprine will remain on these preparations for the duration of the trial. Treatment with ursodeoxycholic acid will not be an exclusion criteria. Patients on this therapy will be advised to continue the drug throughout the trial. Those not on ursodeoxycholic acid will not be allowed to start this drug since it is could affect the alkaline phosphatase levels and is not an accepted efficacious therapy. Subjects will not be excluded for refusal of follow-up MRCP at study completion. There will be no exclusion based on sex, race, and ethnic background.

Study Design

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cholangitis
• Cholangitis, Sclerosing
• Colitis
• Primary Sclerosing Cholangitis

Intervention

Drug:
• Docosahexaenoic Acid (DHA)
800mg twice a day for 1 year

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary outcome will be change in alkaline phosphatase. Outcome in alkaline phosphatase will be defined as:Highly positive: >50% reduction;Positive: >25% reduction;		1 years	No
Primary	No Change: <25% reduction or <25% increase;Negative: >25% increase;Highly negative: >50% increase		1 years	No
Secondary	Secondary outcomes will include changes in:cholangiography;liver biochemistry (ALT, AST, gamma-glutamyl transferase, bilirubin, albumin, prothrombin time);fatty acid profile (docosahexaenoic acid, arachidonic acid);		1 years	No
Secondary	serum/plasma liver fibrosis markers (hyaluronic acid, tumor necrosis factor-a, transforming growth factor-ß, type III procollagen peptide);peripheral blood monocyte PPAR (mRNA by RT-PCR, protein level by western blot, and activity by EMSA);		1 year	No
Secondary	peripheral blood monocyte cytokine secretion (IL-8) in response to Pseudomonas LPS, TNF, IL-10; lipoxin A4 secretion and lipoxygenase expression as well as docosatriene/resolvins;symptoms;safety measures of DHA (Adverse Event recordings)		1 year	No