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

Phase 1
18 Years
80 Years
Open (Enrolling)
Primary Sclerosing Cholangitis, Colitis

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Trial Information

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

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

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

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

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.

Type of Study:


Study Design:

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

Outcome Measure:

Primary outcome will be change in alkaline phosphatase. Outcome in alkaline phosphatase will be defined as:Highly positive: >50% reduction;Positive: >25% reduction;

Outcome Time Frame:

1 years

Safety Issue:


Principal Investigator

Steve D Freedman, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beth Israel Deaconess Medical Center


United States: Federal Government

Study ID:

2005P-000259 (DK71851)



Start Date:

February 2006

Completion Date:

February 2008

Related Keywords:

  • Primary Sclerosing Cholangitis
  • Colitis
  • Primary Sclerosing Cholangitis
  • PSC
  • DHA
  • Docosahexaenoic Acid
  • Cholangitis
  • Cholangitis, Sclerosing
  • Colitis



Mayo Clinic Rochester, Minnesota  55905
Beth Israel Deaconess Medical Center Boston, Massachusetts  02215